MXPA01008565A - Neutrokine-alpha and neutrokine-alpha splice variant - Google Patents

Abstract

An isolated nucleic acid molecule comprising a polynucleotide having anucleotide sequence at least 95%identical to a sequence selected from the groupconsisting of:(a) a nucleotide sequence encoding the Neutrokine-alpha polypeptidehaving the complete amino acid sequence in Figures IA and IB (SEQ ID NO:2);(b) a nucleotide sequence encoding the Neutrokine-alpha polypeptidehaving the complete amino acid sequence encoded by the cDNA clone contained in thedeposit having ATCC accession number 97768;(c) a nucleotide sequence encoding the Neutrokine-alpha polypeptideextracellular domain;(d) a nucleotide sequence encoding the Neutrokine-alpha polypeptidetransmembrane domain;1 5 (e) a nucleotide sequence encoding the Neutrokine-alpha polypeptideintracellular domain;(f) a nucleotide sequence encoding a soluble Neutrokine-alpha polypeptidecomprising the extracellular and intracellular domains but lacking the transmembranedomain;and(g) a nucleotide sequence complementary to any of the nucleotidesequences in (a), (b), (c), (d), (e) or (f) above.

Description

NEUTRALINE-ALPHA AND VARIANTS BY NEUTRAL-EMPLOYMENT-A FA The present invention relates to a new cytokine that has been called neutrocin-alpha. In addition, an apparent splicing variant of neutrokine-alpha has been identified and termed neutrocin-alphaSV. In specific embodiments, the present invention provides nucleic acid molecules that encode the neutrokine-alpha and neutrocin-alphaSV polypeptides. In further embodiments, neutral-alpha and neutrocin-alphaSV polypeptides are also provided; as well as vectors, host cells and recombinant methods to produce them.

BACKGROUND OF THE INVENTION Human factors of tumor necrosis (TNF-alpha and TNF-beta or lymphotoxin) are related members of a broad class of mediating polypeptides that includes interferons, interleukins and growth factors, collectively called cytokines (Beutler B. And Cerami , A., Annu, Rev. Immunol., 7: 625-655 (1989)). Sequential analysis of cytokine receptors has defined several subfamilies of membrane proteins: 1) the immunoglobulin superfamily (Ig), 2) hematopoietin REF: 132144 - - (superfamily of cytokine receptors) and 3) the superfamily of tumor necrosis factor receptors (TNF) / neural growth factor (FCN). For review of the TNF superfamily see Gruss and Dower, Blood 85 (12): 3378-3404 (1995) and Aggarwal and Natarajan, Eur. Cytokine Netw. , 7 (2): 93-124 (1996). The TNF / FCN receptor superfamily contains at least 10 different proteins (Gruss and Dower, Supra). Ligands for these receptors have been identified and belong to at least two superfamilies of cytokines (Gruss and Dower Supra).

Tumor Necrosis Factor (a mixture of TNF-alpha and TNF-beta) was originally discovered as a result of its antitumor activity. However, it is currently recognized as a pleiotropic cytokine capable of numerous biological activities that include apoptosis of some transformed cell lines, mediation of cell activation and proliferation, and also plays important roles in immune regulation and inflammation.

To date, known members of the TNF-ligand superfamily include TNF-alfc, TNF-beta (lymphotoxin alfa), LT-beta, OX40L, Fas ligand, CD30L, CD27L, CD40L and 4-IBBL. The ligands of the TNF superfamily of ligands are acid molecules similar to TNF with sequence homology of approximately 20% in the extracellular domains (range, from 12% to 36%) and exist mainly as membrane-bound forms, where the biologically form active is a trimeric / multimeric complex. The soluble forms of the TNF superfamily of ligands have only been identified to date for TNF, LT-beta and Fas ligand (for a general review, see Gruss and Dower, SK Blood, 85 (12): 3378-3404 (1995)) which is hereby incorporated as a reference in its entirety. These proteins are involved in the regulation of cell proliferation, activation and differentiation, including the control of survival or cell death by apoptosis or cytotoxicity (Armitage, RJ, Curr Opin. Immunol. 6: 407 (1994) and Smith, CA , CeJJ 75: 959 (1994)).

The tumor necrosis factor alpha (TNF-alpha, also called cachectin, hereinafter "TNF"), is secreted mainly by monocytes and macrophages in response to endotoxins or other stimuli, such as a soluble homotrimer of 17 kDa protein subunits ( Smith, RA et al., J. Biol. Chem. 262: 6951-6954, 1987).

A precursor form of membrane-bound 26 kDa TNF has also been described (Kriegler, M. et al., Cell 53: 45-53,1988).

The accumulated evidence indicates that TNF is a regulatory cytokine with pleiotropic biological activities. These activities include the inhibition of lipoprotein lipase synthesis ("caquectin" activity) (Beutler, B. et al., Nature 316: 552 (1985)), activation of polymorphonuclear leukocytes (Klebanoff, SJ et al., J Immunol., 136: 4220 (1986), Perussia, B., et al., J. Immunol., 138: 765 (1987)), inhibition of cell growth or stimulation of cell growth (Vilcek, J. Et al. , J. Exp. Med. 163: 632 (1986); Sugarman, BJ Et al., Science 230: 943 (1985); Lachman, L.

B. Et al., J. Immunol. 138: 2913 (1987)), cytotoxic action in certain types of transformed cells (Lachman, L. B.

Et al., Supra; Darzynkiewicz, Z. Et al., Canc. Res. 44:83 (1984)), antiviral activity (Kohase, M. et al., Cell 45: 659 (1986), Wong, GHW Et al., Nature 323: 819 (1986)), stimulation of bone resorption (Bertolini, DR et al. al., Nature 319: 516 (1986), Saklatvala, J., Nature 322: 547 (1986)), stimulation of the production of collagenase and prostaglandin E2 (Dayer, J.-M. et al., J. Exp. Med. 162: 2163 (1985)) and immunoregulatory actions, including activation of T cells (Yokota, S. et al., J. I munol.140: 531 (1988)), B cells (Kehrl, JH et al. , J. Exp. Med. 166: 786 (1987)), monocytes (Philip, R. et al., Nature 323: 86 (1986)), thymocytes (Ranges, GE et al., J. Exp. Med 167: 1472 (1988)) and stimulation of cell surface expression of class I and class II molecules of the major histocompatibility complex (MHC) (Collins, T. Et al., Proc. Nati, Acad. Sci. USA 83: 446 ( 1986), Pujol-Borrel, R. et al., Nature 326: 304 (1987)). TNF is characterized by its proinflammatory actions, which result in tissue damage such as induction of procoagulant activity of the vascular endothelial cells (Pober, JS et al., J. Immunol., 136: 1680 (1986)), increasing the adhesion of neutrophils and lymphocytes (Pober, JS et al., J. Immunol. 138: 3319 (1987)), and stimulation of the release of platelet activating factor from macrophages, neutrophils and vascular endothelial cells (Camussi, G. Et al., J. Exp. Med. 166: 1390 (1987)).

Recent evidence implicates TNF in the pathogenesis of many infections (Cerami, A. et al., Immunol. Today 9:28 (1988)), immunological diseases, pathologies from neoplasias e.g. the cachexia that accompanies some malignant neoplasms (Oliff, A. et al., Cells 50: 555 - - (1987)) and in autoimmune pathologies and in graft versus host disease (Piguet, P.-F, et al., J. Exp. Med. 166: 1280 (1987)). The association of TNF with cancer and infectious diseases is often related to the catabolic state of the host. A major problem in cancer patients is weight loss, commonly associated with anorexia. The resulting emaciation is known as "cachexia" (Kern, K.A. et al., J. Parent, Enter.Nutr, 12: 286-298 (1988)). Cachexia includes progressive weight loss, anorexia, and persistent erosion of body mass in response to malignant growth. The cachectic state is associated with significant morbidity and is responsible for the majority of cancer mortality. Numerous studies suggest that TNF is an important mediator of cachexia in cancer, infectious pathologies and in other catabolic states. It is thought that TNF plays a central role in the pathophysiological consequences of gram-negative sepsis and endotoxic shock (Michie, HR et al., BR, Surg 76: 670-671 (1989), Debets, JMH et al., Second Vienna Shock Forum P. 463-466 (1989)., Simpson SQ et al., Crit. Care, Clin. 5: 27-47 (1989)), including fever, malaise, anorexia and cachexia. Endotoxin is a potent activator of monocytes / macrophages which stimulate the production and secretion of TNF (Kornblut et al., J. Immunol., 137: 2585-2591 (1986)) and other cytokines. Because TNF can mimic many of the biological effects of endotoxin, it was concluded that it is a central mediator responsible for the clinical manifestations of the endotoxin-related disease. TNF and other cytokines derived from monocytes are mediators of the metabolic and neurohornal responses to endotoxins. (Michi H. R. et al., N. Eng. J. Med. 318: 1481-1486 (1988)). The administration of endotoxins to human volunteers produces acute disease with symptoms similar to the cold, including fever, tachycardia, increased metabolic activity and increased release of hormones by stress (Revhaug, A. et al., Arch. Surg. 123: 162- 170(1988)). In patients who have presented Gram negative sepsis, high circulating TNF values have also been found (Waage, A. et al., Lancet 1: 355-357 (1987)., Hammerel, AF et al Second Vienna Shock Forum 715-718. (1989)., Debets, JMH et al., Crit. Care, Med. 17: 489-497 (1989)., Calandra, T. Et al., J. Infect. Dis. 161: 982-987 (1990)) . Passive immunotherapy aimed at neutralizing TNF can have beneficial effects on sepsis and Gram-negative endotoxemia, based on increased production and elevated TNF levels in these disease states, as described above. The antibodies directed against "modulator" material that was characterized as cachectin (which was later shown to be identical to TNF), were described by Cerami et. to the. (EPO Patent Publication 0,212,489, March 4, 1987). It was said that 'these antibodies were useful in the diagnosis by immunoassay and in the treatment of shock in bacterial infections. Rubin et al. (EPO Patent Publication 0,218,868, April 22, 1987) described monoclonal antibodies against human TNF, the hybridomas that secrete such antibodies, the methods for their production and the use of said antibodies in the immunoassay for TNF. Yone et al. (EPO Patent Publication 0,288,088 October 26, 1988) described anti-TNF antibodies including monoclonal antibodies and their usefulness in the diagnosis of pathologies by immunoassay, in particular Kawasaki syndrome and bacterial infection. It has been mentioned that body fluids in patients with Kawasaki disease (Acute Febrile Syndrome of Mucocutaneous Lymph Nodes, Kawasaki, T. Allergy 16: 178 (1967)., Kawasaki T. Schonica Pediatrics) 26: 935 (1985)) contain high values of TNF, which were related to the progress of the pathology (Yone et al., supra). Other investigators have described specific monoclonal antibodies to recombinant human TNF, which had neutralizing activity in vitro (Liang, CM et al, Biochem, Biophys, Res. Comm. 137: 847-854 (1986)., Meager, A. et al. al.Hybrido at 6: 305-311 (1987)., Fendly at al. Hybridoma 6: 359-369 (1987)., Bringman, TS Et al. Hybridoma 6: 489-507 (1987))., Hirai, M . et al. J. Immunol Meth 96: 57-63 (1987)., Moller A. et al. (cytokine 2: 162-169 (1990)). Some of these monoclonal antibodies were used to map epitopes of human TNF and develop enzyme immunoassays (Fendly et al., Supra., Hirai et al., Supra Moller et al., Supra) and to aid in the purification of recombinant TNF (Bringman et al. supra). However, these studies do not provide the basis for the production of neutralizing anti-TNF antibodies, which can be used for in vivo diagnosis or therapeutic uses in humans, due to their immunogenicity, lack of specificity and / or pharmaceutical convenience. It has been shown that in mammals other than humans, neutralizing monoclonal sera or antibodies against TNF suppress physiological adverse changes and prevent death after a lethal challenge, in experimental bacteremia and endotoxemia. These effects have been demonstrated, e.g., in lethality tests in rodents and in experimental models of primate pathology. (Mathison, J.C. et al., J. Clin Invest. 81: 1925-1937 (1988); Beutler, B. et al., Science 229: 869-871 (1985); Tracey, K. J. Et al. Nature330: 662-664 (1987); Shimamoto, Y.

Et al. Immunol Lett. 17: 311-318 (1988); Silva, A.T. et al.

J. Infect. Dis.162: 421-427 (1990); Opal, S.M. and cois .; J Infect. Dis 161: 1148-1152 (1990); Hins Haw, L. B. Cois .; Circ. Shock 30: 270-292 (1990)). To date, the experience with the use of anti-TNF monoclonal antibodies in humans has been limited but shows beneficial therapeutic results, for example in arthritis and sepsis. See Elliot M. J. et al. Baillieres Clin. Rheumatol. 9: 633-52 (1995); Feldmann M, et al. Cri t.

Care Med. 21: S436-40 (1993); Tracey K. J., et al. , Cri t.

Care Med. 21: S415-22 (1993). The development of mammals depends on cell proliferation and differentiation, as well as the programmed cell death that occurs through apoptosis (Walker, et al., Methods Achi ev. Exp. Pathol. 13:18 (1988)).

Apoptosis plays a critical role in the destruction of immune thymocytes that recognize their own antigens. Failure in this normal process of elimination may have some role in autoimmune diseases (Gammon et al., Immunology Today 12: 193 (1991)). Itoh et al. (Cell 66: 233 (1991)) described a cell surface antigen, Fas / CD95 that regulates apoptosis and participates in the clonal deletion of T cells.

Fas is expressed in activated T cells, B cells, neutrophils and in the thymus, liver, heart, lung and ovary in adult mice (Watanabe-Fukunaga et al., J. Immunol. 148: 1274 (1992)), in addition to activated T cells, B cells and neutrophils. In which a monoclonal antibody crosses with fas induces apoptosis (Yonehara et al., J. Exp. Med. 169: 1747 (1989)). In addition, there is an example where the binding of a monoclonal antibody to Fas stimulates T cells under certain conditions (Alderson et al., J. Exp. Med. 178: 2231 (1993)). The Fas antigen is a cell surface protein that has a MW of 45 kDa. Both the human and murine genes for Fas have been cloned by Watanabe-Fukunaga et al (J. Immuno, 148: 1274 (1992)) and Itoh et al (CeJJ 66: 233, 1991). The proteins encoded by these genes are transmembrane proteins with structural homology to the superfamily of neural growth factor / tumor necrosis factor receptors, which includes two receptors for TNF, the low affinity receptor for neural growth factor, and CD40, CD27, CD30 and OX40. The Fas ligand has recently been described (Suda et al., Ceil 75: 1169, 1993). The amino acid sequence indicates that the Fas ligand is a type II transmembrane protein that belongs to the TNF family. Thus, Fas ligand polypeptide comprises three main domains: a short - - intracellular domain at the amino-terminal end and a longer extracellular domain at the carboxyl-terminal end, connected to a hydrophobic transmembrane domain. The Fas ligand is expressed in splenocytes and thymocytes, which is consistent with T-cell mediated cytotoxicity. The purified Fas ligand has a MW of 40kDa. It has recently been shown that Fas / Fas ligand interactions are required for apoptosis after activation of T cells (Ju et al., Nature 373: 444, 1995). Activation of T cells induces both proteins on the cell surface. The subsequent interaction between the ligand and the receptor results in apoptosis of the cells. This supports the possible regulatory function for apoptosis induced by the Fas / Fas ligand interaction during normal immune responses. In agreement, there is a need to provide cytokines similar to TNF, which are involved in pathological disorders. Such novel cytokines can be used to make new antibodies or other antagonists that bind to these TNF-like cytokines, for the diagnosis and treatment of disorders related to TNF-like cytokines.

- - BRIEF DESCRIPTION OF THE INVENTION According to one embodiment of the present invention, there is provided a new extracellular domain of a neutrocin-alpha polypeptide and a new extracellular domain of a neutrocyl-alphaSV polypeptide, as well as biologically active fragments useful in diagnosis or therapy. , analogs or derivatives thereof. In accordance with another embodiment of the present invention there are provided isolated nucleic acid molecules encoding neutrocin-alpha or human neutrocin-alphaSV, which include mRNA, DNA, cDNA, genomic DNA as well as analogs and biologically active fragments and useful in diagnosis or therapy and derivatives thereof. The present invention provides isolated nucleic acid molecules comprising, or alternatively consist of, a polynucleotide encoding a cytokine and an apparent splicing variant thereof which is structurally similar to TNF and related cytokines and which has similar biological effects and activities. This cytokine is designated neutrokine-alpha and the present invention includes neutrokine-alpha polypeptides having at least a portion of the amino acid sequence of Figures IA and IB (SEQ ID NO: 2) or an amino acid sequence encoded by the clone of cDNA (HNEDU15) deposited on October 22, 1996 and assigned ATCC number 97768. The nucleotide sequence determined by sequencing of the deposited neutrokine-alpha clone, which is shown in Figures IA and IB ( SEQ ID NO: 1), contains an open reading frame that 'codes for a complete polypeptide of 285 amino acid residues, including an N-terminal methionine, a predicted intracellular domain of approximately 46 amino acid residues, a predicted transmembrane domain of approximately 26 amino acids, a predicted extracellular domain of approximately 213 amino acids and a deduced molecular weight for the entire protein of approximately 31 kDa. As for other type II transmembrane proteins, the soluble forms of neutrocin-alpha include all or a portion of the extracellular domain that is shed from the transmembrane domain and a polypeptide comprising the complete neutrocyte-alpha polypeptide lacking the transmembrane domain, ie, the extracellular domain linked to the intracellular domain. The apparent splicing variant of neutrocin-alpha is termed neutrocin-alphaSV and the present invention includes neutrocin-alphaSV polypeptides comprising, or alternatively consisting of, at least a portion of the amino acid sequence of Figures 5A and 5B (SEQ ID. NO: 19) or the amino acid sequence encoded by the HDPMC52 cDNA clone deposited on December 10, 1998 and assigned the ATCC number 203518. The nucleotide sequence determined by sequencing the neutrokine-alphaSV clone deposited , which is shown in Figures 5A and 5B (be 18), contains an open reading frame that encodes a complete polypeptide of 266 amino acid residues, including an N-terminal methionine, a predicted intracellular domain of approximately 46 residues of amino acid, a predicted transmembrane domain of approximately 26 amino acids, a predicted extracellular domain of approximately 194 amino acids and a deduced molecular weight for the complete protein of approximately 29 kDa. As for other type II transmembrane proteins, the soluble forms of neutrokine-alphaSV include all or a portion of the extracellular domain detached from the transmembrane domain and a polypeptide comprising the complete neutrokine-alphaSV polypeptide lacking the transmembrane domain, ie , the extracellular domain linked to the intracellular domain. Thus, one embodiment of the present invention provides an isolated nucleic acid molecule comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence which is selected from the group consisting of: (a) a nucleotide sequence encoding a full-length neutrocin-alpha polypeptide, having the complete amino acid sequence of Figures IA and IB (SEQ ID NO: 2) or encoded by the cDNA clone contained in the deposit having the accession number ATCC 97768; (b) a nucleotide sequence encoding the predicted extracellular domain of the neutrocma-alpha polypeptide, having the amino acid sequence at positions 73 to 285 of Figures IA and IB (SEQ ID NO: 2) or encoded by the clone contained in the deposit with the cDNA access number contained in the deposit with accession number ATCC 97768; (c) a nucleotide sequence encoding a fragment of the polypeptide of part (b) having a functional activity of neutrocma-alpha (e.g., biological activity); (d) a nucleotide sequence encoding a polypeptide comprising the intracellular domain of neutrocma-alpha (which is predicted to constitute the amino acid residues of about the 46th of Figures IA and IB (SEQ ID NO: 2)) encoded by the clone contained in the deposit that has accession number ATCC 97768; (e) a nucleotide sequence encoding a polypeptide comprising the transmembrane dopunium of neutrokine-alpha (which is predicted to constitute the amino acid residues from about 47 to about 72 of Figures IA and IB (SEQ ID NO. : 2) or encoded by the cDNA clone contained in the deposit having the accession number ATCC 97768; (f) a nucleotide sequence encoding a neutrocin-alpha polypeptide comprising the extracellular and intracellular domains, but lacking the transmembrane domain, and (g) a nucleotide sequence complementary to any nucleotide sequence of part (a), (b), (c), (d), (e) or (f) above. invention include isolated nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence with at least 80, 85 or 90% identity and preferably at least 95, 96, 97, 9 8 or 99% identity to any of the nucleotide sequences of subsections (a), (b), (c), (d), (e), (f) or (g) above, or a polynucleotide that is hybridizes, under stringent hybridization conditions, to a polynucleotide of parts (a), (b), (c), (d), (e), (f) or (g) above. This hybridizing polynucleotide does not hybridize under stringent hybridization conditions to a polypeptide having a sequence consisting only of residues A or only of residues T. Another embodiment of the present invention provides an isolated nucleic acid molecule comprising, or alternatively consists of, a polynucleotide having a nucleotide sequence that is selected from the group consisting of: (a) a nucleotide sequence encoding a full-length neutrocin-alphaSV polypeptide having the complete amino acid sequence of Figures 5A and 5B (SEQ ID NO: 19) or encoded by the cDNA clone contained in the ATCC deposit deposited on December 10, 1998 with accession number ATCC 203518; (b) a nucleotide sequence that encodes the predicted extracellular domain of the neutrocyl-alphaSV polypeptide having the amino acid sequence at positions 73 to 266 of Figures IA and IB (SEQ ID NO: 2) or encoded by the clone of CDNA contained in deposit ATCC 203518 deposited on December 10, 1998; (c) a nucleotide sequence encoding a polypeptide comprising the intracellular domain of neutrokine-alphaSV (which is predicted to constitute amino acid residues from about 1 to about 46 of Figures 5A and 5B (SEQ ID.

NO: 19)) or encoded by the cDNA clone contained in deposit ATCC 203518 deposited on December 10, 1998; (d) a nucleotide sequence encoding a polypeptide comprising the transmembrane domain of neutrokine-alphaSV (which is predicted to constitute the amino acid residues from about 47 to about 72 of Figures 5A and 5B (SEQ ID NO. : 19) or encoded by the cDNA clone contained in deposit ATCC 203518 deposited on December 10, 1998; (e) a nucleotide sequence encoding a soluble neutrokine-alphaSV polypeptide having the extracellular and intracellular domains, but which lacks the transmembrane domain, and (f) a nucleotide sequence complementary to any of the nucleotide sequences of part (a), (b), (c), (d) or (e) above. present invention, include isolated nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence with at least 80, 85 or 90% identity and preferably at least 95, 96, 97, 98 or 99% identity to any of the nucleotide sequences of subsections (a), (b), (c), (d), (e) or (f) above, or a polynucleotide that hybridizes, under stringent hybridization conditions, to a polynucleotide of parts (a), (b), (c), (d), (e) or (f) above. This polynucleotide that hybridizes does not hybridize under stringent hybridization conditions to a polynucleotide having a nucleotide sequence consisting only of residues A or only of residues T.

In one embodiment, the apparent splicing variant of neutrokine-alpha comprises, or alternatively consists of, at least a portion of the amino acid sequence of Gly-142 to Leu-266 as shown in Figures 5A and 5B (SEQ. ID NO: 19) or an amino acid sequence encoded by the cDNA clone HDPMC52 deposited on December 10, 1998 and to which the ATCC deposit number 203518 was assigned. In additional embodiments, the nucleic acid molecules of the present invention comprise, or alternatively consist of, a polynucleotide encoding the amino acid sequence of an epitope-bearing portion of a neutrocine-alpha or neutrocin-alphaSV polypeptide having an amino acid sequence of (a), (b), (c), (d), (e), (f) or (g) above.

An additional embodiment of nucleic acid of the present invention relates to an isolated nucleic acid molecule comprising, or alternatively consisting of, a • polynucleotide that encodes the amino acid sequence of a neutrocine-alpha or neutrocin-alphaSV polypeptide having an amino acid sequence that contains at least one addition, substitution and / or deletion of amino acids, but no more than 50 additions, substitutions and / or amino acid deletions, more preferably, no more than 40 amino acid additions, substitutions and / or deletions, still more preferably, no more than 30 amino acid additions, substitutions and / or deletions, and more preferably, no more of 20 amino acid additions, substitutions and / or deletions. Of course, in -increasing preference order, a polynucleotide encoding the amino acid sequence of a neutrocine-alpha or neutrocin-alphaSV polypeptide having the amino acid sequence containing not more than 10, 9, 8 is highly preferable, 7, 6, 5, 4, 3, 2 or 1, or 1-100, 1-50, 1-25, 1-20, 1-15, 1-10 or 1-5 additions substitutions and / or amino acid deletions . Conservative substitutions are preferable. The present invention also relates to recombinant vectors that include the isolated nucleic acid molecules of the present invention and to host cells containing the recombinant vectors, as well as to methods for preparing such vectors and host cells and for use for the production of Neutrocin-alfa by recombinant techniques. In accordance with another embodiment of the present invention, a process for producing such polypeptides is provided by recombinant techniques comprising culturing recombinant prokaryotic and / or eukaryotic host cells, containing a neutrocine-alpha or neutrokine-alphaSV nucleic acid sequence of the present invention, under conditions that promote expression of said polypeptide, and subsequently the polypeptide is recovered. The present invention further provides a neutrokine-alpha polypeptide comprising, or alternatively consisting of, an amino acid sequence that is selected from the group consisting of: (a) the amino acid sequence of the full-length neutrocin-alpha polypeptide having the complete amino acid sequence shown in Figures IA and IB (ie positions 1 to 285 of SEQ ID NO: 2) or encoded by the plasmid cDNA contained in the deposit having the accession number ATCC 97768; (b) the amino acid sequence of the full length neutrocin-alpha polypeptide having the complete amino acid sequence shown in SEQ ID NO: 2, except for the N-terminal methionine (ie, positions 2 to 285 of the SEQ ID NO: 2), (c) a fragment of the polypeptide of part (b) having functional activity of neutrocine-alpha (eg, biological activity); (d) the amino acid sequence of the predicted extracellular domain of the neutrocin-alpha polypeptide having the amino acid sequence of positions 73 to 285 of Figures IA and IB (SEQ.NO: 2) or encoded by the plasmid cDNA contained in the deposit that has the - ATCC access number 97768; (e) a nucleotide sequence encoding the neutrokine-alpha polypeptide having the amino acid sequence of positions 134 to 285 of Figures IA and IB (SEQ ID NO: 2); (f) the amino acid sequence of the intracellular domain of neutrocine-alpha (which is predicted to constitute the amino acid residues from about 1 to about 46 of Figures la and IB (SEQ ID NO: 2)) or encoded by the cDNA plasmid contained in the deposit that has accession number ATCC 97768; (g) the amino acid sequence of the transmembrane domain of neutrocin-alpha (which is predicted to constitute the amino acid residues from 47 to about 72 of Figures IA and IB (SEQ ID NO: 2)) or encoded by the cDNA plasmid contained in the deposit that has accession number ATCC 9768; (h) the amino acid sequence of the soluble neutrocin-alpha polypeptide having the extracellular and intracellular domains, but lacking the transmembrane domain, wherein each of these domains is as defined above; and (i) fragments of the polypeptide of parts (a), (b), (c), (d), (e), (f), (g) or (h). The polypeptides of the present invention also include polypeptides having an amino acid sequence with at least 80% identity, preferably at least 85 or 90% identity and still more preferably 95, 96, 97, 98 or 99% identity. those described in (a), (b), (c), (d), (e), (f), (g), (h) or (i) above, as well as polypeptides having an amino acid sequence with at least 80, 85 or 90% similarity and preferably at least 95% similarity to the previous ones. Additional embodiments of the present invention relate to polypeptides comprising, or alternatively consisting of, the amino acid sequence of an epitope-bearing portion of a neutrocyan-alpha polypeptide having the amino acid sequence described in (a), (b) , (c), (d), (e), (f), (g), (h) or (i) above. Polypeptides having the amino acid sequence of an epitope-bearing portion of a neutrokine-alpha polypeptide of the present invention, include such portions as polypeptides with at least 4, at least 5, at least 6, at least 7, at least 8 and preferably at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 25, at least 30, at least 40, at least 50 and more preferably at least about 30 amino acids to about 50 amino acids, although epitope-bearing polypeptides of any length up to and including the complete amino acid sequence of a polypeptide of the present invention described above, are also included in the present invention. Highly preferred embodiments of the present invention refer to nucleic acid molecules comprising, or alternatively consist of, a polynucleotide having a nucleotide sequence with at least 80, 85, 90% identity and preferably at least 95, 96, 97 , 98, 99 or 100% identity to a polynucleotide sequence encoding the neutrocin-alpha polypeptide having the amino acid sequence of positions 134 to 285 of Figures IA and IB (SEQ ID NO: 2). Preferred embodiments of the present invention refer to nucleic acid molecules that comprise, or alternatively consist of, a polynucleotide having a nucleotide sequence with at least 90% identity to a polynucleotide sequence encoding the neutrocin-alpha polypeptide having the amino acid sequence of positions 134 to 285 of Figures IA and IB (SEQ ID NO: 2). More preferred embodiments of the present invention refer to nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence with at least 95% identity to a polynucleotide sequence encoding the neutrocin-alpha polypeptide having the amino acid sequence of positions 134 to 285 of Figures IA and IB (SEQ ID NO: 2). More preferred embodiments of the present invention refer to nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence with at least 96% identity to a polynucleotide sequence encoding the neutrocytic polypeptide. alpha having the amino acid sequence of positions 134 to 285 of Figures IA and IB (SEQ ID NO: 2). Additionally, more preferred embodiments of the present invention relate to nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence with at least 97% identity to a polynucleotide sequence encoding the neutrocyte polypeptide. -alpha having the amino acid sequence of positions 134 to 285 of Figures IA and IB (SEQ ID NO: 2). Additionally, more preferred embodiments of the present invention relate to nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence with at least 98% identity to a polynucleotide sequence encoding the Neutrocin-alpha having the amino acid sequence of positions 134 to 285 of Figures IA and IB (SEQ ID NO: 2). Additionally, further preferred embodiments of the present invention relate to nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence with at least 99% identity to a polynucleotide sequence encoding the Neutrocin-alpha having the amino acid sequence of positions 134 to 285 of Figures IA and IB (SEQ ID NO: 2). The present invention also encompasses the above polynucleotide sequences fused to a heterologous polynucleotide sequence. The polypeptides encoded by these polynucleotides and nucleic acid molecules are also included in the present invention. The invention further provides an isolated neutrocine-alphaSV polypeptide comprising, or alternatively consists of, a nucleotide sequence that is selected from the group consisting of: (a) the amino acid sequence of the full length neutrocin-alphaSV polypeptide having the complete amino acid sequence shown in Figures 5A and 5B (ie , positions 1 to 266 of SEQ ID NO: 19) or encoded by the cDNA clone contained in the ATCC deposit deposited on December 10, 1998 with accession number ATCC 203518; (b) the amino acid sequence of the full-length neutrokine-alphaSV polypeptide having the complete amino acid sequence shown in SEQ ID NO: 19, except for the N-terminal methionine (ie, positions 2 to 266 of the SEQ ID NO: 19); (c) the amino acid sequence of the predicted intracellular domain of the neutrokine-alphaSV polypeptide having the amino acid sequence of positions 73 to 266 of Figures 5A and 5B (SEQ ID NO: 19) or encoded by the 7? DNc clone contained in the ATCC deposit number 203518 deposited on December 10, 1998; (d) the amino acid sequence of the intracellular domain of neutrokine-alphaSV (which is predicted to constitute the amino acid residues from about 1 to about 46 of Figures 5A and 5B (SEQ ID NO: 19)) or encoded by the cDNA clone contained in the ATCC deposit number 203518 deposited on December 10, 1998; (e) the amino acid sequence of the transmembrane domain of neutrokine-alphaSV (which is predicted to constitute the amino acid residues from about 47 to about 72 of Figures 5A and 5B (SEQ ID NO: 19)) or encoded by the cDNA clone contained in the ATCC deposit number 203518 deposited on December 10, 1998; (f) the amino acid sequence of the soluble neutrocin-alphaSV polypeptide having the extracellular to intracellular domains, but lacking the transmembrane domain, wherein each of these domains is as previously defined; and (g) polypeptide fragments of part (a), (b), (c), (d), (e) or (f). The polypeptides of the present invention also include polypeptides having an amino acid sequence with at least 80% identity, preferably at least 85 or 90% identity and still more 95, 96, 97, 98 or 99% identity at described in subparagraphs (a), (b), (c), (d), (e), (f) or (g) above, as well as polypeptides having an amino acid sequence with at least 80, 85 or 90 % similarity and preferably at least 95% similarity to the previous ones. Additional embodiments of the present invention relate to polypeptides comprising, or alternatively consisting of, the amino acid sequence of an epitope-bearing portion of a neutrocyl-alphaSV polypeptide having an amino acid sequence described in subparagraphs (a), ( B C D) , (e), (f) or (g) above. Peptides or polypeptides having the amino acid sequence of an epitope-bearing portion of a neutrocyl-alphaSV polypeptide of the present invention, include portions of such polypeptides with at least 4, at least 5, at least 6, at least 7, at least 8, and preferably at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 25, at least 30, at least 40, at least 50 and more preferably at least 30 amino acids to about 50 amino acids, although epitope-bearing polypeptides of any length up to and including the complete amino acid sequence of a polypeptide of the present invention described above are also included in the present invention. Certain non-exclusive embodiments of the present invention relate to a polypeptide having an amino acid sequence of an epitope-bearing portion of a neutrocin-alpha or neutrocin-alphaSV polypeptide having an amino acid sequence described in subparagraphs (a), ( b), (c), (d), (e), (f), (g), (h) or (i) above. In other embodiments, the present invention provides an isolated antibody that specifically binds (ie, only) to a neutrocine-alpha or neutrocin-alphaSV polypeptide having an amino acid sequence as described in subparagraphs (a), (b) , (c), (d), (e), (f), (g), (h) or (i) above. The present invention further provides methods for isolating antibodies that specifically bind (i.e., only) to a neutrocine-alpha or neutrocin-alphaSV polypeptide having an amino acid sequence as described herein. Such antibodies are useful for diagnostic or therapeutic uses, as will be described below. The present invention also provides pharmaceutical compositions comprising soluble neutrokine-alpha and / or neutrokine-alphaSV polypeptides, particularly human neutrokine-alpha and / or neutrocin-alphaSV polypeptides and / or anti-neutrocyanin-alpha antibodies and / or anti-neutrocin-alphaSV antibodies which they can be used, for example, for the treatment, prevention, prognosis and / or diagnosis of tumors and tumor metastases, infections caused by bacteria, viruses and other parasites, immunodeficiencies, inflammatory diseases, lymphadenopathy, autoimmune diseases, graft versus host disease, to stimulate peripheral tolerance, to destroy some transformed cell lines, to mediate cell activation, survival and proliferation, to mediate immune regulation and inflammatory responses and to enhance or inhibit immune responses. In certain embodiments, the soluble neutrokine-alpha and / or neutrokine-alphaSV polypeptides of the present invention, or agonists thereof, are administered for the treatment, prevention, prognosis and / or diagnosis of an immunodeficiency (eg, severe combined immunodeficiency). (IDCG) linked to sex, autosomal IDCG, adenosine deaminase deficiency (ADA deficiency), sex-linked agammaglobulinemia (XLA), Bruton's disease, congenital agammaglobulinemia, infantile sex-linked agammaglobulinemia, acquired agammaglobulinemia, adult agammaglobulinemia, agammaglobulinemia late onset, dysgammaglobulinemia, hypogammaglobulinemia, transient hypogammaglobulinemia of childhood, nonspecific hypogammaglobulinemia, agammaglobulinemia, common variable immunodeficiency (EIVC) (acquired), Wiskott-Aldrich syndrome (SWA), sex-linked immunodeficiency with hyper IgM, immunodeficiency not linked to sex with hyper IgM, selective deficiency d and IgA, IgG subclass deficiency (with or without IgA deficiency), antibody deficiency with normal or elevated Igs, immunodeficiency with thymoma, heavy chain Ig deletions, kappa chain deficiency, B cell lymphoproliferative disorder (BLPD), selective immunodeficiency of IgM, recessive agammaglobulinemia (Swiss type), reticular dysgenesis, neonatal neutropenia, severe congenital leukopenia, alinfoplasia-thymic aplasia or dysplasia with immunodeficiency, ataxia-telangiectasia, short limb dwarfism, sex-linked lymphoproliferative syndrome (XLP) , Nezelof syndrome combined with immunodeficiency with Igs, deficiency of purine nucleoside phosphorylase (PNP), deficiency of MHC class II (syndrome of rare lymphocytes) and combined severe immunodeficiency or disorders associated with an immunodeficiency. In a specific embodiment, the neutrokine-alpha and / or neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, are administered for the treatment, prevention, prognosis and / or diagnosis of the common variable immunodeficiency. In a specific embodiment, the neutrokine-alpha and / or neutrocine-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, are administered for the treatment, prevention, prognosis and / or diagnosis of sex-linked agammaglobulinemia. In another specific embodiment, the neutrokine-alpha and / or neutrocine-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, are administered for the treatment, prevention, prognosis and / or diagnosis of severe combined immunodeficiency (IDCG) ). In another specific embodiment, the neutrokine-alpha and / or neutrocine-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, are administered for the treatment, prevention, prognosis and / or diagnosis of Wiskott-Aldrich syndrome. In another specific embodiment, the neutrokine-alpha and / or neutrocine-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, are administered for the treatment, prevention, prognosis and / or diagnosis of Ig deficiency linked to sex with hyper IgM. In another specific embodiment, the neutrokine-alpha and / or neutrocin-alphaSV antagonists (eg, an antineutrocin-alpha antibody), are administered for the treatment, prevention, prognosis and / or diagnosis of an autoimmune disease (eg, rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, autoimmune neonatal thrombocytopenia, autoimmunocytopenia, hemolytic anemia, antiphospholipid syndrome, dermatitis, allergic encephalomyelitis, myocarditis, recurrent polychondritis, rheumatic heart disease, glomerulonephritis (IgA, IgA nephropathy), multiple sclerosis , neuritis, uveitis, ophthalmia, polyendocrinopathies, purpura (eg, Henloch-Scoenlein purpura), Reiter's disease, Stiff-Man syndrome, autoimmune pulmonary inflammation, Guillain-Barre syndrome, insulin-dependent diabetes mellitus and autoimmune eye inflammation, autoimmune thyroiditis , hypothyroidism (i.e., Hashimoto's thyroiditis), Goodpasture syndrome, pemphigus, recipient autoimmunities such as for example (a) Graves' disease, (b) myasthenia gravis and (c) insulin resistance, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, scleroderma with anti-collagen antibodies, mixed connective tissue disease, polymyositis / dermatomyositis, pernicious anemia, idiopathic Addison, infertility, glomerulonephritis such as primary glomerulonephritis and IgA nephropathy, pemphigus bullosa, Sjogren's syndrome, diabetes mellitus and resistance to adrenergic drugs (including resistance to adrenergic drugs with asthma or cystic fibrosis), chronic active hepatitis, primary biliary cirrhosis, other insufficiencies of endocrine glands, vitiligo, vasculitis, post-MI, cardiotomy syndrome, urticaria, atopic dermatitis, asthma, inflammatory myopathies and other disorders or inflammatory, granulomatous, degenerative and atrophic conditions associated with an autoimmune disease. In a specific preferred embodiment, rheumatoid arthritis is treated, prevented, predicted and / or diagnosed using antibodies antineutrocin-alpha and / or antineutrocin-alphaSV and / or other antagonists of the present invention. In another specific preferred embodiment, systemic lupus erythematosus is treated, prevented, predicted and / or diagnosed using antibodies antineutrocin-alpha and / or antineutrocin-alphaSV and / or other antagonists of the present invention. In another specific preferred embodiment, idiopathic thrombocytopenic purpura is treated, prevented, predicted and / or diagnosed using antineutrocin-alpha and / or antineutrocin-alphaSV antibodies and / or other antagonists of the present invention. In another specific preferred embodiment, IgA nephropathy is treated, prevented, predicted and / or diagnosed using antineutrocin-alpha and / or antineutrocin-alphaSV antibodies and / or other antagonists of the present invention. In a preferred embodiment, the diseases and disorders and / or autoimmune conditions associated with the aforementioned diseases and disorders are treated, prevented, prognosed and / or diagnosed using antineutrocin-alpha and / or antineutrocin-alphaSV antibodies. The present invention further provides compositions comprising a neutrokine-alpha or neutrocin-alphaSV polynucleotide, a neutrocine-alpha or neutrocin-alphaSV polypeptide and / or an antineutrocin-alpha antibody or antineutrocin-alphaSV, for administration to cells in vi tro, to ex vivo cells and to cells in vi, or to a multicellular organism. In preferred embodiments, the compositions of the present invention comprise a neutrokine-alpha and / or neutrocine-alphaSV polynucleotide for the expression of a neutrocine-alpha and / or neutrocine-alphaSV polypeptide in a host organism, for the treatment of diseases. In a more preferred embodiment, the compositions of the present invention comprise a neutrokine-alpha and / or neutrocine-alphaSV polynucleotide for the expression of a neutrocine-alpha and / or neutrocine-alphaSV polypeptide in a host organism, for the treatment of an immunodeficiency and / or conditions associated with an immunodeficiency. In this regard, expression in a human being is particularly preferred for the treatment of a dysfunction associated with an aberrant endogenous activity of a neutrokine-alpha or neutrocin-alphaSV gene (eg, expression to increase the function of normal B cells). by expanding the number of B cells or increasing the half-life of B cells). The present invention also provides a screening method for identifying compounds capable of enhancing or inhibiting a cellular response induced by neutrocine-alpha and / or neutrocine-alphaSV, which includes contacting cells that express neutrocine-alpha and / or neutrocine-alphaSV with the candidate compound, evaluate the cellular response and compare the cellular response with a standard cellular response, wherein the standard is evaluated when contact is made in the absence of the candidate compound; whereby an increased cellular response with respect to the standard indicates that the compound is an agonist; and a diminished cellular response with respect to the standard indicates that the compound is an antagonist.

In another embodiment, a method is provided for identifying neutrokine-alpha and / or neutrocine-alphaSV receptors, as well as a screening assay for agonists and antagonists using such receptors. This assay includes determining the effect that a candidate compound has on the binding of neutrokine-alpha and / or neutrocine-alphaSV to the neutrokine-alpha and / or neutrocine-alphaSV receptor. In particular, the method includes contacting a neutrokine-alpha and / or neutrocin-alphaSV receptor with a neutrokine-alpha and / or neutrocine-alphaSV polypeptide of the present invention and a candidate compound, and determining whether the binding of the polypeptide Neutrokine-alpha and / or neutrocine-alphaSV to the neutrokine-alpha receptor and / or neutrocine-alphaSV is increased or decreased because of the presence of the candidate compound. Agonists can be used to prevent septic shock, inflammation, malaria or cerebral malaria, HIV virus activation, graft rejection, bone resorption, rheumatoid arthritis, cachexia, (emaciation or malnutrition), immune system function, lymphoma and disorders autoimmune diseases (eg, rheumatoid arthritis and systemic lupus erythematosus). The inventors hereby discovered that neutrocin-alpha is expressed not only in cells of the monocytic lineage, but also in kidney, lung, peripheral leukocytes, bone marrow, T-cell lymphoma, B-cell lymphoma, activated T cells, cancer stomach, smooth muscle, macrophages and umbilical cord blood. The inventors of the present further discovered that neutrocin-alphaSV appears to be highly expressed only in primary dendritic cells. For a number of disorders of these tissues and cells, such as tumor and tumor metastasis, infections by bacteria, viruses and other parasites, immunodeficiencies (eg, chronic variable immunodeficiency), septic shock, inflammation, malaria or cerebral malaria, activation of the HIV virus, graft rejection, bone resorption, rheumatoid arthritis, autoimmune diseases (eg, rheumatoid arthritis and systemic lupus erythematosus) and cachexia, wasting or malnutrition). It is thought that significantly high or low concentrations of neutrokine-alpha and / or neutrocine-alphaSV gene expression can be detected in certain tissues (eg, bone marrow) or body fluids (eg, serum, plasma, urine, synovial fluid). or spinal fluid) taken from individuals suffering from such disorders, in relation to a gene expression level of neutrokine-alpha and / or neutrokine-alphaSV "standard", ie the level of expression of neutrocine-alpha and / or neutrocin-alphaSV in tissues or body fluids of an individual not suffering from said disorder. Thus, the present invention provides a diagnostic method useful for the diagnosis of a disorder, which includes: (a) evaluating the level of expression of the neutrokine-alpha and / or neutrocin-alphaSV gene in cells or body fluids of a individual; (b) compare the expression level of the neutrokine-alpha gene and / or neutrocine-alphaSV with a level of expression of the neutrokine-alpha and / or neutral-alphaSV gene standard, whereby an increase or decrease in the level of expression of the neutrokine-alpha and / or neutrocine-alphaSV gene tested compared to the standard expression level, is indicative of a disorder. A further embodiment of the present invention relates to a method for the treatment of an individual in need of an increase or a constitutive level of neutrocine-alpha and / or neutrocine-alphaSV activity in the body, which comprises administering to such a individual a composition comprising a therapeutically effective amount of an isolated neutrocine-alpha and / or neutrocine-alphaSV polypeptide of the present invention, or an agonist thereof. Yet another embodiment of the present invention relates to a method for the treatment of an individual in need of a decreased level of neutrokine-alpha and / or neutrocine-alphaSV activity in the body., which comprises administering to such an individual a composition comprising a therapeutically effective amount of an antagonist of neutrocine-alpha and / or neutrocin-alphaSV. Preferred antagonists for use in the present invention are antibodies specific for neutrocine-alpha and / or neutrocine-alphaSV. BRIEF DESCRIPTION OF THE FIGURES The following drawings are illustrative embodiments of the present invention and are not intended to limit the scope of the invention as encompassed by the claims. Figures IA and IB show the nucleotide sequence (SEQ ID NO: 1) and the deduced amino acid sequence (SEQ ID NO: 2) of the neutrokine-alpha. Amino acids from 1 to 46 represent the predicted intracellular domain, amino acids from 47 to 72 predicted the transmembrane domain (the doubly underlined sequence) and amino acids from 73 to 285 predicted the extracellular domain (the remaining sequence). The potential sites of glycosylation linked to asparagine are marked in Figures IA and IB with the symbol of asparagine in bold type (N) in the sequence of amino acids of neutrocin-alpha and with a sign of numbers (#) in bold type above the first nucleotide coding for that asparagine residue, in the nucleotide sequence of neutrokine-alpha. Potential N-linked glycosylation sequences are found in the following locations of the amino acid sequence of neutrokine-alpha: N-124 to Q-127 (N-124, S-125, S-126, Q-127) and N-242 to C-245 (N-242, N-243, S-244, C-245). The regions of high identity between neutrocin-alpha, neutrocin-alphaSV, TNF-alpha, TNF-beta, LT-beta and the closely related Fas ligand (an alignment of these sequences is presented in Figure 2), are underlined in the Figures IA and IB. These regions are not limiting and are marked as Preserved Domain (CD) -I, CD-II, CD-III, CD-IV, CD-V, CD-VI, CD-VII, CD-VIII, CD-IX, CD -X and CD-XI in Figures IA and IB. Figures 2A-2D show the regions of identity between the amino acid sequences of neutrokine-alpha (SEQ ID NO: 2) and neutrocine-alphaSV (SEQ ID NO: 19) and TNF-alpha ("TNF-alpha" ) in Figures 2A to 2D; GenBank, No. Z15026; SEQ ID NO: 3), TNF-beta ("TNFbeta" in Figures 2A to 2D, GenBank No. Z15026, SEQ ID NO: 4), lymphotoxin-beta ("LTbeta" in Figures 2A to 2D, GenBank No. L11016, SEQ ID NO: 5) and FAS ligand ("FasL" in Figures 2A to 2D, GenBank No. U11821; SEQ ID NO: 6), which were determined by the routine "MegAlign" technique, which is part of the computer program called "DNA * STAR". The residues that are consensual are shaded. Figure 3 shows an analysis of the amino acid sequence of neutrocin-alpha. The alpha, beta, torsion and helical regions; hydrophilicity and hydrophobicity; the amphipathic regions; flexible regions; Antigenic index and surface probability are shown as predicted values for the amino acid sequence of SEQ ID NO: 2 using the default parameters of the aforementioned computer programs. In the graph "Antigenic Index - Jameson Wolf", the indicated location of the highly antigenic regions of neutrokine-alpha, i.e., regions that are epitope-bearing peptides of the present invention can be obtained. Antigenic polypeptides include from about Phe-115 to about Leu-147, from about Ile-150 to about Tyr-163, from about Ser-171 to about Phe-194, from about Glu-223 to about Tyr-246 and from about Ser-271 to about Phe-278, of the amino acid sequence of SEQ ID NO: 2. The data presented in Figure 3 are also represented in tabular form in Table I. The columns are marked with the headings "Res" , "Position" and Roman numerals I-XIV. The column headings refer to the following characteristics of the amino acid sequence presented in Figure 3 and Table I: "Res": amino acid residue of SEQ ID NO: 2 and - - Figures IA and IB; "Position": position of the corresponding residue within SEQ ID NO: 2 and Figures IA and IB; I: alpha regions - Garnier-Robson; II: alpha regions - Chou-Fasman; III: beta regions - Garnier-Robson; IV: beta regions - Chou-Fasman; V: torsion regions - Garnier-Robson; VI: torsion regions - Chou-Fasman; VII: helical regions - Garnier-Robson; VIII: hydrophilicity chart - Kyte-Doolittle; IX: hydrophobicity graph - Hopp-Woods; X: alpha amphipathic regions -Eisenberg; XI: beta amphipathic regions - Eisenberg; XII: flexible regions - Karplus-Schulz; XIII: antigenic index - Jameson-Wolf; and XIV: surface probability graph - Emini. Figures 4A, 4B and 4C show the alignment of the nucleotide sequence of neutrocin-alpha determined from the human cDNA deposited in the ATCC with accession number 97768, with the related human cDNA clones of the present invention, which they were designated as HSOAD55 (SEQ ID NO: 7), HSLAH84 (SEQ ID NO: 8) and HLTBM08 (SEQ ID NO: 9). Figures 5A and 5B show the nucleotide sequence (SEQ ID NO: 18) and the deduced amino acid sequence (SEQ ID NO: 19) of the neutrokine-alphaSV protein. Amino acids from 1 to 46 represent the predicted intracellular domain, amino acids from 47 to 72 predicted the transmembrane domain (the doubly underlined sequence) and amino acids from 73 to 266 predicted the extracellular domain (the remaining sequence). The potential glycosylation sites linked to asparagine are marked in Figures 5A and 5B with the asparagine symbol in bold letters (N) in the amino acid sequence of the neutrocin-alphaSV and with a number sign (#) in letters bold above the first nucleotide coding for that asparagine residue, in the nucleotide sequence of neutrokine-alphaSV. The potential N-linked glycosylation sequences are found in the following locations of the amino acid sequence of neutrokine-alphaSV: N-124 to Q-127 (N-124, S-125, S-126, Q-127) and N-223 to C-226 (N-223, N-224, S-225, C-226). Antigenic polypeptides include from about Pro-32 to about Leu-47, from about Glu-116 to about Ser-143, from about Phe-153 to about Tyr-173, from about Pro-218 to about Tyr-227, from about Ala-232 at about Gln-241; from about Ile-244 to about Ala-249; and from about Ser-252 to about Val-257 of the amino acid sequence of SEQ ID NO: 19. The regions of high identity between neutrocin-alpha, neutrocin-alphaSV, TNF-alpha, TNF-beta, LT-beta and the closely related Fas ligand (an alignment of these sequences is presented in Figure 2), are underlined in Figures IA and IB. These conserved regions (from neutrocine-alpha and neutrocine-alphaSV) are marked as Preserved Domain (CD) -I, CD-II, CD-III, CD-V, CD-VI, CD-VII, CD-VIII, CD-IX, CD-X and CD-XI in Figures 5A and 5B. Neutrocin-alphaSV does not contain the CD-IV sequence described in the legend of Figures IA and IB. An additional alignment of the neutrokine-alpha polypeptide sequence (SEQ ID NO: 2) with APRIL, TNF-alpha and LT-alpha, is presented in Figures 7A-I-7A-II. In Figures 7A-I-7A-II, the beta sheet regions are indicated in the manner described below in the legends of Figures 7A-I-7A-II. Figure 6 shows an analysis of the amino acid sequence of neutrocine-alphaSV. The alpha, beta, torsion and helical regions; of hydrophilicity and hydrophobicity; amphipathic regions; Flexible regions, antigenic index and surface probability are shown as predicted for the amino acid sequence of SEQ ID NO: 19, using the default parameters of the aforementioned computer programs. The location of the highly antigenic regions of the neutrocin-alpha protein, i.e. regions from which epitope-bearing peptides of the present invention can be obtained, are indicated in the "antigenic-Jameson-Wolf index" graph. Antigenic polypeptides include, but are not limited to, a polypeptide comprising amino acid residues from about Pro-32 to about Leu-47, from about Glu-116 to about Ser-143, from about Phe-153 to about Tyr- 173, from about Pro-218 to about Tyr-227, from about Ser-252 to about Thr-258; from about Ala-232 to about Gln-241; from about Ile-244 to about 249 W; and from about Ser-252 to about Val-257 of the amino acid sequence of SEQ ID NO: 19. The data shown in Figure 6 can be easily represented in tabular form, similarly to the data shown in Table I Such a tabular representation of the exact data described in Figure 6 can be generated using the "MegAlign" component of the DNA * STAR computer sequence analysis package, setting the parameters by default. This is identical to the program that was used to generate Figures 3 and 6 of the present application. Figures 7A-I - 7A-II. Amino acid sequence of the α-neutrocin-alpha and alignment of its ligand-binding domain predicted with that of APRIL, TNF-alpha and LT-alpha (specifically, amino acid residues 115 to 250 of the human APRIL polypeptide (SEQ ID NO. : 20), ATCC Accession No. AF046888), amino acid residues 88 to 233 of TNF-alpha (SEQ ID NO: 3, GenBank access no Z15026) and LT-alpha (also referred to as TNF-beta) residues of amino acid 62 to 205 of SEQ ID NO: 4; GenBank no. of access Z15026). The predicted membrane extension region of neutrokine-alpha is indicated and the cleavage site of neutrokine-alpha is indicated by an arrow. The sequences marked with a line above (A to H) represent the predicted beta sheet regions. Figure 7B. Neutrocin-alpha mRNA expression. A Northern blot analysis was performed using the neutrokine-alpha orf as a probe in immunoblots of poly (A) + RNA (Clontech) from a spectrum of human tissue types and a selection of cancer cell lines. Neutrokine-alpha mRNA of 2.6 kb was detected at high concentrations in placenta, heart, lung, fetal liver, thymus and pancreas. Neutrokine-alpha mRNA of 2.6 kb was also detected in cell lines HL-60 and K562. Figures 8A-8C. The expression of neutrocine-alpha is increased after activation of human monocytes by IFN-gamma. Figures 8A-8B. Flow cytometric analysis of the expression of the protein neutrocin-alpha in monocytes cultured in vi tro. Purified monocytes were cultured for 3 days in the presence or absence of IFN-gamma (100 U / mL). Then the cells were stained with a specific monoclonal antibody against neutrocine-alpha (2E5) (solid lines) or with a control of the same isotype (IgGl) (dashed lines). Comparable results were obtained with purified monocytes from different donors in three independent experiments. Figure 8c. Neutralcin-alpha-specific TaqMan primers were prepared and used to evaluate the relative expression levels of neutrokine-alpha mRNA in unstimulated monocytes and in monocytes treated with IFN-gamma (100 U / mL). The nucleotide sequences of the TaqMan primers were as follows: (a) probe: 5 '-CCA CCA GCT CCA GGA GAA GGC AAC TC-3' (SEQ ID NO: 24); (b) 5 'amplification primer: 5' -ACC GCG GGA CTG AAA ATC T-3 '(SEQ ID NO: 25); and (c) 3 'amplification primer: 5' -CAC GCT TAT TTC TGC TGT TCT GA-30 (SEQ ID NO: 26). Figures 9A and 9B. Neutrokine-alpha is a potent B lymphocyte stimulator. Figure 9A. The biological activity of Neutrocin-alpha was evaluated in a standard B lymphocyte co-stimulation assay, using the strain Staphylococcus aureus Cowan 1 SAC as the - primer agent. SAC alone produces fund accounts of 1427 +/- 316. Values are reported as the average +/- standard deviation of tests in triplicate. Similar results were obtained using purified recombinant Neutrocin-alpha from stable transfectant CHO cells and transiently transfected HEK 293T cells. Figure 9B. Proliferation of tonsillar B cells with Neutrocin-alpha and co-stimulation with anti-IgM. The bioassay was performed in the manner described for SAC, with the exception that individual wells were previously coated with goat anti-human IgM antibody, at 10 micrograms / ml in PBS. Figures 10A-10G. Expression of Neutrocin-alpha receptor in normal human peripheral blood mononuclear cells and in tumor cell lines. Figures 10A-10E. Nucleated human peripheral blood cells were obtained from normal volunteers and isolated by density gradient centrifugation. The cells were stained with biotinylated Ñeutrocin-alpha, followed by streptavidin conjugated with PE and FITC or PerCP monoclonal antibodies specific for CD3, CD20, CD14, CD56 and CD66b. The cells were analyzed in a FACScan equipment from Becton Dickinson, using the CellQuest software. The data represent one of four independent experiments. Figures 10F-10G. Neutrocin-alpha binding to the histiocytic cell line U-937 and to the IM-9 myeloma cell line. Figures HA - 11F. Effects of administration of Neutrocin-alfa in BALB / cAnNCR mice. Figure HA. Smalts fixed in formalin were covered with paraffin and 5 micron sections were cut and stained with hematoxylin and eosin (upper panels). The lower panels are sections taken from the same animals, stained with the monoclonal antibody anti-CD45R (B220) mAb and developed with rabbit anti-rat Ig serum coupled with horseradish peroxidase (absorbed from mouse) and the substrate was tetrahydrochloride diaminobenzidine (DAB) The slides were stained for contrast with Mayer's hematoxylin. Cells expressing CD45R (B220) appeared in brown. Figures 11B-11C. Flow cytometry analysis of normal cells (left panel) and treated with Neutrocin-alpha (right panel) stained with PE-CD45R (B220) and FITC-ThB (Ly6D). Figures 11D-11F. Concentrations of IgM, IgG and IgA in serum, in normal mice and mice treated with Neutrocin-alpha. DETAILED DESCRIPTION OF THE INVENTION The present invention provides isolated nucleic acid molecules comprising a polynucleotide encoding a Neutrocin-alpha polypeptide having the amino acid sequence shown in Figures IA and IB (SEQ ID No. 2), which was determined by sequencing a cDNA clone. The nucleotide sequence shown in Figures IA and IB (SEQ ID No. 1) was obtained by sequencing the clone HNEDU15, which was deposited on October 22, 1996, in the North American Type Culture Collection, 10801 University Boulevard, Manassas, Virginia 20110-2209, and assigned accession number ATCC 97768. The deposited clone is contained in the pBluescript SK (-) plasmid (Stratagene, La Jolla, CA). The present invention also provides isolated nucleic acid molecules comprising a polynucleotide encoding Neutrokine-alphaSV polypeptides having the amino acid sequence shown in Figures 5A and 5B (SEQ ID No. 19), which was determined by sequencing of a cDNA clone. The nucleotide sequence shown in Figures 5A and 5B (SEQ ID No. 18) was obtained by sequencing the HDPMC52 clone, which was • deposited on December 10, 1998, in the North American Type Culture Collection and assigned the accession number ATCC 203518. The deposited clone is contained in the plasmid pBluescript SK (-) (Stratagene, La Jolla, CA). The Neutrokine-alpha and Neutrocin-alpha polypeptides of the present invention share a sequence-homology with the translation products of human mRNAs for TNF-alpha, TNF-beta, LT-beta, ligand FAS, APRIL and LT- alpha (see Figures 2A-2D and 7A-I- 7A-II). As noted above, it is thought that TNF-alpha is an important cytokine that plays a role in cytotoxicity, necrosis, apoptosis, co-stimulation, proliferation, lymph node formation, immunoglobulin class switching, differentiation, antiviral activity and regulation of the adhesion of molecules and other cytokines and growth factors. Nucleic Acid Molecules Unless otherwise indicated, all sequences determined by sequencing of a DNA molecule were determined using an automated DNA sequencer (such as Model 373 from Applied Biosystems, Inc., Foster City, CA) and all the amino acid sequences of the polypeptides encoded by the DNA molecules determined herein were predicted by the translation of a DNA sequence determined in the manner described above. Therefore, as is known in the art for any DNA sequence determined by its automated approach, any nucleotide sequence determined herein may contain some errors. The nucleotide sequences determined by automation typically have at least about 90% identity, more - typically at least about 95% to at least about 99.9% identity with the actual nucleotide sequence of the DNA molecule sequenced. The actual sequence can be determined more accurately by other means, including manual DNA sequencing methods that are known in the art. As is known in the art, a single insertion or deletion in a given nucleotide sequence, compared to the actual sequence, will cause a modification of the frame in the translation of the nucleotide sequence, such that the encoded predicted amino acid sequence for a given nucleotide sequence, it will be completely different from the amino acid sequence actually encoded by the sequenced DNA molecule, starting at the point of such insertion or deletion. The term "nucleotide sequence" of a nucleic acid molecule or polynucleotide, refers to a DNA or polynucleotide molecule, a deoxyribonucleotide sequence and an RNA or polynucleotide molecule, the corresponding sequence of ribonucleotides (A, G, C and U), wherein each thymidine deoxyribonucleotide (T) in the specified deoxyribonucleotide sequence is replaced by the ribonucleotide uridine (U). Using the information provided herein, such as the nucleotide sequence of Figures IA and IB, a nucleic acid molecule of the present invention encoding a Neutrocin-alpha polypeptide can be obtained, using the standard methods of cloning and selection. , such as those used to clone cDNA using mRNA as a raw material. Illustrative of the present invention, the nucleic acid molecule described in Figures IA and IB (SEQ ID No. 1) was discovered in a cDNA library derived from neutrophils. Expressed sequence tags corresponding to a portion of the Neutrocin-alpha cDNA were also found in kidney, lung, peripheral leukocytes, bone marrow, T-cell lymphoma, B-cell lymphoma, activated T cells, stomach cancer, smooth muscle, macrophages and umbilical cord blood. In addition, using the nucleotide information provided in Figures 5A and 5B, a nucleic acid molecule of the present invention can be obtained that encodes a Neutrocin-alphaSV polypeptide, using the standard methods of cloning and selection, such as those used for clone cDNA using mRNA as a raw material. Illustrative of the present invention, the nucleic acid molecule described in Figures 5A and 5B (SEQ ID No. 18) was discovered in a cDNA library derived from primary dendritic cells.

The Neutrokine-alpha HNEDU15 plasmid deposited with accession number ATCC 97768, contains an open reading frame coding for a protein of approximately 285 amino acid residues, a predicted intracellular domain of approximately 46 amino acids (amino acid residues of about 1 to approximately 46 of Figures IA and IB (SEQ ID No. 2)), a predicted transmembrane domain of about 26 amino acids (the underlined amino acid residues from about 47 to about 72 of Figures IA and IB (SEQ ID No 2)), a predicted extracellular domain of approximately 213 amino acids (amino acid residues from about 73 to about 285 in Figures IA and IB (SEQ ID No. 2)); and a deduced molecular weight of approximately 31 kDa. The Neutrocin-alpha polypeptide shown in Figures IA and IB (SEQ ID No. 2), has approximately 20% similarity and approximately 10% identity to human TNF-alpha, which can be obtained in GenBank with the number of access 339764. The Neutrokine-alpha HDPMC52 plasmid, deposited with accession number ATCC 203518, contains a predicted open reading frame encoding a protein of approximately 266 amino acid residues, a predicted intracellular domain of approximately 46 amino acids (residues of amino acid from about 1 to about 46 of Figures 5A and 5B (SEQ ID No. 19)), a predicted transmembrane domain of about 26 amino acids (the amino acid residues underlined from about 47 to about 72 of Figures 5A and 5B (SEQ ID No. 19)), a predicted extracellular domain of approximately 194 amino acids (amino acid residues from about 73 to about 266 in the 5A and 5B (SEQ ID No. 19)); and a deduced molecular weight of about 29"kDa.The Neutrocin-alpha polypeptide shown in Figures 5A and 5B (SEQ ID No. 19), has approximately 33.9% similarity and approximately 22.0% identity with human TNF-alpha. , which can be obtained in GenBank with the access number 339764. As will be observed by a person skilled in the art, due to the possibilities of sequencing errors described above, the actual complete Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides encoded by the deposited 7? DNc clones, comprising approximately 285 and 266 amino acids, respectively, could be a little shorter.In particular, the Neutrocin-alpha and Neutrocin-alphaSV coding sequences determined contain a second codon of common methionine, which serves as an alternative start codon for the translation of the open reading frame, at nucleotide positions 210-212 of Figures IA and IB (SEQ ID No. 1) and n the nucleotide positions 64-66 in Figures 5A and 5B (SEQ ID No. 18). More generally, the actual open reading frame can be anywhere in the range of ± 20 amino acids, most likely in the range of ± 10 amino acids of the predicted site of the first or second methionine codon of the N-terminal end of Figures IA and IB (SEQ ID No. 1) and in Figures 5A and 5B (SEQ ID No. 18). It will be further noted that, the polypeptide domains described herein have been predicted by computer analysis and, accordingly, depend on the analytical criteria used to identify various functional domains, wherein the exact "direction" of the extracellular, intracellular domains and transmembrane of Neutrocin-alpha and Neutrocin-alphaSV polypeptides, may be slightly different. For example, the exact location of the extracellular domains of Neutrokine-alpha and Neutrokine-alphaSV in Figures IA and IB (SEQ ID No. 2) and in Figures 5A and 5B (SEQ ID No. 19), could vary slightly ( eg, the address could "change" in about 1 to about 20 amino acid residues, most likely in about 1 to about 5 residues), depending on the criteria used to define the domain. In this case, the ends of the transmembrane domains and the principle of the extracellular domains were predicted based on the identification of the hydrophobic amino acid sequence in the positions indicated above, as shown in Figures 3 and 6 and in the Table I In any case, as will be described below, the present invention also provides polypeptides that have undergone deletion of several N-terminal and / or C-terminal residues of the entire polypeptide, including polypeptides lacking one or more amino acids of the N-terminal end of the extracellular domains, as described herein, which constitute the soluble forms of the extracellular domains of the Neutrocin-alpha and Neutrocin-alphaSV polypeptides. As indicated, the nucleic acid and polynucleotide molecules of the present invention may be in the form of RNA, such as mRNA, or in the form of DNA, including for example cDNA and genomic DNA, obtained by cloning or synthetically produced. The DNA can be double-stranded or single-stranded. The DNA or RNA of a single chain can be the coding chain, also known as the sense chain, or it can be the non-coding chain, also known as the antisense strand. The term "isolated" nucleic acid molecule means a nucleic acid molecule (DNA or RNA) that was removed from its native environment. For example, recombinant DNA molecules contained in a vector are considered as isolated for the purposes of the present invention. Other examples of isolated DNA molecules include recombinant DNA molecules maintained in heterologous host cells or DNA molecules purified (partially or substantially) in solution. Isolated RNA molecules include RNA transcripts in vivo or in vi tro of the DNA molecules of the present invention. However, a nucleic acid contained in a clone that is a member of a library. { and. g. , a genomic DNA library or cDNA) that has not been isolated from other members of the library (eg, in the form of a homogeneous solution containing the clone and other members of the library) or an isolated chromosome or removed from a cell or a cell lysate { and. g. , a "chromosomal separation", as in a karyotype), is not considered "isolated" for the purposes of the present invention. As will be described below, nucleic acid molecules isolated in accordance with the present invention can be produced naturally, recombinantly or synthetically. The isolated nucleic acid molecules of the present invention include DNA molecules comprising or alternatively consisting of, an open reading frame (ORF) with a start codon at positions 147-149 of the nucleotide sequence shown in FIG. and IB (SEQ ID NO: 1). In addition, the isolated nucleic acid molecules of the present invention include DNA molecules comprising, or alternatively consisting of, a sequence substantially different from those previously described, but which due to the degeneracy of the genetic code, still encodes the neutrocytic protein. alpha. Of course, the genetic code is well known in the art. Thus, it would be routine for a person skilled in the art to generate the degenerate variants described above. In another embodiment, the present invention provides isolated nucleic acid molecules comprising, or alternatively consisting of, a coding sequence for the neutrocin-alpha polypeptide having an amino acid sequence encoded by the cDNA contained in the plasmid having the accession number ATCC 97768. Preferably, this nucleic acid molecule comprises, or alternatively consists of, a sequence encoding the extracellular domain of the soluble mature polypeptide sequence of the polypeptide encoded by the cDNA contained in the plasmid having the accession number ATCC 97768 The isolated nucleic acid molecules of the present invention include DNA molecules that comprise or alternatively consist of, an open reading frame (ORF) with a start codon at positions 1-3 of the nucleotide sequence shown in Figure 5A and 5B (SEQ ID NO: 18). In addition, the isolated nucleic acid molecules of the present invention include DNA molecules that comprise, or alternatively consist of, a sequence substantially different from those described above, but which, due to the degeneracy of the genetic code, still codes for the neutrocyte polypeptide. -alfaSV. Of course, the genetic code is well known in the art. Thus, it would be routine for a person skilled in the art to generate the degenerate variants described above. In another embodiment, the present invention provides isolated nucleic acid molecules comprising, or alternatively consisting of, a coding sequence for the neutrocin-alphaSV polypeptide having an amino acid sequence encoded by the cDNA contained in the plasmid having the accession number ATCC 203518. Preferably, this nucleic acid molecule comprises, or alternatively consists of, a sequence encoding the extracellular domain of the soluble mature polypeptide sequence of the polypeptide encoded by the cDNA contained in the plasmid having the accession number ATCC 203518 The present invention further provides an isolated nucleic acid molecule comprising, or alternatively consisting of, the nucleotide sequence shown in Figures IA and IB (SEQ ID NO: 1) or the nucleotide sequence of the neutrokine-alpha cDNA. contained in the plasmid that has accession number ATCC 97768, a molecule of nucleic acid having a complementary to a sequence of the above sequences. In addition, the present invention provides an isolated nucleic acid molecule comprising, or alternatively consisting of, the nucleotide sequence shown in Figures 5A and 5B (SEQ ID NO: 18) or the nucleotide sequence cDNA of neutrocine-alphaSV contained in the plasmid having the accession number ATCC 203518, or of a nucleic acid molecule having a sequence complementary to one of the above sequences. Such isolated molecules, particularly DNA molecules have uses that include, but are not limited to, use as probes for gene mapping by in situ hybridization with chromosome and to detect the expression of neutrocine-alpha and neutrocin-alphaSV in tissue human, for example, by Northern blot or Western blot analysis (Northern in blot or Western in blot). In one embodiment, the polynucleotides of the present invention comprise, or alternatively consist of, the sequence shown in SEQ ID NO: 5. The sequence provided in SEQ ID NO: 22 was constructed from several overlapping murine EST sequences obtained at GenBank (AI182472, AA422749, AA254047, and AI122485). The EST sequences were aligned to generate the neutrokine-alpha-like polynucleotide sequence provided as SEQ ID NO: 25. The amino acid sequence resulting from the translation of SEQ ID NO: 22 is given as SEQ ID NO: 23. Fragments, variants and derivatives of the sequences provided as SEQ ID NO: 22 and SEQ ID NO: 23, are also encompassed by the present invention. In another embodiment, the polynucleotides of the present invention comprise or alternatively consist of, the sequence shown in SEQ ID NO: 27 and / or a sequence encoding the amino acid sequence described in SEQ ID NO: 28, fragments, variants and derivatives thereof. These polynucleotides are also encompassed by the present invention. For example, certain embodiments of the present invention relate to polynucleotides comprising or alternatively consisting of, a sequence encoding a polynucleotide having at least 80, 85, 90, 92, 95, 96, 97, 98, or 99% of identity to the amino acids of 68-219 of SEQ ID NO: 28. The amino acid sequence resulting from the translation SEQ ID NO: 27, is provided as SEQ ID NO: 28. Polynucleotides comprising, or alternatively consisting of the amino acid sequence of SEQ ID NO: 28 and fragments, variants and derivatives of the sequence provided as SEQ ID NO: 28, are also encompassed by the present invention. For example, certain embodiments of the present invention relate to polypeptides comprising or alternatively consisting of, a polypeptide sequence having at least 80, 85, 90, 92, 95, 96, 97, 98, or 99% identity to amino acids 68-219 of SEQ ID NO: 28. A nucleic acid molecule having the sequence provided as SEQ ID NO: 27, obtained by PCR-TI from CMSP (Peripheral Blood Mononuclear Cells) of mono cyanomologist (ie, macaca iru), using two degenerate primers. Briefly, total TARN of peripheral blood mononuclear cells was prepared (CMSP) of mono cyanomologist, using trizol (available from Life Technologies, Inc., Rockville, MD) in accordance with the manufacturer's protocol. The single-stranded cDNA was then synthesized from the cyanomologous monkey CMSP preparation, using the standard methods with an oligo-dT primer. Neutrocin-alpha-specific primers were designed based on the conserved region between murine and human neutrocine-alpha molecules (SEQ ID NO: 22 and SEQ ID NO: 1 respectively). A cyanomologous mono-neutrophil nucleic acid molecule was then generated by PCR, using the cDNA template in combination with the following two degenerate primer oligonucleotides: 5 'primer: 5' -TAC CAG ITG GCI GCC ITG CAA G-3 '(SEQ ID NO: 35) and 3' primer: 5'-GTI ACÁ GCA GTT TIA IIG CAC C-3 '(SEQ ID NO: 36). In the sequence of the degenerate primers (SEQ ID NO: 35 and SEQ ID NO: 36) the literal "I" represents deoxyinosine or dideoxyinosine. In another embodiment, the polynucleotides of the present invention comprise or alternatively consist of, the sequence shown in SEQ ID NO: 29 and / or a sequence encoding the amino acid sequence described in SEQ ID NO: 30 fragments, variants and derived from them. These polynucleotides are also encompassed by the present invention. For example, certain embodiments of the present invention relate to polynucleotides comprising or alternatively consisting of, a sequence encoding a polynucleotide having at least 80, 85, 90, 92, 95, 96, 97, 98, or 99% of identity to the amino acids of 68-219 of SEQ ID NO: 30. The amino acid sequence resulting from the translation SEQ ID NO: 29 is given as SEQ ID NO: 30. The polynucleotide comprising, or alternatively consisting of the amino acid sequence of SEQ ID NO: 30 and fragments, variants and derivatives of the sequence provided as SEQ ID NO: 29 and SEQ ID NO: 30, are also encompassed by the present invention. For example, certain embodiments of the present invention relate to polypeptides comprising, or alternatively consisting of, a polypeptide sequence having at least 80, 85, 90, 92, 95, 96, 97, 98, or 99% identity to the amino acids of 68-219 of SEQ ID NO: 30. A nucleic acid molecule having the sequence provided as SEQ ID NO: 29 was obtained by PCR-TI from CMSP (peripheral blood mononuclear cells) of rhesus monkey, using two degenerate primers. Briefly, total cMSP RNA from rhesus monkey was prepared using trizol (available from Life Technologies, Inc., Rockville, MD) in accordance with the manufacturer's protocol. Next, single-stranded cDNA was synthesized from the rhesus monkey PBMC preparation, using the standard methods with an oligo-dT primer. Neutrocin-alpha-specific primers were designed based on the conserved region between murine and human neutrocine-alpha molecules (SEQ ID NO: 22 and SEQ ID NO: 1, respectively). A rhesus monkey neutrocine-alpha nucleic acid molecule was then generated by PCR, using the cDNA template in combination with the following two degenerate primer oligonucleotides: 5 'primer: 5' -TAC CAG ITG GCI GCC ITG CAA G-3 '(SEQ ID NO: 35) and 3' primer: 5'-GTI ACÁ GCA GTT TIA IIG CAC C-3 '(SEQ ID NO: 36). In the sequence of the degenerate primers (SEQ ID NO: 35 and SEQ ID NO: 36) the literal "I" represents deoxyinosine or dideoxyinosine. The present invention also provides nucleic acid molecule having nucleotide sequences related to extensive portions of SEQ ID NO: 1 and SEQ ID NO: 18, which have been determined from the following related cDNA clones: HSOAD55 (SEQ. ID NO: 7, HSLAH84 (SEQ ID NO: 8), and HLTBM08 (SEQ ID NO: 9) The present invention further relates to nucleic acid molecule encoding portions of the nucleotide sequences described herein, as well as for fragments of the isolated nucleic acid molecules described herein. In one embodiment, the present invention provides a polynucleotide having a nucleotide sequence representing the portion of SEQ ID NO: 1 consisting of the nucleotides of position 1-1001 of SEQ ID NO: 1. In another embodiment, The present invention provides a polynucleotide having a nucleotide sequence that represents the portion of SEQ ID NO: 18 consisting of positions 1-798 of SEQ ID NO: 18. The present invention also refers to fragments of the molecules of nucleic acid (ie polynucleotides) described herein. A fragment of a nucleic acid molecule has, for example, the nucleotide sequence of the cDNA contained in the plasmid having the accession number ATCC 97768, a nucleotide sequence that encodes the polynucleotide sequence encoded by the cDNA contained in the plasmid having the accession number ATCC 97768, the nucleotide sequence of SEQ ID NO: 1, a nucleotide sequence encoding a polypeptide sequence of SEQ ID NO: 2, the nucleotide sequence of cDNA contained in the plasmid having the accession number ATCC 203518, a nucleotide sequence encoding the polypeptide sequence encoded by the cDNA contained in the plasmid having the accession number ATCC 203518, the nucleotide sequence of SEQ ID NO: 18, a nucleotide sequence encoding the sequence of the polypeptide of SEQ ID NO: 20 or the chain complementary thereto, wherein these fragments contain at least 15 nucleotides (nt) and preferably at least 20 nt or at least 25 nt, still more preferably at least 30 nt and even more preferably at least 40, 50, 100, 150, 200, 250, 300, 325, 350, 375 , 400, 450 or 500 nt in length. These fragments have numerous uses, which include but are not limited to, uses as a diagnostic probe and primers as described herein. Of course, large fragments such as those of 501-1500 nt in length, are also useful in accordance with the present invention, as are the fragments corresponding to most, if not all, of the nucleotide sequences. of the cDNA contained in the plasmid having the accession number ATCC 97768, the nucleotide sequence of SEQ ID NO: 1, the nucleotide sequence of the cDNA contained in the plasmid having the accession number ATCC 203518 and the nucleotide sequence of SEQ ID NO: 18. The preferred nucleic acid fragments of the present invention include nucleic acid molecules encoding polypeptide comprising, or alternatively consisting of, epitope-bearing portions of the neutrocytic-alpha and / or neutrocytic polypeptide. alphaSV as identified in Figures IA and IB (SEQ ID NO: 2) and Figures 5A and 5B (SEQ ID NO: 19), respectively, and described in more detail below. Polypeptides encoded by these polynucleotide fragments are also encompassed by the present invention. Also a nucleic acid fragment has, for example, the nucleotide sequence of SEQ ID NO: 21, the nucleotide sequence of SEQ ID NO: 22, the dt nucleotide sequence of SEQ ID NO: 27, the sequence of nucleotide of SEQ ID NO: 29, a sequence of -1 nucleotide coding for the polypeptide sequence of SEQ ID NO: 23, a nucleotide sequence coding for the polypeptide sequence of SEQ ID NO: 28, a nucleotide sequence encoding the sequence of the polypeptide of SEQ ID NO: 30 or the strands complementary thereto, wherein these fragments have at least 15 nucleotides (nt) and preferably at least 20 nt or at least 25 nt , still more preferably at least 30 nt and even more preferably at least 40, 50, 100, 150, 200, 250, 300, 325, 350, 375, 400, 450 or 500 nt in length. These fragments have numerous uses, which include but are not limited to, uses as a diagnostic probe and primers as described herein. Of course, large fragments such as those of 501-1500 nt in length, are also useful in accordance with the present invention, as are the fragments corresponding to most, if not all, of the nucleotide sequences. of SEQ ID NO: 21, the nucleotide sequence of SEQ ID NO: 22, the nucleotide sequence of SEQ ID NO: 29, a nucleotide sequence encoding the polypeptide sequence of SEQ ID NO: 23, a nucleotide sequence coding for the polypeptide sequence of SEQ ID NO: 28, a nucleotide sequence coding for the polypeptide sequence of SEQ ID NO: 30, or the complementary chain thereof. The polypeptides encoded by these polynucleotide fragments are also encompassed by the present invention. Representative examples of the neutrokine-alpha polynucleotide fragments of the present invention include, for example, fragments comprising, or alternatively consisting of, a sequence from about nucleotide 1 to 50, 51 to 100, 101 to 146, 147 to 200, 201 to 250, 251 to 300, 301 to 350, 351 to 400, 401 to 450, 451 to 500, 501 to 550, 551 to 600, 600 to 650, 651 to 700, 701 to 750, 751 to 800, 801 to 850 , 851 to 900, 901 to 950, 951 to 1000, 1001 to 1050 and / or 1051 to 1082, of SEQ ID NO: 1 or the complementary chain thereof, or the cDNA contained in the plasmid having the number of ATCC access 97768. In this context the term "approximately" includes the particularly cited ranges and ranges that are higher or lower in several (5, 4, 3, 2, or 1) nucleotides at either terminal end.

Representative examples of the neutrokine-alphaSV polynucleotide fragments of the present invention include, for example, fragments comprising, or alternatively consisting of, a sequence of about 1 to 50 nucleotide, 51 to 100, 101 to 150, 151 to 200, 201 to 250, 251 to 300, 301 to 350, 351 to 400, 401 to 450, 451 to 500, 501 to 550, 551 to 600, 600 to 650, 651 to 700, 701 to 750, 751 to 800, 800 to 850 and / or 851 to 900, of SEQ ID NO: 18 or the complementary chain thereof, or the cDNA contained in the plasmid having the accession number ATCC 203518. In this context the term "approximately" includes the ranges particularly cited and ranges that are higher or lower in several (5, 4, 3, 2, or 1) nucleotides in either terminal end. In certain preferred embodiments, the polynucleotides of the present invention comprise, or alternatively consist of, the nucleotide residues from 571 to 627, 580-627, 590-627, 600-627, 610-627, 571-620, 580-620 , 590-620, 600-620, 571-610, 580-610, 590-610, 571-600, 580-600 and / or 571-590 of SEQ ID NO: 1. In certain preferred embodiments, the polynucleotides of the present invention comprise, or alternatively, consist of the nucleotide residues of 1-879, 25-879, 50-879, 75-879, 100-879, 125-879, 150-879, 175-879, 200-879 , 225-879, 250-879, 275-879, 300-879, 325-879, 350-879, 375-879, 400-879, 425-879, 450-879, 475-879, 500-879, 525 -879, 550-879, 575-879, 600-879, 625-879, 650-879, 675-879, 700-879, 725-879, 750-879, 775-879, 800-879, 825-879 , 850-879, 1-850, 25-850, 50-850, 75-850, 100-850, 125-850, 150-850, 175-850, 200-850, 225-850, 250-850, 275 -850, 300-850, 325-850, 350-850, 375-850, 400-850, 425-850, 450-850, 475-850, 500-850, 525-850, 550-850, 575-850 , 600, 850, 625-850, 650-850, 765-850, 700-850, 725-850, 750-850, 775-850, 800-850, 825-850, 1-825, 25-825, 50- 825, 75-825, 100-825, 125-825, 150-825, 175-825, 200-825, 225-825, 250-825, 275-825, 300-825, 325-825, 350-825, 375-825, 400-825, 425-825, 450-825, 475-825, 500-825, 525-825, 550-825, 575-825, 600-825, 625-825, 650-825, 675- 825, 700-825, 725-825, 750-825, 775-825, 800-825, 1-800, 25-800, 50-800, 75-800, 100-800, 125-800, 150-800, 175-800, 200-800, 225-800, 250-800, 275-800, 300-800, 325-800, 350-800, 375-800, 400-800, 425-800, 450-800, 475- 800, 500-800, 525-800, 550-800, 575-800, 600-800, 625-800, 650-800, 675-800, 700-800, 725-800, 750-800, 775-800, 1-775-, 25-775, 50-775, 75-775, 100-775, 125-775, 150-775, 175-775, 200-775, 225-775, 250-775, 275-775, 300 -775, 325-775, 350-775, 375-775, 400-775, 425-775, 450-775, 475-775, 500-775, 525-775, 550-775, 575-775, 600-775 , 625-775, 650-775, 675-775, 700-775, 725-775, 750-775, 1-750, 25-750, 50-750, 75-750, 100-750, 125-750, 1 50-750, 175-750, 200-750, 225-750, 250-750, 275-750, 300-750, 325-750, 350-750, 375-750, 400-750, 425-750, 450- 750, 475-750, 500-750, 525-750, 550-750, 575-750, 600-750, 625-750, 650-750, 675-750, 700-750, 725-750, 1-725, 25-725, 50-725, 75-725, 100-725, 125-725, 150-725, 175-725, 200-725, 225-725, 250-725, 275-725, 300-725, 325- 725, 350-725, 375-725, 400-725, 425-725, 450-725, 475-725, 500-725, 525-725, 550-725, 575-725, 600-725, 625-725, 650-725, 675-725, 700-725, 1-700, 25-700, 50-700, 75-700, 100-700, 125-700, 150-700, 175-700, 200-700, 225- 700, 250-700, 275-700, 300-700, 325-700, 350-700, 375-700, 400-700, 425-700, 450-700, 475-700, 500-700, 525-700, 550-700, 575-700, 600-700, 625-700, 650-700, 675-700, 1-675, 25-675, 50-675, 75-675, 100-675, 125-675, 150- 675, 175-675, 200-675, 225-675, 250-675, 275-675, 300-675, 325-675, 350-675, 375-675, 400-675, 425-675, 450-675, 475-675, 500-675, 525-675, 550-675, 575-675, 600-675, 625-675, 650-675, 1-650, 25-650, 50-650, 75-650, 10 0-650, 125-650, 150-650, 175-650, 200-650, 225-650, 250-650, 275-650, 300-650, 325-650, 350-650, 375-650, 400- 650, 425-650, 450-650, 475-650, 500-650, 525-650, 550-650, 575-650, 600-650, 65-650, 1-625, 25-625, 50-625, 75-625, 100-625, 125-625, 150-625, 175-625, 200-625, 225-625, 250-625, 275-625, 300-625, 325-625, 350-625, 735- 625, 400-625, 425-625, 450-625, 475-625, 500-625, 525-625, 550-625, 575-625, 600-625, 1-600, 25-600, 50-600, 75-600, 100-600, 125-600, 150-600, 175-600, 200-600, 225-600, 250-600, 275-600, 300-600, 325-600, 350-600, 375-600, 400-600, 425-600, 450-600, 475- 600, 500-600, 525-600, 550-600, 575-600, 1-575, 25-575, 50-575, 75-575, 100- 575, 125-575, 150-575, 175-575, 200-575, 225-575, 250-575, 275-575, 300-575, 325-575, 350-575, 375-575, 400-575, 425-575, 450-575, 475-575, 500- 575, 525-575, 550-575, 1-500, 25-550, 50-550, 75-550, 100-550, 125-550, 150-550, 175-550, 200-550, 225-550, 250-550, 275-550, 300-550, 325-550, 350-550, 375-550, 400-550, 425-550, 450-550, 475-550, 500-550, 525-550, 1- 525, 25-525, 50-525, 75-525, 100-525, 125-525, 150-525, 175-525, 200-525, 225-525, 250-525, 275-525, 300-525, 325-525, 350-525, 375-525, 400-525, 425-525, 450-525, 475-525, 500-525, 1-500, 25-500, 50-500, 75-500, 100- 500, 125-500, 150-500, 175-500, 200-500, 225-500, 250-500, 275-500, 300-500, 325-500, 350-500, 375-500, 400-500, 425-500, 450-500, 475-500, 1-475, 25-475, 50-475, 75-475, 100-475, 125-475, 150-475, 175-475, 200-475, 225- 475, 250-475, 275-475, 300-475, 325-475, 350-475, 375-475, 400-475, 425-475, 450-475, 1-450, 25-450, 50-450, 75-450, 100-450, 125-450, 150-450, 175-450, 200-450, 225-450, 250-450, 275-450, 300-450, 325-450, 350-450, 375-450, 400-450, 425-450, 1-425, 25-425, 50-425, 75-425, 100-425, 125- 425, 150-425, 175-425, 200-425, 225-425, 250-425, 275-425, 300-425, 325-425, 350-425, 375-425, 400-425, 1-400, 25-400, 50-400, 75-400, 100-400, 125-400, 150-400, 175-400, 200-400, 225-400, 250-400, 275-400, 300-400, 325- 400, 350-400, 375-400, 1-375, 25-375, 50-375, 75-375, 100-375, 125-375, 150-375, 175-375, 200-375, 225-375, 250-375, 275-375, 300-375, 325-375, 350-375, 1-350, 25-350, 50-350, 75-350, 100-350, 125-350, 150-350, 175- 350, 200-350, 225-350, 250-350, 275-350, 300-350, 325-350, 1-325, 25-325, 50-325, 75-325, 100-325, 125-325, 150-325, 175-325, 200-325, 225-325, 250-325, 275-325, 300-325, 1-300, 25-300, 50-300, 75-300, 100-300, 125- 300, 150-300, 175-300, 200-300, 225-300, 250-300, 275-300, 1-275, 25-275, 50-275, 75-275, 10-275, 125-275, 150-275, 175-275, 200-275, 225-275, 250-275, 1-250, 25-250, 50-250, 75-250, 100-250, 125-250, 150-250, 175- 250, 20-250, 225- 250, 1-225, 25-225, 50-225, 75-225, 100-225, 125-225, 150-225, 175-225, 200-225, 1-200, 25-200, 50-200, 75-200, 100-200, 125-200, 150-200, 175-200, 1-175, 25-175, 50-175, 75-175, 100-175, 125-175, 150-175, 1- 150, 25-150, 50-150, 75-150, 100-150, 125-150, 1-125, 25-125, 50-125, 75-125, 100-125, 1-100, 25-100, 50-100, 75-100, 1-75, 25-75, 50-75, 1-50, 25-50 and / or 1-25 of SEQ ID NO: 18. In certain preferred embodiments, the polynucleotides of the present invention comprise, or alternatively consist of, the nucleotide residues of 400-627, 425-627, 450-627, 475-627, 500-627, 525-627, 550-627 , 575-627, 600-627, 400-600, 425-600, 450-600, 475-600, 500-600, 525-600, 550-600, 575-600, 400-575, 425-575, 450 -575, 475-575, 500-575, 525-575, 550-575, 400-550, 425-550, 450-550, 475-550, 500-550, 525-550, 400-500, 425-500 , 450-500, 475-500, 400-475, 425-475, 450-475, 400-450, 425-450, 571-800, 600-800, 625-800, 650-800, d ^ S-dOO , 700-800, 725-800, 750-800, 775-800, 571-775, 600-775, 625-775, 650-775, 675-775, 700-775, 725-775, 750-775, 571 -750, 600-750, 625-750, 650-750, 675-750, 700-750, 725-750, 571-725, 600-725, 625-725, 650-725, 675-725, 700-725 , 571-700, 600-700, 625-700, 650-700, 675-700, 571-675, 600-675, 625-675, 650-675, 571-650, 600-650, 625-650, 571 -625, 600-625 and / or 571-600 of SEQ ID NO: 1. In additional preferred embodiments, the polynucleotides of the present invention comprise, or alternatively consist of, the nucleotide residues of 147-500, 147-450, 147-400, 147-350, 200-500, 200-450, 200-400, 200-350, 250-500 , 250-450, 250-400, 250-350, 300-500, 300-450, 300-400, 300-350, 350-750, 350-700, 350-650, 350-600, 350-550, 400 -750, 400-700, 400-650, 400-600, 400-550, 425-750, 425-700, 425-650, 425-600, 425-550, 450-1020, 450-1001, 450-950 , 450-900, 450-850, 450-800, 450-775, 500-1001, 500-950, 500-900, 500-850, 500-800, 500-775, 550-1001, 550-950, 550-900, 550-850, 550-800, 550 -775, 600-1001, 600-950, 600-900, 600-850, 600-800, 600-775, 650-1001, 650-950, 650-900, 650-850, 650-800, 650-775 , 700-1001, 700-950, 700-900, 700-850, 700-800, 700-775, 825-1082, 850-1082, 875-1082, 900-1082, 925-1082, 950-1082, 975 -1082, 1000-1082, 1025-1082 and / or 1050-1082 of SEQ ID NO: 1. Preferably, the polynucleotide fragments of the present invention code for a polypeptide that demonstrates a functional activity of neutrocine-alpha and / or neutrocin-alfaSV. The term "a polypeptide demonstrating" functional activity "means a polypeptide capable of displaying one or more known functional activities associated with a full-length and / or secreted neutral-alpha and / or neutrocine-alphaSV polypeptide. Such functional activities include, but are not limited to biological activity (eg, ability to stimulate proliferation, survival, differentiation and / or activation of B cells), antigenicity [ability to bind (or compete with a neutrokine-alpha polypeptide and / or neutrocine-alphaSV by binding) to an antineutrocin-alpha antibody and / or antineutrocin-alphaSV], immunogenicity (ability to generate antibodies that bind to a neutrocine-alpha and / or neutrocine-alphaSV polypeptide), ability to form multimers with neutrokine-alpha and / or neutrocin-alphaSV polypeptides of the present invention and ability to bind to a receptor or ligand of the neutrocine-alpha and / or neutrocine-alphaSV polypeptide. In additional specific embodiments, the polynucleotide fragments of the present invention encode a polypeptide comprising, or alternatively consisting of, the predicted intracellular domain (amino acids 1 through 46 of SEQ ID NO: 2), the predicted transmembrane domain (amino acids from 47 to 72 of SEQ ID NO: 2), the predicted extracellular domain (amino acids 73 to 285 of SEQ ID NO: 2) or the predicted conserved TNF domain (amino acids 191 to 284 of SEQ ID NO: 2 ) of neutrocine-alpha. In additional embodiments, the polynucleotide fragments of the present invention encode a peptide comprising, or alternatively consisting of, any combination of 1, 2, 3 or the above-mentioned 4 domains. The polypeptides encoded by these polynucleotides are also encompassed by the present invention. In additional specific embodiments, the polynucleotide fragments of the present invention encode a polypeptide comprising, or alternatively consisting of, the predicted intracellular domain (amino acids 1 to 46 of SEQ ID NO: 19), the predicted transmembrane domain (amino acids from 47 to 72 of SEQ ID NO: 19), the predicted extracellular domain (amino acids 73 to 266 of SEQ ID NO: 19) or the predicted conserved TNF domain (amino acids 72 to 265 of SEQ ID NO: 19 ) of neutrocin-alfaSV. In further embodiments, the polynucleotide fragments of the present invention encode a polypeptide comprising, or alternatively consisting of, any combination of 1, 2, 3 or the above-mentioned 4 domains. The polypeptides encoded by these polynucleotides are also encompassed by the present invention. In another embodiment, the polynucleotide fragments of the present invention comprise, or alternatively consist of, polynucleotides that encode an amino acid sequence that is selected from residues Met-1 through Lys-113, Leu-114 through Thr-141, Ile -142 to Lys-160, Gly-161 to Gln-198, Val-199 to Ala-248 and Gly-250 to Leu-285 of SEQ ID NO: 2. In addition, the polynucleotides that code for any combination of two, three, four, five or more of these amino acid sequences are also encompassed by the present invention. The polypeptides encoded by these polynucleotides are also encompassed by the present invention. In another embodiment, the polynucleotide fragments of the present invention comprise or alternatively consist of polynucleotides that encode an amino acid sequence that is selected from the residues of Met-1 through Lys-113., Leu-114 to Thr-141, Gly-142 to Gln-179, Val-180 to Ala-229 and Gly-230 to Leu-266 of SEQ ID NO: 19. In addition, the polynucleotides that code for any combination of two, three, four, five or more of these amino acid sequences are also encompassed by the present invention. The polypeptides encoded by these polynucleotides are also encompassed by the present invention. In another embodiment, the polynucleotide fragments of the present invention comprise or alternatively consist of, polynucleotides that encode an amino acid sequence that is selected from the residues of Met-1 to Lys-106, Leu-107 to Thr-134, Glu -135 to Asn-165, Ile-167 to Lys-184, Gly-185 to Gln-224, Val-225 to Ala-272 and Gly-273 to Leu-309 of SEQ ID NO: 23. In addition, the polynucleotides which code for any combination of two, three, four, five or more of these amino acid sequences are also encompassed by the present invention. The polypeptides encoded by these polynucleotides are also encompassed by the present invention. In another embodiment, the polynucleotide fragments of the present invention comprise or alternatively consist of polynucleotides encoding - for an amino acid sequence that is selected from the residues of Tyr-1 to Lys-47, Leu-48 to Thr-75, Ile-76 to Lys-94, Gly-95 to Gln-132, Val-133 to Ala -182 and Gly-183 to Ala-219 of SEQ ID NO: 28. In addition, polynucleotides that code for any combination of two, three, four, five or more of these amino acid sequences are also encompassed by the present invention . The polypeptides encoded by these polynucleotides are also encompassed by the present invention. In another embodiment, the polynucleotide fragments of the present invention comprise or alternatively consist of polynucleotides that encode an amino acid sequence that is selected from the residues of Tyr-1 to Lys-47, Leu-48 to Thr-75, Ile- 76 to Lys-94, Gly-95 to Gln-132, Val-133 to Ala-182 and Gly-183 to Ala-219 of SEQ ID NO: 30. In addition, the polynucleotides that code for any combination of two, three , four, five or more of these amino acid sequences are also encompassed by the present invention. The polypeptides encoded by these polynucleotides are also encompassed by the present invention. In another embodiment, the polynucleotides of the present invention comprise, or alternatively consist of, the sequence shown in SEQ ID NO: 21. This sequence shown as SEQ ID NO: 21 encodes a polypeptide consisting of an initial methionine residue bound to the Ala-134 to Leu-285 residues of the neutrokine-alpha polypeptide sequence shown as SEQ ID NO: 2. The polypeptides encoded by these polynucleotides are also encompassed by the present invention. In certain preferred additional embodiments, the polynucleotides of the present invention comprise, or alternatively consist of, the nucleotide residues of 1-459, 15-459, 30-459, 45-459, 60-459, 75-459, 90-459 , 105-459, 120-459, 135-459, 150-459, 165-459, 180-459, 195-459, 210-459, 225-459, 240-459, 255-459, 270-459, 285 -459, 300-459, 315-459, 330-459, 345-459, 360-459, 375-459, 390-459, 405-459, 420-459, 435-459, 450-459, 1-450 , 15-450, 30-450, 45-450, 60-450, 75-450, 90-450, 105-450, 120-450, 135-450, 150-450, 165-450, 180-450, 195 -450, 210-450, 225-450, 240-450, 255-450, 270-450, 285-450, 300-450, 315-450, 330-450, 345-450, 360-450, 375-450 , 390-450, 405-450, 420-450, 435-450, 1-435, 15-435, 30-435, 45-435, 60-435, 75-435, 90-435, 105-435, 120 -435, 135-435, 150-435, 165-435, 180-435, 195-435, 210-435, 225-435, 240-435, 255-435, 270-435, 285-435, 300-435 , 315-435, 330-435, 345-435, 360-435, 375-435, 390-435, 405-435, 420-435, 1-420, 15-420, 30-420, 45-420, 60 -420, 75-420 , 90-420, 105-420, 120-420, 135-420, 150-420, 165-420, 180-420, 195-420, 210-420, 225-420, 240-420, 255-420, 270 -420, 285-420, 300-420, 315-420, 330-420, 345-420, 360-420, 375-420, 390-420, 405-420, 1-405, 15-405, 30-405 , 45-405, 60-405, 75-405, 90-405, 105-405, 120-405, 135-405, 150-405, 165-405, 180-405, 195-405, 210-405, 225 -405, 240-405, 255-405, 270-405, 285-405, 300-405, 315-405, 330-405, 345-405, 360-405, 375-405, 390-405, 1-390 , 15-390, 30-390, 45-390, 60-390, 75-390, 90-390, 105-390, 120-390, 135-390, 150-390, 165-390, 180-390, 195 -390, 210-390, 225-390, 240-390, 255-390, 270-390, 285-390, 300-390, 315-390, 330-390, 345-390, 360-390, 375-390 , 1-375, 15-375, 30-375, 45-375, 60-375, 75-375, 90-375, 105-375, 120-375, 135-375, 150-375, 165-375, 180 -375, 195-375, 210-375, 225-375, 240-375, 255-375, 270-375, 285-375, 300-375, 315-375, 330-375, 345-375, 360-375, 1-360, 15-360, 30-360, 45-360, 60-360, 75-360, 90-360, 105-360, 120-360, 135-360, 150-360, 165- 360, 180-360, 195-360, 210-360, 225-360, 240-360, 255-360, 270-360, 285-360, 300-360, 315-360, 330-360, 345-360, 1-345, 15-345, 30-345, 45-345, 60-345, 75-345, 90-345, 105-345, 120-345, 135-345, 150-345, 165-345, 180- 345, 195-345, 210-345, 225-345, 240-345, 255-345, 270-345, 285-345, 300-345, 315-345, 330-345, 1-330, 15-330, 30-330, 45-330, 60-330, 75-330, 90-330, 105-330, 120-330, 135- 330, 150-330, 165-330, 180-330, 195-330, 210- 330, 225-330, 240-330, 255-330, 270-330, 285-330, 300-330, 315-330, 1-315, 15-315, 30-315, 45-315, 60-315, 75-315, 90-315, 105-315, 120-315, 135-315, 150- 315, 165-315, 180-315, 195-315, 210-315, 225-315, 240-315, 255-315, 270-315, 285-315, 300-315, 1-300, 15-300, 30-300, 45-300, 60-300, 75-300, 90-300, 105-300, 120-300, 135-300, 150-300, 165-300, 180-300, 195-300, 210-300, 225-300, 240-300, 255-300, 270-300, 285-300, 1-285, 15-285, 30-285, 45- 285, 60-285, 75-285, 90-285, 105-285, 120-285, 135-285, 150-285, 165-285, 180-285, 195-285, 210-285, 225-285, 240-285, 255-285, 270-285, 1-270, 15-270, 30-270, 45-270, 60-270, 75-270, 90-270, 105-270, 120-270, 135- 270, 150-270, 165-270, 180-270, 195-270, 210-270, 225-270, 240-270, 255-270, 1-255, 15-255, 30-255, 45-255, 60-255, 75-255, 90-255, 105-255, 120-255, 135-255, 150-255, 165-255, 180-255, 195-255, 210-255, 225-255, 240- 255, 1-240, 15-240, 30-240, 45-240, 60-240, 75-240, 90-240, 105-240, 120-240, 135-240, 150-240, 165-240, 180-240, 195-240, 210-240, 225-240, 1-225, 15-225, 30-225, 45-225, 60-225, 75-225, 90-225, 105-225, 120- 225, 135-225, 150-225, 165-225, 180-225, 195-225, 210-225, 1-210, 15-210, 30-210, 45-210, 60-210, 75-210, 90-210, 105-210, 120-210, 135-210, 150-210, 165-210, 180-210, 195-210, 1-195, 15-195, 30-195, 45-195, 60- 195, 75-195, 90-195, 105-195, 120- 195, 135-195, 150-195, 165-195, 180-195, 1-180, 15-180, 30-180, 45-180, 60-180, 75-180, 90-180, 105-180, 120-180, 135-180, 150-180, 165-180, 1-165, 15-165, 30-165, 45-165, 60-165, 75-165, 90-165, 105-165, 120- 165, 135-165, 150-165, 1-150, 15-150, 30-150, 45-150, 60-150, 75-150, 90-150, 105-150, 120-150, 135-150, 1-135, 15-135, 30-135, 45-135, 60-135, 75-135, 90-135, 105-135, 120-135, 1-120, 15-120, 30-120, 45- 120, 60-120, 75-120, 90-120, 105-120, 1-105, 15-105, 30-105, 45-105, 60-105, 75-105, 90-105, 1-90, 15-90, 30-90, 45-90, 60-90, 75-90, 1-75, 15-75, 30-75, 45-75, 60-75, 1-60, 15-60, 30- 60, 45-60, 1-45, 15-45, 30-45, 1-30 and / or 15-30 of SEQ ID NO: 21. Polypeptides encoding these polynucleotides are also encompassed by the present invention. Accordingly, specific embodiments of the present invention relate to polynucleotides encoding polypeptides comprising, or alternatively consisting of, the amino acid sequence of the sheet region beta A, A ', B, B', C, D, E, F, G or H described in Figures 7A-I-7A-II and described in Example 6. Additional embodiments of the present invention relate to polynucleotides encoding neutrokine-alpha polypeptides comprising, or alternatively consisting of , any combination of 1, 2, 3, 4, 5, 6, 7, 8, 9 or the 10 beta sheet regions AH described in Figures 7A-I-7A-II and described in Example 6. Additional Preferred Modalities of the present invention, refer to polypeptides comprising or alternatively consisting of, the amino acid sequence of neutrocin-alpha of the leaf region beta A, A ', B, B', C, D, E, F, G or H are described in Figures 7A-I-7A-II and described in Example 6. Addition Modalities of the present invention refer to neutrokine-alpha polypeptides comprising or alternatively consisting of, any combination of 1, 2, 3, 4, 5, 6, 7, 8, 9 or the 10 regions of beta sheet A to H described in Figures 7A-I-7A-II and described in Example 6. In certain other preferred embodiments, the polynucleotides of the present invention comprise, or alternatively consist of, the nucleotide residues of 34-57, 118-123 , 133-141, 151-159, 175-216, 232-255, 280-315, 328-357, 370-393 and / or 430-456 of SEQ ID NO: 21. The polypeptides encoded by these polynucleotides are also encompassed by the present invention. These polynucleotide and polypeptide fragments correspond to the predicted beta sheet regions shown in Figures 7A-I-7A-II. In certain embodiments, the polynucleotides of the present invention comprise, or alternatively consist of, a polynucleotide sequence having at least 90, 95, 96, 97, 98 or 99% identity to the polynucleotide sequence encoding one, two, three, four, five, six, seven, eight, nine or the ten beta sheet regions described above. The present invention also encompasses polynucleotide sequences fused to a heterologous polynucleotide sequence. The polypeptides encoded by these polynucleotide sequences are also encompassed by the present invention. In another embodiment, the present invention provides an isolated nucleic acid molecule comprising a polynucleotide that hybridizes, under stringent hybridization conditions, to one, two, three, four, five, six, seven, eight, nine or all ten polynucleotides of beta sheet of the present. invention described above. The meaning of the phrase "strict conditions" as used herein is described below. In further preferred embodiments, the polynucleotides of the present invention comprise, or alternatively consist of, nucleotide residues 576 through 599, 660-665, 675-683, 693-701, 717-758, 774-803, 822-857, 870-899, 912-935 and / or 972-998 of SEQ ID NO: 1. The polypeptides encoded by these polynucleotide fragments are also encompassed by the present invention. These polynucleotide and polypeptide fragments correspond to the predicted beta sheet regions shown in Figures 7A-I-7A-II. In additional preferred embodiments, the polynucleotides of the present invention comprise, or alternatively consist of, the nucleotide residues from 457 to 462, 472-480, 490-498, 514-555, 571-600, 619-654, 667-696 , 699-732 and / or 769-795 of SEQ ID NO: 18. Polypeptides encoded by these polynucleotide fragments are also encompassed by the present invention. These polynucleotide and polypeptide fragments correspond to the predicted beta sheet regions shown in Figures 7A-I-7A-II. In yet further preferred embodiments, the polynucleotides of the present invention comprise, or alternatively consist of, the nucleotide residues of 124 to 129, 139-147, 157-165, 181-222, 238-267, 286-321, 334- 363, 376-399 and / or 436-462 of SEQ ID NO: 22. Polypeptides encoded by these polynucleotide fragments are also encompassed by the present invention. These polynucleotide and polypeptide fragments correspond to the predicted beta sheet regions shown in Figures 7A-I-7A-II. Polypeptides comprising or alternatively consisting of the amino acid sequence of any combination of one, two, three, four, five, six, seven, eight, nine, ten or all of these regions are encompassed by the present invention. The relative positions of several intron / exon boundaries were determined for murine neutrocine-alpha (SEQ ID NO: 22 and SEQ ID NO: 23) based on the sequence analysis of murine genomic DNA. The second exon apparent from the 5 'end of the murine neutrocine-alpha genomic clone (preliminarily designated as "exon 2"), consists of Tyr-187 to Gln-222 of the sequence shown in SEQ ID NO: 23. The third apparent exon from the 5 'end of the genomic clone of murine neutrocine-alpha (preliminarily designated as "exon 3") comprises Val-223 to Gly-273 of the sequence shown in SEQ ID NO: 23. Thus , in one embodiment, the present invention provides polynucleotides that encode polypeptides comprising or alternatively consist of, the amino acid sequence of residues Tyr-187 to Gln-222 of SEQ ID NO: 23. The present invention also relates to nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide sequence having at least 80, 85, 90, 95, 96, 97, 98 or 99% identity with the polynucleotide sequence encoding the neutrokin polypeptides -alfa died previously described. The present invention also encompasses the above polynucleotide sequences fused to a heterologous polynucleotide sequence. The polynucleotides encoded by these nucleic acids and / or polynucleotide sequences are also encompassed by the present invention. In another embodiment, the present invention provides polynucleotides that encode polypeptides that comprise, or alternatively consist of, the amino acid sequence of residues Val-223 to Gly-273 of SEQ ID NO: 23. The present invention also relates to nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide sequence having at least 80, 85, 90, 95, 96, 97, 98 or 99% identity with the polynucleotide sequence encoded by the neutrocyte polypeptides murine alpha previously described. The present invention also encompasses the above polynucleotide sequences fused to a heterologous polynucleotide sequence. Polypeptides encoded by these nucleic acids and / or polynucleotide sequences, they are also encompassed by the present invention. In addition, the relative positions of the corresponding intron / exon boundaries were determined for human neutrokine-alpha (SEQ ID NO: 1 and SEQ ID NO: 2), based on an alignment of the sequences of murine neutrocytoma-alpha polypeptides and humans. The second exon apparent from the 5 'end of human neutrokine-alpha (also preliminarily designated as "exon 2"), consists of Tyr-163 to Gln-198 of the sequence shown in SEQ ID NO: 2. The third exon apparent from the 5 'end of human neutrokine-alpha (also preliminarily designated as "exon 3") comprises Val-199 to Gly-249 of the sequence shown in SEQ ID NO: 2. Thus, in one embodiment, The present invention provides polynucleotides encoding peptides comprising, or alternatively consisting of, the amino acid sequence of residues Tyr-163 through Gln-198 of SEQ ID NO: 2. The present invention also relates to - - nucleic acid comprising, or alternatively consisting of, a polynucleotide sequence having at least 80, 85, 90, 95, 96, 97, 98 or 99% identity with the polynucleotide sequence encoding the neutrokine-alpha polypeptides previously described. The present invention also encompasses the above polynucleotide sequences fused to a heterologous polynucleotide sequence. Polypeptides encoded by these nucleic acids and / or polynucleotide sequences are also encompassed by the present invention. In another embodiment, the present invention provides polynucleotides that encode polypeptides that comprise, or alternatively consist of, the amino acid sequence of residues Val-199 to Gly-249 of SEQ ID NO: 2. The present invention also relates to nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% identity with the polynucleotide sequence encoding the neutrophil polypeptides alpha previously described. The present invention also encompasses the above polynucleotide sequences fused to a heterologous polynucleotide sequence. Polypeptides encoded by these amino acids and / or polynucleotide sequences are also encompassed by the present invention. The functional activity of the neutrokine-alpha and / or neutrocine-alphaSV polypeptides, and fragments, variant derivatives and analogs thereof, can be tested by various methods such as those described herein and as are known in the art. For example, in a modality in which the ability to bind or compete with the neutrokine-alpha and / or neutrokine-alphaSV full-length polypeptide is evaluated by binding with an antineutrocin-alpha and / or antineutrocin-alphaSV antibody or by binding to the neutrokine-alpha and / or neutrocine-alphaSV receptor or receptors in B cells, various immunoassays known in the art can be used, including but not limited to competitive and non-competitive assay systems, employing techniques such as radioimmunoassay, ELISA, (enzyme-linked immunosorbent assay), "sandwich" immunoassays, uniradiometric assays, gel diffusion precipitation reactions, immunodiffusion assays, immunoassays in itself (using colloidal gold, enzymes or radioisotopic labels, for example), Western-type immunoblotting, precipitation reactions, agglutination assays (eg, gel agglutination assays, hemagglutination assays) n) assays - - complement fixation assays, immunofluorescence assays, protein A assays, and immunoelectrophoresis and so forth. In one embodiment, the binding of the antibody is detected by detecting a tag in the primary antibody. In another embodiment, the primary antibody is detected by detecting the binding of a secondary antibody or reagent to the primary antibody. In an additional mode, the secondary antibody is labeled. Numerous mechanisms are known in the art to detect binding in an immunoassay and are within the scope of the present invention. In another embodiment, when a neutrokine-alpha and / or neutrocin-alphaSV ligand is identified, or when the ability of a polypeptide fragment, variant or derivative of the present invention to be multimerized is identified, the binding can be assayed, eg, by means known in the art such as for example gel chromatography under reducing or non-reducing conditions, protein affinity chromatography and affinity immunoblotting. See generally Phizicky, E., et al. , 1995, Microbiol. Rev. 59: 94-123. In another embodiment, the physiological correlation of the binding of neutrokine-alpha and / or neutrocine-alphaSV with its substrate (signal transduction) can be tested. In addition, the assays described herein (see, Examples 6 and 7) and others known in the art can be routinely applied to measure the capacity of the neutrokine-alpha and / or neutrocine-alphaSV polypeptides and fragments, variant derivatives and analogs thereof, to induce the biological activity related to neutrokine-alpha and / or neutrocine-alphaSV (eg, to stimulate or alternatively inhibit (in the case of neutrokine-alpha and / or neutrocine-alphaSV antagonists) proliferation , differentiation and / or activation of B cells, and / or to extend the survival of B cells in vi tro or in vivo). Other methods will be known to those skilled in the art and are within the scope of the present invention. In additional embodiments, the polynucleotides of the present invention encode for polypeptides comprising, or alternatively consisting of, functional attributes of neutrokine-alpha and neutrocin-alphaSV. Preferred embodiments of the present invention in this regard include fragments comprising or alternatively consisting of the alpha helix region and the alpha helix forming region ("alpha regions"), the beta sheet and the beta sheet forming regions ("regions"). beta "), the torsion region and the torsion-forming regions (" torsion regions "), the helical region and the helix-forming regions (" helical regions "), hydrophilic regions, hydrophobic regions, amphipathic alpha regions, regions amphipathic beta, flexible regions, surface-forming regions, and regions of high antigenic index of the neutrocine-alpha and neutrocin-alphaSV polypeptides. It is thought that one or more of the beta-sheet regions of neutrokine-alpha described in Figures 7A-I-7A-II is important for dimerization and also for the interactions between neutrocin-alpha and its ligands. Certain preferred regions in this regard are presented in Figure 3 (Table I). The data presented in Figure 3 and those presented in Table I, only present a different format from the same results obtained when the amino acid sequence of SEQ ID NO: 2 is analyzed using the default parameters of the DNA * computer algorithm. STAR. The above-mentioned preferred regions set forth in Figure 3 and Table I include, but are not limited to, regions of the aforementioned types identified by analysis of the amino acid sequence set forth in Figures IA and IB. As presented in Figure 3 and Table I, such preferred regions include the Garnier-Robson alpha regions, beta regions, torsion regions and helical regions, Chou-Fasman alpha regions, beta regions and helical regions, regions Kyte-Doolittle hydrophilic and hydrophobic regions, Eisenberg alpha regions and amphipathic beta regions, Karplus-Zchulz flexible regions, Emini surface-forming regions and Jameson-Wolf regions of high antigenic index. Among the highly preferred polynucleotides in this regard, there are those that code for polypeptides comprising, or alternatively consist of, neutrokine-alpha and / or neutrocin-alphaSV regions that combine several structural characteristics, such as several (e.g. 1, 2, 3 or 4) of the above-stated characteristics. The polypeptides encoded by the polynucleotides are also encompassed by the present invention. Additionally, the data presented in columns VIII, IX, XIII and XIV of Table I, can routinely be used to determine regions of neutrocin-alpha that exhibit a high degree of antigenicity potential (column VIII of Table I represents Hydrophobicity according to Kyte-Doolittle; column IX of Table I represents hydrophobicity in accordance with Hopp-Woods; column XIII of Table I represents the antigenic index according to Jameson-Wolf and column XIV of Table I represents the surface probability in accordance with Emini). The regions of high antigenicity are determined from the data presented in columns VIII, IX, XIII and / or IV, by selecting values representing regions of the polypeptide that are likely to be exposed on the surface thereof, in an environment in which which can occur the recognition of the antigen in the process of initiation of an immune response. The data presented in Figure 6 can also be presented routinely in a similar tabular format, simply by examining the amino acid sequence described in Figure 6 (SEQ ID NO: 19), using the modules and algorithms of the DNA * STAR, with the default parameters. As before, the amino acid sequence presented in Figure 6 also can be used to determine regions of neutrocin-alpha that exhibit a high degree of antigenicity potential, either in the form of a figure (as in Figure 6), or in the form of a table (such as in Table I). twenty _______ M_MÉiÉÉ Table I fte *. Position I II III IV VI VII VII IX XI XII XIII XIV Mel 1 A 0 73 -071 0 95 1 39 Asp 2 A T 1 12 -066 1 15 1 56 Asp 3 A T 1 62 -109 '15 2 12 Ser 4 A T 2 01 -1-51 i 15 4 19 Thr 5 A T 2 40 -213 F 1 30 4 35 Glu 6 A A 2 70 -173 F 0 90 4 51 Arg 7 A A 2 81 -134 F 0 90 4 51 Glu 8 A A 2 00 -173 F 090 6 12 Gln 9 A A 1 99 -153 F 0 90 2 91 Ser 10 A B 2 00 -I 04 F 0 90 2 15 Arg 1 1 A B 1 33 • 066 F 0 90 1 66 Leu 12 A B 041 -009 F 045 051 Thr 13 A B 046 020 F -0 15 0 32 Ser 14 A A 0 50 -019 0 30 0 32 Cys 15 A A 0 91 -019 0 30 0 7S Leu 16 A A 080 -087 F 0 90 1 Ob Lvs 17 A A 161 -136 F 090 1 37 Lys 18 A A 132 -174 F 0 90 4 44 Arg 19 A A 167 -170 F 0 90 5 33 Glu 20 A A 152 -239 F 0 90 5? Glu 21 A A 238 -170 F 0 90 2 20 Met 2 * > A A 233 -170 F 0 90 2 24 Lys 23 A A 162 -170 F 0 90 2 24 Leu 24 A A 066 -113 F 0 75 0 69 Lys 25 A A 036 -049 F 045 052 Glu 26 A A B -053 -071 0 60 0 35 Cys 27 A A B -074 -003 0 30 0 30 Val 28 A A B -100 -003 0 30 0 12 Ser 29 A A B -008 040 -030 0 1 1 I have 30 A B -008 040 -0 30 040 Leu 31 A B -008 -017 045 1 08 Pro 32 B 029 -081 F 1 10 1 39 Arg 33 T 09- * -081 F 1 50 2 66 Lvs 34 T 093 -107 F 1 84 4 98 Glu 35 c 097 -137 F 1 9S 4 32 Ser 36 T c 189 -116 F 2 52 1 64 Pro 37 T c 180 -116 F 2 86 1 60 Ser 38 T 139 -077 F 3 40 1 24 Val 39 A t 139 -039 F 2 36 1 24 Arg 40 A 139 -077 F 2 46 1 60 Ser 41 A 134 -120 F 2 46 2 00 Ser 42 T T 160 -116 F 3 06 2 67 Lvs 43 T T 109 -180 F 3 06 2 72 Asp 44 T T 1 13-I 11 F 3 40 I 67.

Gly 45 A T 043 -081 F 2 66 1 03 Lys 46 A A 014 -070 F 1 77 0 52 Leu 47 A A or p -020 0 98 0 31 Leu 48 A A -072 029 004 046 Wing 49 A A -153 0S4 -060 0 19 Wing 50 A A -200 1 23 -0 60 0 19 Thr 51 A A -263 1 23 -060 0 19 Leu 52 A A -263 1 04 -060 0 19 Leu 53 A A -263 1 23 -0 60 0 15 Leu S4 A A -234 1 41 -060 0 09 A1J 55 A A -242 1 31 -060 0 14 Leu 56 A A -278 1 0 -060 009 Leu 57 A -278 1 09 -0 20 006 o o > > > > > > > > > > > > > > > > > > > > > > > > > > > . > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > • ¡H H H H -. -i H o o O - O O O O O -n-n -t? -nt? -p -p "pt? -pt? -? -p oooooooo? pppww 4» 'fc oopopppp .- p - - OOOOOOO 0>?? o?? iJ WW Í4 i J (O -. - O -i 4 - O -1 4- - VO UJ OO OO OO vO IJ i JU *? UJ '- " ? o o 7_ c. zr r < n rz < ~ a _t! _ - - - < __ _. > = r or r 0 > 0 H < H 00 '00 < > > ____ 3 lQ - »3 3 * - '-' 3, < -: < O t_) O O c o or > c M ^ J s > and > t > > > > > > J. > > > > > > > > > > > J > > > DO 03 TO CD 0O O3 O0 00 C-. 0D CO 00 00 CB CD H -i H H -i -i -i -i H H H -. -i -H H -í -J H -. H -. -. -i -.-.-! -. H -. -I -. - -. H -I -I H H H o r¡ ¿-.::: ooooooo- - o o o o o o c o o -p -Ti -n -p -p -p -p -n ti "ti" ti "pt? * pt? t? * ti • 71 -n -p -n -p -ti t? -t? TÍ - n -n -n -n OOOOO W O * O1 or ^ t o »X v. o o o. . o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o - o - - Table I (continued) = i Position III iv VI Vil VIII IX XI XII XIII XIV Ter 171 019 046 020 071 Phe 172 T 010 -003 180 085 Lys 173 TT -020 -033 F 260 138 Arg 174 TC -020 -051 F 300 104 GW 175 TC 061 -021 F 225 09O Ser 176 AT 091 -100 F 205 086 Wing 177 AA 166 -100 F 1 i5 076 Leu 178 AA 161 -100 F 120 154 Glu 179 AA 150 -143 F 090 198 siu 180 AA 189 -141 F 090 316 Lys 181 A A 130 -191 F 090 766 Glu 182 A A IOS -191 F 090 310 Asn 183 A A 103 -123 F 090 14S Lys 184 A A 108 -059 F 075 055 lie 185 A A 108 -059 060 0 b '" Leu 18b A A 072 -059 060 068 Val 187 A A 038 -050 030 0 4 Lvs 188 A A 013 -007 F 045 069 Glu 189 A T -061 000 F 040 132 Thr 1 0 T T -042 010 F OSO 154 Gly 191 T T -050 024 F 065 067 Tvr 192 T T 011 093 020 027 Phe 193 B B -028 169 -060 029 Phe 194 B B -02S 163 -060 029 He 195 B B -082 160 -060 032 Tyr 196 B B -129 1 9 -060 028 Gly 197 B T -129 139 -020 026 Gln 198 B T -090 136 -020 059 Val 199 B C -020 1 16 -040 054 Leu 200 B C 073 040 -010 092 Tyr 201 T T 067 -003 125 106 Thr 202 T T 077 006 F 080 206 Asp 203 T T 018 017 F 080 391 Lvs 204 A T 041 -001 F 100 252 Thr 205 A A 090 -016 F 060 173 Tvr 206 A A 111 -021 045 103 Wing 207 A A 061 029 -030 070 Mel 208 A A -028 097 -060 04U Glv 209 A A B -032 117 -060 018 His 210 A A B 010 081 -060 031 Leu 211 A A B 039 031 -030 061 lie 212 A A B 102 -030 045 122 Gln 213 A A B 077 -073 075 180 Arg 214 A A B 108 -059 F 090 162 Lv¡ 215 A A B 026 -077 F 090 314 Lys 216 A A B 037 -081 F 090 135 Val 217? B B 091 -043 030 060 His 218 A B B 091 -000 030 029 Val 219 A B B 080 -000 030 025 Phe 220 B B -006 -000 030 0.57 Gly 221 A B -040 004 -030 035 Asp 222 A -036 -007 050 063 Glu 223 A -1 18 -003 050 060 Leu 224 A B -063 -017 030 045 Ser 225 A B -074 -011 030 039 Leu 226 A B -1 10 057 -060 018 Val 227 A B -099 136 -060 019 r; ** í? fi? D5c? »N oo o o o o o o o -, ooo o p o o o o o. _ or soo ooooso U.ULU.U-IJLU. __. U-U- u. or. or. or. or. or. U. U.U. or. . . or. or. X O ¡- S- H H I- f- f- HH-h H- or I- H H f- H (- H H- I- Hr-f- < < < < < < - < < < < < < < < < < < < < _ < < < < < < < < < < < < < < < < < < < < < < r < < < < < < < < < < < • * "< - < < < < • or to H U H I? O _ 5? P = .- 3! ^? ? ? rt 3 »? 3 3 A < U = O < S £ O H -. < < or. UH < ? < = _. _) 000 < 0 _) 0 < __\ to. < < < l-. = (? _l <0 < > -1-. K 4 J J 4 c-i - Additional preferred nucleic acid fragments of the present invention include nucleic acid molecules comprising, or alternatively consisting of, a sequence encoding one or more epitope-bearing regions of neutrocin-alpha. In particular, such nucleic acid fragments of the present invention include nucleic acid molecules that comprise or alternatively consist of a sequence encoding a polypeptide that is selected from the group consisting of: from about Phe-115 to about Leu-147, from about Ile-150 to about Tyr-163, from about Ser-171 to about Phe-194, from about Glu-223 to about Tyr-246 and from about Ser-271 to about Phe-278 of the amino acid sequence of the SEQ ID NO: 2. In this context, the term "approximately" means the ranges particularly mentioned and ranges greater or lesser in several, a few, 5, 4, 3, 2 or 1 amino acid residues in either or both amino termini -terminal or carboxyl-terminal. The polypeptides encoded by these nucleic acid molecules are also encompassed by the present invention. The polypeptide fragments that carry antigenic epitopes of neutrokine-alpha can be readily determined by a person skilled in the art using the above-described analysis of the Jameson-Wolf antigenic index, in the manner shown in Figure 3. Methods for determining other epitope-carrying portions of neutrokine-alpha are described in more detail below. Additional preferred nucleic acid fragments of the present invention include nucleic acid molecules comprising, or alternatively consisting of, a sequence that codes for one or more epitope-carrying portions of neutrocine-alphaSV. In particular, such nucleic acid fragments of the present invention include nucleic acid molecules that comprise or alternatively consist of a sequence encoding a polypeptide that is selected from the group consisting of: from about Pro-32 to about Leu-47, from about Glu-116 to about Ser-143, from about Phe-153 to about Tyr-173, from about Prp-218 to about Tyr-227, from about Ser-252 to about Thr-258, from about Ala-232 to about approximately Gln-241; from about Ile-244 to about Ala-249; and from about Ser-252 to about Val-257 of the amino acid sequence of SEQ ID NO: 19. In this context, the term "about" means the particularly-mentioned ranges and higher or lower ranges in several, a few , 5, 4, 3, 2 or 1 amino acid residues at either or both amino-terminal and carboxyl-terminal ends. The polypeptides encoded by these nucleic acid molecules are also encompassed by the present invention. The polypeptide fragments that carry antigenic epitopes of neutrokine-alpha, can be readily determined by a person skilled in the art using the above described analysis of the Jameson-Wolf antigenic index. Methods for determining other epitope-carrying portions of neutrokine-alphaSV are described in more detail below. In specific embodiments, the polynucleotides of the present invention have less than 100,000 kb, 50,000 kb, 10,000 kb, 1,000 kb, 500 kb, 400 kb, 350 kb, 300 kb, 250 kb, 200 kb, 175 kb, 150 kb, 100 kb, 75 kb, 50 kg, 40 kb, 30 kb, 25 kb, 20 kb, 15 kb, 10 kb, 7.5 kb or 5 kb in length. In additional embodiments, the polynucleotides of the present invention comprise at least 15, at least 50, at least 100 or at least 250, at least 500 or at least 1000 contiguous nucleotides of the neutrocin-alpha coding sequence, but consist of less that or equal to 1000 kb, 500 kb, 250 kb, - 200 kb, 150 kb, 100 kb, 75 kb, 50 kb, 30 kb, 25 kb, 20 kb, 15 kb, 10 kb, or 5 kb of the genomic DNA flanking the 5 'or 3' ends of the coding nucleotide such as is set forth in Figures IA and IB (SEQ ID NO: 1) or in Figures 5A and 5B (SEQ ID NO: 18). In further embodiments, the polynucleotides of the present invention comprise at least 15, at least 30, at least 50, at least 100, or at least 250, at least 500, or at least 1000 contiguous nucleotides of the neutrocin-alpha coding sequence, but they do not comprise all or a portion of any neutrocin-alpha intron. In another embodiment, the nucleic acid comprising the neutrocin-alpha coding sequence does not contain coding sequences for a genomic flanking gene (i.e., toward 5 'or 3' of the neutrocine-alpha gene in the genome). In other embodiments, the polynucleotides of the present invention do not contain the coding sequence of more than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2 or 1 genomic flanking genes. In another embodiment, the present invention provides an isolated nucleic acid molecule comprising a polynucleotide that hybridizes, under stringent hybridization conditions, to a portion of the polynucleotide in a nucleic acid molecule of the present invention described above, e.g. - - sequence complementary to the coding and / or non-coding sequence illustrated in Figures IA and IB (SEQ ID NO: 1), the sequence of the cDNA clone contained in the deposit having the accession number ATCC 97768, the sequence complementary to the coding sequence and / or non-coding sequence illustrated in Figures 5A and 5B (SEQ ID NO: 18), the sequence of the cDNA clone contained in the deposit with accession number ATCC 203518, the sequence complementary to the coding sequence and / or non-coding sequence (ie, transcribed, untranslated) illustrated in SEQ ID NO: 21, the sequence complementary to the coding sequence and / or the non-coding sequence illustrates in SEQ ID NO: 22, the sequence complementary to the coding sequence and / or the non-coding sequence illustrated in SEQ ID NO: 27, the sequence complementary to the coding sequence and / or to the non-coding sequence illustrated in SEQ ID NO: 29, or fragments (such as per axis) mplo, the open reading frame or a fragment thereof) of these sequences, as described herein. The term "stringent hybridization conditions" as used herein, refers to an overnight incubation at 42 ° C in a solution comprising: 50% formamide, 5 x SSC (750 mM NaCl, trisodium citrate 75 mM), phosphate of faith, 50 mM sodium (pH 7.6), 5 x Denhardt's solution, 10% dextran sulfate and 20 μg / mL of denatured cut salmon sperm DNA, followed by a wash of the filters with 0.1 x SSC at approximately 65 ° C. The term "a polynucleotide that hybridizes with a" portion "of a polynucleotide, refers to a polynucleotide (either DNA or RNA) that hybridizes to at least about 15 nucleotides (nt) and preferably at least about 20 nt, more preferably at least about 30 nt and still more preferably about 30-70 (eg, 40, 50 or 60) nucleotides and even still more preferably about any whole number in the range of 30 to 70 or 80 to 150 nucleotides, or the length whole of the reference polynucleotide. These have uses which include, but are not limited to, diagnostic probes and primers as described above, and which will be described in greater detail below. The term "a portion of a polynucleotide of" at least about 20 nt in length ", for example, refers to the ranges particularly cited, at higher or lower ranges in several (ie 5, 4, 3, 2, 1 or 0) amino acids, at either or both ends of the nucleotide sequence of the reference polypeptide (eg, the sequence of one or both deposited cDNA clones, the complementary strand of the nucleotide sequence - - shown in Figures IA and IB (SEQ ID NO: 1), the complementary strand of the nucleotide sequence shown in Figures 5A and 5B (SEQ ID NO: 18), the complementary strand of the nucleotide sequence shown in SEQ ID NO: 21, the complementary strand of the nucleotide sequence shown in SEQ ID NO: 22, the complementary strand of the sequence of nucleotides shown in SEQ ID NO: 27 and / or the complementary strand of the nucleotide sequence shown in SEQ ID NO: 29). Of course, a polynucleotide that hybridizes only with a polyA sequence (such as the poly (A) 3 'terminal portion of the neutrokine-alpha cDNA shown in Figures IA and IB (SEQ ID NO: 1), the poly ( A) 3 'terminal of the neutrokine-alphaSV cDNA shown in Figures 5A and 5B (SEQ ID NO: 18) or the poly (A) 3' terminal portion of the neutrokine-alphaSV cDNA shown in SEQ ID NO: 22 ) or a complementary portion of T (or U) residues would not be included in a polynucleotide of the present invention used to hybridize with a portion of a nucleic acid of the present invention, since such a polynucleotide would hybridize to any nucleic acid molecule that contained a poly (A) moiety or the complement thereof (eg, practically any double-stranded cDNA clone generated using oligo-dT as a primer). As indicated, the nucleic acid molecules of the present invention that encode a neutrocin-alpha or neutrocin-alphaSV polypeptide, may include, but are not limited to, polynucleotides that encode the amino acid sequence of the respective extracellular domains of the polypeptides, by themselves; and the coding sequence of the extracellular domains of the respective polypeptides and additional sequences, such as those coding for the intracellular and transmembrane domains, or a pre-protein or pro-protein or prepro-protein; the coding sequence of the respective extracellular domains of the polypeptides, with or without the additional coding sequences mentioned above. Also encoded by the nucleic acids of the present invention are the above protein sequences together with additional non-coding sequences, including, but not limited to, introns and 5 'and 3' non-coding sequences, such as transcribed, untranslated sequences , which play a role in transcription, mRNA processing, including splicing and polyadenylation signals, eg, ribosome binding and mRNA stability; an additional coding sequence that codes for additional amino acids, such as those that provide additional functionalities.

Thus, the polypeptide coding sequence can be fused with a marker sequence, such as a sequence encoding a peptide that facilitates purification of the fused polypeptide. In certain preferred embodiments of this embodiment of the invention, the marker amino acid sequence is a hexahistidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chastworth, CA; 91311), among others, many of which are available in the trade. As described in Gentz et al. , Proc. Nat 'l Acad. Sci. USA 86: 821-824 (1989), for example, hexahistidine provides a convenient purification of the fused protein. The "HA" tag is another peptide useful for purification, which corresponds to an epitope derived from the influenza hemagglutinin protein, which has been described by Wilson et al. , Cell 37: 767 (1984). As will be described below, other fusion proteins include the neutrokine-alpha or neutrokine-alphaSV polypeptides fused to Fc at the N-terminus or C-terminus. The present invention furthermore relates to variants of nucleic acid molecules of the present invention, which code for portions, analogs or derivatives of the neutrokine-alpha or neutrocin-alphaSV polypeptides of SEQ ID NO: 2. - - variants may occur. naturally, such as a natural allelic variant. The term "allelic variant" refers to one of several alternate forms of a gene that occupies a given locus on a chromosome of an organism. Genes II, Lewin, B., ed., John Wiley / Sons, New York (1985). Variants of non-natural origin can be produced using known mutagenesis techniques, which include but are not limited to, oligonucleotide-mediated mutagenesis, alanine scanning, PCR mutagenesis, site-directed mutagenesis (see, eg, Carter et al., Nuci Acids Res 13: 4331 (1986) and Zoller et al., Nuci Acids Res 10: 6487 (1982)), cartridge mutagenesis (see, eg, Wells et al., Gene 34: 315 (1985 )), mutagenesis by restriction selection (see, eg, Wells et al., Philos, Trans.R. Soc. London SerA 317: 415 (1986)). Such variants include those produced by substitutions, deletions or additions of nucleotides. The substitutions, deletions or additions may include one or more nucleotides. The variants can be altered in coding regions, non-coding regions or both. Alterations in coding regions can produce conservative or non-conservative amino acid substitutions. Especially preferred among these are silent substitutions, additions and deletions, which do not alter the properties and activities of the neutrokine-alpha and / or neutrocine-alphaSV polypeptides or portions thereof. Likewise, conservative substitutions are especially preferred in this regard. Additional embodiments of the present invention relate to isolated nucleic acid molecules comprising a polynucleotide that encodes the amino acid sequence of a neutrocine-alpha and / or neutrocine-alphaSV polypeptide (eg, a neutrokine-alpha polypeptide fragment and / or neutrocin-alphaSV described herein) having an amino acid sequence that contains at least one conservative amino acid substitution, but not more than 50 conservative amino acid substitutions, preferably no more than 40 conservative amino acid substitutions, still more preferably no more than 30 conservative amino acid substitutions and even more preferably no more than 20 conservative amino acid substitutions, 10-20 conservative amino acid substitutions, 5-10 conservative amino acid substitutions, 1-5 conservative amino acid substitutions, 3-5 substitutions of conservative amino acids or 1-3 substitutions of conservative amino acids. Of course, in always increasing order of preference, it is highly preferable that a polynucleotide encoding the amino acid sequence of a neutrocyne-alpha-and / or neutrocine-alphaSV polypeptide, have an amino acid sequence that contains no more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 conservative amino acid substitutions. In addition, some embodiments include an isolated nucleic acid molecule comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence with at least 80, 85 or 90% identity and preferably at least 95, 96, 97, 98 or 99% identity with a polynucleotide that is selected from the group consisting of: (a) a nucleotide sequence encoding the neutrokine-alpha polypeptide having the complete amino acid sequence of Figures IA and IB (ie, positions from 1 to 285 of SEQ ID NO: 2); (b) a nucleotide sequence encoding the neutrocin-alpha polypeptide having the complete amino acid sequence of SEQ ID NO: 2, except for the N-terminal methionine (ie, positions 2 through 285 of SEQ ID NO. : 2), (c) a fragment of the polypeptide of part (b) having functional activity of neutrocine-alpha (eg, antigenic or biological activity); (d) a nucleotide sequence encoding the predicted extracellular domain of the neutrokine-alpha polypeptide, having the amino acid sequence of positions 73-285 of Figures IA and IB (SEQ ID NO: 2); (e) a nucleotide sequence encoding the neutrocyan-alpha-polypeptide having the amino acid sequence of positions 134-285 of Figures IA and IB (SEQ ID NO:); (f) a nucleotide sequence encoding a neutrokine-alpha polypeptide having the complete amino acid sequence encoded by the cDNA clone contained in the deposit with accession number ATCC 97768; (g) a nucleotide sequence encoding the extracellular domain of the neutrokine-alpha polypeptide having the amino acid sequence encoded by the cDNA contained in the deposit having accession number ATCC 97768; and (h) a nucleotide sequence complementary to any nucleotide sequence of subsections (a), (b), (c), (d), (e), (f), (g) or (h) above. The present invention also encompasses the aforementioned polynucleotide sequences fused to a heterologous polynucleotide sequence. The polypeptides encoded by these polynucleotides and nucleic acid molecules are also encompassed by the present invention. Highly preferred embodiments of the present invention refer to nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence with at least 80, 85, 90% identity and preferably at least 95, 96, 97, 98, 99 or 100% identity to a polynucleotide sequence encoding the neutrokine-alpha polypeptide having the amino acid sequence of positions 134 to 285 of Figures IA and IB (SEQ ID NO: 2) ). Preferred embodiments of the present invention refer to nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence with at least 90% identity to a polynucleotide sequence encoding the neutrocin-alpha polypeptide that has the amino acid sequence of positions 134-285 of Figures IA and IB (SEQ ID NO: 2). More preferred embodiments of the present invention refer to nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence with at least 95% identity to a polynucleotide sequence encoding the neutrocyte polypeptide -alpha having the amino acid sequence of positions 134-285 of Figures IA and IB (SEQ ID NO: 2). More preferred embodiments of the present invention relate to nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence with at least 96% identity to a polynucleotide sequence encoding the neutrocytic polypeptide. alpha having the amino acid sequence of positions 134-285 of Figures IA and IB (SEQ ID NO: - - 2) . Additionally, more preferred embodiments of the present invention refer to nucleic acid molecules that comprise, or alternatively consist of, a polynucleotide having a nucleotide sequence with at least 97% identity to a polynucleotide sequence that encodes the Neutrocin-alpha having the amino acid sequence of positions 134-285 of Figures IA and IB (SEQ ID NO: 2). Additionally, embodiments of the present invention relate to nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence with at least 98% identity to a polynucleotide sequence encoding the neutrocine-alpha polypeptide having the amino acid sequence of positions 134-285 of Figures IA and IB (SEQ ID NO: 2). Additionally, more preferred embodiments of the present invention, refer to nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide having a nucleotide sequence with at least 99% identity to a polynucleotide sequence encoding the polypeptide of neutrocine-alpha having the amino acid sequence of positions 134-285 of Figures IA and IB (SEQ ID NO: 2).

- A further embodiment of the present invention relates to an isolated nucleic acid molecule comprising a polynucleotide that encodes the amino acid sequence of a neutrocine-alphaSV polypeptide (eg, a neutrocine-alphaSV polypeptide fragment described herein) , which has an amino acid sequence that contains at least one conservative acid substitution, but no more than 50 conservative amino acid substitutions, preferably no more than 40 conservative amino acid substitutions, still more preferably no more than 30 conservative amino acid substitutions and even more preferably not more than 20 conservative amino acid substitutions. Of course, in always increasing order of preference, it is highly preferable that a polynucleotide encoding the amino acid sequence of a neutrocine-alpha polypeptide, have an amino acid sequence that contains no more than 7-10, 5-10, 3 -7, 3-5, 2-5, 1-5, 1-3, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 conservative amino acid substitutions. Additional moieties include an isolated nucleic acid molecule comprising or alternatively consisting of a polynucleotide having a nucleotide sequence with at least 80, 85 or 90% identity and more preferably at least 95, 96, 97, 98 or 99% - - identity with a polynucleotide that is selected from the group consisting of: (a) a nucleotide sequence encoding the neutrokine-alphaSV polypeptide having the complete amino acid sequence of Figures 5A and 5B (ie, positions of the 1 to 266 of SEQ ID NO: 19); (b) a nucleotide sequence encoding the neutrokine-alphaSV polypeptide having the complete amino acid sequence of SEQ ID NO: 19, except for the N-terminal methionine (ie, positions 2 to 266 of SEQ ID NO: 2), (c) a nucleotide sequence encoding the predicted extracellular domain of the neutrokine-alphaSV polypeptide, having the amino acid sequence of positions 73-285 of Figures 5A and 5B (SEQ ID NO: 19 ); (d) a nucleotide sequence encoding the neutrokine-alphaSV polypeptide having the complete amino acid sequence encoded by the cDNA clone contained in the deposit with accession number ATCC 203518; (e) a nucleotide sequence encoding the extracellular domain of the neutrokine-alphaSV polypeptide, having the amino acid sequence encoded by the cDNA clone contained in the deposit having the accession number ATCC 203518; and (f) a nucleotide sequence complementary to any nucleotide sequence of parts (a), (b), (c), (d) or (e) above.

- - In addition, the present invention includes a polypeptide comprising or alternatively consisting of a sequence with at least 90, or at least 95% identity to any portion of at least about 10 contiguous nucleotides, about 20 contiguous nucleotides, about 25 contiguous nucleotides or about 30 contiguous nucleotides, preferably at least about 40 contiguous nucleotides or at least about 50 nucleotides of the nucleotide sequence from 1 to 1082 of Figures IA and IB (SEQ ID NO: 1), preferably excluding the determined nucleotide sequences of the four cDNA clones listed above and the nucleotide sequences of nucleotides 797 to 1082, 810 to 1082 and 346 to 542. The present invention also includes a polynucleotide comprising or alternatively consisting of a sequence with at least 90 or at least 95 % identity with any portion of when meno s about 10 contiguous nucleotides, about 20 contiguous nucleotides, about 25 contiguous nucleotides or about 30 contiguous nucleotides, preferably at least about 40 contiguous nucleotides or at least about 50 nucleotides of the sequence of Figures 5A and 5B (SEQ ID NO: 18 ), preferably excluding the nucleotide-determined sequences of the four cDNA clones listed above. The present invention also includes a polynucleotide comprising or alternatively consisting of a sequence with at least 90 or at least 95% identity to any portion of at least about 10 contiguous nucleotides, about 20 contiguous nucleotides, about 25 contiguous nucleotides or about 30 nucleotides contiguous, preferably at least about 40 contiguous nucleotides or at least about 50 nucleotides of the sequence of SEQ ID NO: 21, preferably excluding the nucleotide sequences determined from the four cDNA clones listed above. The present invention also includes a polynucleotide comprising a sequence with at least 90 or at least 95% identity to any portion of at least about 10 contiguous nucleotides, about 20 contiguous nucleotides, about 25 contiguous nucleotides or about 30 contiguous nucleotides, preferably at least about 40 contiguous nucleotides or at least about 50 nucleotides of the sequence of SEQ ID NO: 22, preferably excluding the nucleotide sequences determined from the four cDNA clones listed above. The present invention also includes a polypeptide comprising a sequence with at least 90 or at least 95% identity to any portion of at least about 10 contiguous nucleotides, about 20 contiguous nucleotides, about 25 contiguous nucleotides, or about 30 contiguous nucleotides, preferably at least about 40 contiguous nucleotides or at least about 50 nucleotides of the sequence of SEQ ID NO: 27, preferably excluding the nucleotide sequences determined from the four clones of AüNc listed above. The present invention also includes a polypeptide comprising a sequence with at least 90 or at least 95% identity to any portion of at least about 10 contiguous nucleotides, about 20 contiguous nucleotides, about 25 contiguous nucleotides, or about 30 contiguous nucleotides, preferably at least about 40 contiguous nucleotides or at least about 50 nucleotides of the sequence of SEQ ID NO: 29, preferably excluding the nucleotide sequences determined from the four cDNA clones listed above. In this context, the term "approximately" includes the ranges particularly mentioned, higher or lower ranges in several (i.e. 5, 4, 3, 2 or 1) amino acids at either end or both ends.

- - A polynucleotide having a nucleotide sequence with at least, for example, 95% "identity" with a reference nucleotide sequence coding for a neutrocine-alpha and / or neutrocin-alphaSV polypeptide, means that the nucleotide sequence of the polynucleotide is identical to the reference sequence, except that the polynucleotide sequence can include up to five non-pairings per 100 nucleotides of the reference nucleotide sequence coding for the neutrocine-alpha and / or neutrocine-alphaSV polypeptide. In other words, to obtain a polynucleotide having a nucleotide sequence with at least 95% identity to a reference nucleotide sequence, up to 5% of the nucleotides of the reference sequence may have been deleted or replaced by other nucleotides , or a number of nucleotides of up to 5% of the total nucleotides of the reference sequence, could have been inserted into the reference sequence. These mutations of the reference sequence can occur at the 5 'or 3' terminal positions of the reference nucleotide sequence or anywhere between these terminal positions, interspersed either individually between the nucleotides of the reference sequence, or in one or more contiguous groups within the reference sequence. The reference sequence - - (standard) can be the complete nucleotide sequence coding for neutrokine-alpha or neutrokine-alphaSV, as shown in Figures IA and IB (SEQ ID NO: 1) and in Figures 5A and 5B (SEQ ID NO. : 18), respectively, or any neutrokine-alpha such as for example, the neutrokine-alpha polynucleotides shown as SEQ ID NOS: 21, 22, 27 or 28, or any neutrokine-alpha or neutrocin-alphaSV polynucleotide fragment as those described in the present. As a practical matter, the fact whether any particular nucleic acid molecule has at least 80, 85, 90, 95, 96, 97, 98 or 99% identity to, for example, the nucleotide sequences shown in Figs. IB or the nucleotide sequences shown in Figures 5A and 5B or to the nucleotide sequences of the deposited cDNA clones or to any neutrokine-alpha polynucleotide such as for example the neutrokine-alpha polynucleotides shown as SEQ ID NOS: 21 , 22, 27 or 28, or fragments thereof, can be conveniently determined using known computer programs, such as the Bestfit program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, 575 Science Drive , Madison, Wl 53711). The Bestfit program uses the local homology algorithm of Smith and Waterman to - find the best homology segment between two sequences (Advances in Applied Mathematics 2: 482- ^ 89 (1981)). When the Bestfit program or any other sequence alignment program is used to determine whether a particular sequence has, for example, 95% identity to a reference sequence in accordance with the present invention, the parameters are, of course, set to such that the percent identity is calculated over the entire length of the reference nucleotide sequence and that they are permissible in unpaired hollow homology up to 5% of the total number of nucleotides in the reference sequence. In a specific embodiment, the identity between a reference sequence (pattern) (a sequence of the present invention) and a subject sequence, also referred to as global sequence alignment, is determined using the FASTDB computer program based on the Brutlag algorithm. and colleagues (Comp. App. Biosci. 6: 237-245 (1990)). In a sequence alignment, the subject and subject sequences are DNA sequences. An RNA sequence can be compared by transforming the U into T. The result of this global sequence alignment is given in percent identity. The preferred parameters used in the FASTDB alignment of DNA sequences to calculate the percentage of - - identity, are: Matrix = Unitary, k-tuple = 4, Mismatch Penalty = l, Joining Penalty = 30, Randomization Group Length = 0, Cutoff Score = l, Gap Penalty = 5, Gap Size Penalty 0.05, Window Size = 500 or length of the subject nucleotide sequence, whichever is shorter. In accordance with this embodiment, if the subject sequence is shorter than the master sequence due to 5 'or 3' deletions, but not due to internal deletions, a manual correction is made to the results taking into consideration the fact that the FASTDB program does not account for 5 'and 3' truncations of the subject sequence when calculating percent identity. For subject sequences truncated at the 5 'or 3' ends, relative to the standard sequence, the percent identity is corrected by calculating the number of bases of the standard sequence that are 5 'and 3' of the subject sequence and not they are paired / aligned, as a percentage of the total bases of the master sequence. A determination of whether a nucleotide is paired / aligned is made by the results of the FASTDB sequence alignment. This percentage is then subtracted from the identity percentage calculated by the previous FASTDB program, using the specified parameters, to arrive at a final identity percentage. This corrected grade is what is used for the purposes of this modality. Only the bases - - outside the 5 'and 3' ends of the subject sequence, as displayed in the FASTDB alignment, which are not paired / aligned with the pattern sequence, are calculated for the purposes of manual adjustment of the rating. of the percentage of identity. For example, a subject sequence of 90 bases is aligned with a standard sequence of 100 bases to determine the percent identity. Deletions occurred at the 5 'end of the subject sequence and, therefore, the alignment program FASTDB does not show an alignment / alignment of the first 10 bases at the 5' end. The 10 unpaired bases represent 10% of the sequence (number of bases at the 5 'and 3' ends that do not mate / total number of bases of the master sequence), so that 10% of the sequence is subtracted from the identity percentage score calculated by the FASTDB program. If the remaining 90 bases matched perfectly, the final identity percentage would be 90%. In another example, a subject sequence of 90 bases is compared to a standard sequence of 100 bases. This time, the deletions are internal deletions, such that there are no bases at the 5 'or 3' ends of the subject sequence that are not paired / aligned with the pattern. In this case, the identity percentage calculated by the FASTDB program is not corrected manually. Again, only the 5 'and 3' bases of the subject sequence that are not - - paired / aligned with the pattern sequence, are manually corrected. No other manual correction is made for the purposes of this modality. The present application relates to nucleic acid molecules with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% identity to nucleic acid sequences (ie, polynucleotides) described herein (eg, those described in Figures IA and IB (SEQ ID NO: 1) or the nucleic acid sequence of the deposited cDNAs), regardless of whether they encode a polypeptide having neutral-alpha and / or neutrocin-alphaSV functional activity (eg , biological activity). In addition, the present application also relates to nucleic acid molecules with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% identity to nucleic acid sequences shown in Figures 5A and 5B (SEQ. ID NO: 18) or to the nucleic acid sequence of the deposited cDNA, regardless of whether or not they code for a polypeptide having neutrocine-alphaSV activity. In addition, the present application also relates to nucleic acid molecules with at least 80, 85, 90, 92, 95, 96, 97, 98, 99% identity to the nucleic acid sequences shown in SEQ ID NOS: 21, 22, 27 or 28, regardless of whether or not they code for a polypeptide having neutrocyan-alpha activity. This - - is because even when a particular nucleic acid molecule does not code for a polypeptide having neutrocine-alpha and / or neutrocine-alphaSV activity, a person skilled in the art would know how to use the nucleic acid molecule, for example , as a hybridization probe or as a primer for a polymerase catalyzed chain reaction (PCR). The uses of the nucleic acid molecules of the present invention that do not encode a neutrokine-alpha and / or neutrokine-alphaSV polypeptide with activity, include inter alia (1) the isolation of neutrokine-alpha and / or neutrocyanin genes. alphaSV or allelic variants thereof in a cDNA library, (2) in-situ hybridization (eg, "FISH") with separate metaphase chromosomes to provide the precise chromosomal localization of the neutrocine-alpha and / or neutrocin-alphaSV gene , as described in Verma et al. , Human Chromosomes: A Manual of Basic Techniques, Pergamon Press, New York (1988) and Northern blot analysis to detect the expression of neutrocine-alpha and / or neutrocine-alphaSV mRNA in specific tissues. However, nucleic acid molecules having sequences with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% identity to the nucleic acid sequences described herein are preferred (eg, the sequence - - of nucleotides shown in Figures IA and IB (SEQ ID NO: 1) and the nucleic acid sequence of the deposited cDNAs, or fragments thereof), which in fact encode a polypeptide having neutrocytic-functional activity alpha and / or neutrocine-alphaSV (eg biological activity). Also preferred are nucleic acid molecules having sequences with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% identity to the nucleic acid sequence shown in Figures 5A and 5B (SEQ ID NO. : 18) or to the nucleic acid sequence of the deposited cDNAs that in fact encode a polypeptide having neutrocine-alpha and / or neutrocine-alphaSV functional activity (eg biological activity). Also preferred are nucleic acid molecules having sequences with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% identity to the nucleic acid sequences shown in SEQ ID NOS: 21, 22, 27 or 28 which in fact encode a polypeptide having functional activity of neutrokine-alpha and / or neutrocin-alphaSV (eg, biological activity). The terms "a polypeptide having neutrokine-alpha functional activity" (eg, biological activity) and "a polypeptide having neutrokine-alphaSV functional activity" (eg, biological activity), refer to polypeptides that exhibit similar activity, but not necessarily identical, to the activity of the extracellular domain - or the full-length neutrokine-alpha or neutrocine-alphaSV polypeptides of the present invention, which is measured in a particular functional assay (eg, immunological or biological assays) . For example, the functional activity of the neutrokine-alpha and / or neutrocin-alphaSV polypeptide can be measured by the ability of a polypeptide sequence described herein to form multimers (eg, homodimers and homotrimers) with neutrocin-alpha and / or neutrocine-alphaSV complete or with the extracellular domain of neutrokine-alpha and / or neutrocine-alphaSV, and to bind to the ligand of neutrocine-alpha and / or neutrocine-alphaSV. The functional activity of the neutrocine-alpha and / or neutrocine-alphaSV polypeptide can also be measured by determining the ability of a polypeptide of the present invention to induce the proliferation, differentiation or activation of lymphocytes (eg, B cells), and / or extend the survival of B cells. These functional assays can be performed routinely using the techniques described herein (eg, see Example 6) and techniques otherwise known in the art. Additionally, the neutrocin-alpha or neutrocin-alphaSV polypeptides of the present invention modulate cell proliferation, cytotoxicity, cell survival and cell death. In assays of cell proliferation, cytotoxicity, cell survival and cell death to measure the effect of a protein on certain cells, they can be performed using reagents known and commonly available in the art to detect replication and / or cell death. For example, numerous of these assays for the activity of TNF-related proteins are described in the various references presented herein. Briefly, an example of such assays includes pooling human or animal (eg murine) cells and mixing them with (1) the supernatant of transfected host cells containing the neutrocyan-alpha protein (or a candidate polypeptide) or (2) the cell supernatant non-transfected host control, and measure the effect on the number of cells or on the viability thereof after an incubation for a certain period of time. Such modulation activities of cell proliferation and / or survival can be measured in this type of assays and are useful for the treatment of tumors, tumor metastasis, infections, autoimmune diseases, inflammation and other diseases related to the immune system. Neutrocin-alpha modulates cell proliferation and differentiation in a dose-dependent manner in the assays described above. Accordingly, it is preferred that "a polypeptide having neutral-alpha functional activity" (eg, biological activity) includes polypeptides that also exhibit any of the same cell modulating activities (particularly immunomodulatory) in the assays described above, way dependent on the dose. Although the degree of dose-dependent activity does not necessarily have to be identical to that of the neutrokine-alpha polypeptides, preferably "a polypeptide having neutral-alpha functional activity" will substantially exhibit a similar dose dependence in a given activity, compared to neutrokine-alpha polypeptides (ie, the candidate polypeptide will exhibit greater activity or no more than about 25-fold less and preferably no more than about 10-fold less activity compared to the reference neutrokine-alpha polypeptides) . In certain preferred embodiments, "a polypeptide having neutrocin-alpha functional activity" (eg, biological activity) and "a polypeptide having neutrocin-alphaSV functional activity" (eg, biological activity, include polypeptides that also exhibit any of the same modulatory activities (particularly immunomodulatory) of B cells (or other cell types), as described in Figures 8A-8C, 9A, 9B, 10, and 11, and in Example 6.

- - Like other members of the TNF family, neutrocin-alpha exhibits activity on leukocytes, including for example monocytes, lymphocytes (e.g., B cells) and neutrophils. For this reason, neutrocin-alpha is active to direct the proliferation, differentiation and migration of these cell types. Such activity is useful for the intensification or suppression, myeloprotection, mobilization of stem cells, for the control of acute and chronic inflammatory disorders and the treatment of leukemia. Tests to measure such activity are known in the art. For example, see Peters et al. I'm a. Today 17: 273 (1996); Young et al. , J. Exp. Med. 182: 1111 (1995); Caux et al. , Nature 390: 258 (1992); and Santiago-Schwartz et al. , Adv. Exp. Med. Biol. 378: 7 (1995). Of course, due to the degeneracy of the genetic code, a person skilled in the art will immediately recognize that a large number of nucleic acid molecules having a sequence with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% identity to the nucleic acid sequence contained in the cDNA clone deposited with accession number ATCC no. 97768, or the nucleic acid sequence shown in Figures IA and IB (SEQ ID NO: 1) or fragments thereof, will code for a polypeptide "having functional activity of neutrocin-alpha" (e.g. - - biological activity). A person skilled in the art will also immediately recognize that a large number of nucleic acid molecules having a sequence with at least 880, 85, 90, 92, 95, 96, 97, 98 or 99% identity to the nucleic acid sequence contained in the cDNA clone deposited with accession number ATCC 203518 or the nucleic acid sequence shown in Figures 5A and 5B (SEQ ID NO: 18), will code for a polypeptide "having functional activity of neutrocine-alphaSV" ( eg, biological activity). In fact, as the degenerate variants of these nucleic acid sequences all code for the same polypeptide, this will be clear to a person skilled in the art even without performing any comparison test described above. It will further be recognized in the art that, for such nucleic acid molecules that are not degenerate variants, a reasonable number will also code for a polypeptide having neutrocine-alpha and / or neutrocine-alphaSV activity. This is because a person skilled in the art is aware that there are amino acid substitutions that are less likely or that are not likely to significantly affect protein function (eg, replacing an aliphatic amino acid with a second aliphatic amino acid), as describe later. Similarly, polynucleotides that encode for polypeptides that contain all or a portion of the V-142 to K-160 region of SEQ ID NO: 2 are likely to be valuable as diagnostic and therapeutic polypeptides with respect to to the detection and / or alteration of the expression of the neutrokine-alpha or neutrocin-alphaSV polynucleotides. In addition, the polynucleotides that include amino acid residues T-141 and G-142 of the neutrokine-alphaSV polypeptide shown in SEQ ID NO: 19 (among which the amino acid sequence V-142 to K-160 of neutrocine) -alpha is apparently inserted), they are also likely to be useful both diagnostically and therapeutically. Such T-141 / G-142 extension nucleotides will exhibit a much higher probability of hybridization with the neutrokine-alphaSV polynucleotides, as compared to the neutrokine-alpha polynucleotides. A non-limiting partial list of such neutrokine-alphaSV polypeptides that are encoded by the polynucleotides of the present invention, includes polypeptides comprising or alternatively consisting of an amino acid sequence that is selected from the following: from G-121 to E-163; E-122 to E-163; G-123 to E-163; N-124 to E-163; S-125 to E-163 S-126 to E-163; Q-127 to E-163; N-128 to E-163; S-129 to E-163 R-130 to E-163; N-131 to E-163; K-132 to E-163; K-132 to E-163 R-133 to E-163; A-134 to E-163; V-135 to E-163; Q-136 to E-163 - - G-137 to E-163; P-138 to E-163; E-139 to E-163; E-140 to E-163 T-141 to E-163; G-142 to E-Í63; S-143 to E-163; Y-144 to E-163 T-145 to E-163; F-146 to E-163; V-147 to E-163; P-148 to E-163 W-149 to E-163; L-150 to E-163; L-151 to E-163; S-152 to E-163 F-153 to E-163; K-154 to E-163; R-155 to E-163; G-156 to E-163 S-157 to E-163; A-158 to E-163; L-159 to E-163; E-160 to E-163 E-161 to E-163; K-162 to E-163; G-121 to K-162; G-121 to E-161 G-121 to E-160; G-121 to L-159; G-121 to E-158; G-121 to S-157 G-121 to G-156; G-121 to R-155; G-121 to K-154; G-121 to F-153 G-121 to S-152; G-121 to L-151; G-121 to L-150; G-121 to W-149 G-121 to P-148; G-121 to V-147; G-121 to F-146; G-121 to T-145 G-121 to Y-144; G-121 to S-143; G-121 to G-142; G-121 to T-141 G-121 to E-140; G-121 to E-139; G-121 to P-138; G-121 to G-137 G-ll to Q-136; G-121 to V-135; G-121 to A-134; G-121 to R-133 G-121 to K-132; G-121 to N-131; G-121 to R-130; G-121 to S-129 G-121 to N-128; G-121 to Q-127; G-121 to S-126; G-121 to S-125 G-121 to N-124; G-121 to G-123; and G-121 to E-122 of SEQ ID NO: 19. Polypeptides encoding these polynucleotides are also encompassed by the present invention. Vectors and host cells The present invention also relates to vectors that include the isolated DNA molecules of the present invention, host cells that are engineered with the recombinant vectors or that are otherwise engineered to produce the polypeptides of the present invention, and the production of a neutrocine-alpha and / or neutrocine-alphaSV polypeptide or fragments thereof by recombinant or synthetic techniques. In one embodiment, the polynucleotides of the present invention bind to a vector (e.g., a cloning or expression vector). The vector can be, for example, a phage, plasmid, viral or retroviral vector. retroviral vectors may be competent for replication or defective in replication. In the latter case, viral propagation will usually occur only in complementary host cells. The polynucleotides can be attached to a vector that contains a selectable marker for propagation in a host. The induction of vector construction in the host cell can be carried out by known techniques including, but not limited to, calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection or other methods. Such methods are described in numerous laboratory manuals, such as Davis et al. , Basic Methods in Molecular Biology (1986).

- In general, recombinant expression vectors will include origins of replication and selectable markers that allow the transformation of the host cell, eg, the ampicillin resistance gene of E. coli and S. cereviciae TRP1, and a promoter derived from a gene highly expressed to direct the transcription of a downstream structural sequence. Such promoters can be derived from operons encoding glocolytic enzymes such as 3-phosphoglycerate kinase (PGK), acid factor-a phosphatase or heat shock proteins, among others. The heterologous structural sequence is assembled at an appropriate stage with translation initiation and translation termination sequences and preferably a leader sequence capable of directing the secretion of the translated protein into the periplasmic space or into the extracellular environment. Optionally, the heterologous sequence can encode a fusion protein including an N-terminal identification peptide that imparts certain desired characteristics, for example, the stabilization or simplified purification of the expressed recombinant product. In one embodiment, the DNA of the present invention is operably associated with an appropriate heterologous regulatory element (e.g., a promoter or enhancer) - such as the FL promoter from lambda phage, the lac promoters., trp, phoA and tac of E. coli, the SV40 early and late promoters and promoters of retroviral LTRs, to name a few. Other suitable promoters will be known to those skilled in the art. As indicated, the expression vectors of preference will include at least one selectable marker. Such markers include dihydrofolate reductase, resistance to G418 or neomycin for eukaryotic cell cultures and tetracycline, kanamycin or ampicillin resistance genes for cultures in E. coli and other bacteria. Representative examples of suitable hosts include, but are not limited to, bacterial cells such as E. coli, Streptomyces and Salmonella typhimurium.; fungal cells such as yeast cells (e.g., Saccharomyces cerevisiae or Pichia pastoris (accession number ATCC 201178)); insect cells such as S2 cells from Drosophila and Sf9 from Spodoptera; animal cells such as CHO, COS, 293 and Bowes melanoma cells; and plant cells. The appropriate culture media and conditions for the host cells described above are known in the art. The host cell can be a higher eukaryotic cell, such as a mammalian cell (eg, a cell derived from humans), or a lower eukaryotic cell such as a yeast cell, or the host cell can be a prokaryotic cell , such as a bacterial cell. The host strain may be selected such that it modulates the expression of the inserted gene sequences, or that it modifies and processes the gene product in the specific manner desired. The expression of certain promoters can be raised in the presence of certain inducers; thus, the expression of the engineered polypeptide can be controlled. In addition, different host cells have specific characteristics and mechanisms for translational and post-translational processing and modification (e.g., phosphorylation, cleavage) of the proteins. Appropriate cell lines can be selected to ensure the desired modifications and processing of the foreign protein being expressed. The selection of appropriate vectors and selectors for expression in a host cell is a known procedure and the techniques required for the construction of expression vectors, introduction of the vector into the host and expression in the host are routine techniques. Expression vectors useful for bacterial use are constructed by inserting a structural DNA sequence encoding a desired protein, together with appropriate translation initiation and termination signals, in a reading phase operable with a functional translator. The vector will comprise one or more selectable phenotypic markers and an origin of replication to ensure maintenance of the vector, and for, if desired, to provide amplification in the host. Suitable prokaryotic hosts for transformation include E. coli, Bacillus subtilis, Salmonella typhimurium, and several species within the genus Pseudomonas, Streptomyces, and Staphylococcus, although others may also be used as selection materials. As a representative but not limiting example, expression vectors useful for bacteria may comprise a selectable marker and a bacterial origin of replication derived from commercially available plasmids comprising genetic elements of the known cloning vector pBR322 (ATCC 37017). Such commercial vectors include, for example, vectors pKK223-3 (Pharmacia Fine Chemical, Uppsala, Sweden) and GEMÍ (Promega Biotech, Madison, Wl, USA). These "vertebral" sections of pBR322 are combined with an appropriate promoter and the structural sequence to be expressed. Preferred vectors for use in bacteria include vectors pHE4-5 (accession number ATCC 209311; and variants thereof), pQE-70, pQE60 and pQE-9, available from QIAGEN, Inc., supra; pBS vectors, Phagescrip vectors, vectors - Bluescript, vectors pNH8A, pNH16a, pNH18A, pNH46A, available from Stratagene; and vectors ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 available from Pharmacia. Preferred expression vectors for use in yeast systems include but are not limited to the vectors pYES2, pYDl, pTEFl / Zeo, PYES2 / GS, pPICZ, pGAPZAlpha, pPIC9, pPIC3.5, pHIL-D2, pHIL-Sl, pPIC3 .5K, pPIC9K, and PA0815 (all available Invitrogen, Carlsbad, CA). Among the preferred eukaryotic vectors are the vectors, pWLNEO, pSV2CAT, pOG44, pXT1 and pSG available from Stratagene; and pSVK3, pBPV, pMSG and pSVL (available from Pharmacia). Other suitable vectors will be readily apparent to those skilled in the art. After transformation of an appropriate host strain and growth of the host strain to an appropriate cell density, the selected promoter is induced by appropriate means (eg, a change in temperature or chemical induction) and the cells are cultured for a period of time. additional. The cells are typically harvested by centrifugation, broken by physical or chemical means and the resulting crude extract is retained for further purification. The microbial cells employed in the expression of proteins can be broken by any convenient method, including freeze-thaw cycles, sonication, mechanical disruption or use of cell lysis agents, such methods are known to those skilled in the art. In one embodiment, the yeast Pichia pastoris is used to express the neutrocyan-alpha protein in a eukaryotic system. Pichia pastoris is a methylotrophic yeast that can metabolize methanol as the sole source of energy. A major step in the route of methanol metabolization is the oxidation of methanol to formaldehyde using 02. This reaction is catalyzed by the enzyme alcohol oxidase. In order to metabolize alcohol as its sole carbon source, Pichia pastoris must generate high levels of the alcohol oxidase enzyme due, in part, to the relatively low affinity of alcohol oxidase for 02. Consequently, in a growth medium that depends on methanol as the sole carbon source, the region Promoter of one of the alcohol oxidase genes (AOXl) is highly active. In the presence of methanol, the alcohol oxidase produced by the AOXl gene comprises up to about 30% of the total soluble protein in Pichia pastoris. See Ellis, S.B., et ai. , Mol. Cell. Biol. 5: 1111-21 (1985); Koutz, P.J, et ai. , Yeast 5: 197-77 (1989); Tschopp, J.F., et ai. , Nucí. Acids Res. 15: 3859-76 (1987). Thus, a heterologous coding sequence, such as for example an alpha-neutrocin-alpha or neutrocin-alphaSV polynucleotide of the present invention under the transcriptional regulation of all or a part of the AOxl regulatory sequence, is expressed at concentrations exceptionally high in Pichia yeast cells growing in the presence of methanol. In one example, the plasmid vector pPIC9K is used to express DNA encoding a neutrocin-alpha or neutrocin-alphaSV polypeptide of the present invention, as set forth herein in a Pichia yeast system essentially in the manner described in " Pichia protocols: Methods in Molecular Biology, "DR Higgins and J. Cregg, eds. This expression vector allows the expression and secretion of a neutral-alpha or neutrocin-alphaSV protein of the present invention, by virtue of the potent AOX1 promoter linked to the secretory signal of alkaline phosphatase (PHO) of Pichia pastoris (ie, leader) located upstream of a multiple cloning site. Many other yeast vectors can be used in place of pPIC9K, such as vectors pYES2, pYDl, pTEFl / Zeo, pYES2 / GS, pPICZ, pGAPZ, pGAPZalpha, pPIC9, pPIC3.5, pHILL-D2, pHIL-Sl, pPIC3 .5K, and PA0815, as will be observed by a person skilled in the art as long as the proposed expression construction produces - - appropriately localized signals for transcription, translation, secretion (if desired) and the like, inducing an AUG within the framework as be required. In one embodiment, high-level expression of a heterologous coding sequence, such as for example a neutrokine-alpha or neutrocin-alphaSV polynucleotide of the present invention can be achieved by cloning the heterologous polynucleotide of the present invention into a vector of expression such as, for example, pGAPZ or pGAPZalpha, and growing the yeast culture in the presence of methanol. Transcription of the DNA encoding the polypeptides of the present invention by higher eukaryotic cells is increased by inserting an enhancer sequence into the vector. Intensifiers are cis-active elements of DNA, normally approximately 10 to 300 bp, that act on a promoter to increase its transcription. Some examples include the SV40 enhancer on the late side of the replication origin from 100 to 270 bp, an early cytomegalovirus promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. Various mammalian cell culture systems may also be employed to express the recombinant protein. Examples of mammalian expression systems include the COS-7 monkey kidney fibroblast cell lines, described by Gluzman (cell 23: 175 (1981)), and other cell lines capable of expressing a compatible vector, for example C127 cell lines, 3T3, CHO, Hela and BHK. The mammalian expression vectors will comprise an origin of replication, a promoter in suitable enhancer and also any necessary ribosome site, a polyadenylation site, splice donor and receptor sites, transcription termination sequences and non-transcribed 5 'flanking sequences. . The DNA sequences derived from the SV40 splice and the polyadenylation sites can be used to provide the required non-transcribed genetic elements. In a specific embodiment constructs designed to express a portion of the extracellular domain of neutrokine-alpha (e.g., the amino acid residues of Ala-134 to Leu-285) are preferred. A person skilled in the art will be able to use the polynucleotide and polypeptide sequences provided as SEQ ID NO: 1 and SEQ ID NO: 2 respectively, or SEQ ID NO: 18 and SEQ ID NO: 19, respectively to design polynucleotide primers to generate such expression constructions.- - In another embodiment, constructs designed to express the entire predicted extracellular domain of neutrocin-alpha (i.e., amino acid residues from Gln-73 to Leu-285) are preferred. A person skilled in the art will be able to use the polynucleotide and polypeptide sequences provided as SEQ ID NO: 1 and SEQ ID NO: 2, respectively, or SEQ ID NO: 18 and SEQ ID NO: 19, respectively, to design polynucleotide primers. to generate such expression constructs. In addition, to encompass host cells containing the vectors described herein, the present invention also includes primary, secondary and immortalized host cells of vertebrate origin, particularly of mammalian origin, which have been engineered to eliminate or replace endogenous genetic material. (eg, the neutrokine-alpha coding sequence) and / or to include genetic material (eg, heterologous polynucleotide sequences) that is operably associated with the neutrokine-alpha polynucleotides of the present invention and that activates, alters and / or amplifies the endogenous neutrokine-alpha polynucleotides. For example, known techniques can be used to operably associate heterologous control regions (eg, promoter and / or enhancer) and endogenous alpha-neutrocin-polynucleotide sequences by homologous recombination (see, eg, Patent No. 5,641,670, issued on June 24, 1997; International Publication WO 96/29411, published September 26, 1996; International Publication WO 94/12650, published August 4, 1994; Koller etai., Proc. Nati. Acad. Sci. USA 86 : 8932-8935 (1989); and Zijlstra et al., Nature 342: 435-438 (1989), the descriptions of which are incorporated herein by reference in their entirety). The host cells described infra, can be used in a conventional manner to produce the gene product encoded by the recombinant sequence. Alternatively, cell-free translation systems may also be employed to produce the polypeptides of the present invention, employing RNAs derived from DNA constructs of the present invention. The polypeptide of the present invention can be expressed or synthesized in modified form, such as a fusion protein (comprising the polypeptide linked by peptide bonds to a heterologous protein sequence (or a different protein)) and can include not only secretion, but also additional heterologous functional regions. Such a fusion protein can be prepared by ligating polynucleotides of the present invention and the desired nucleic acid sequence encoding the desired amino acid sequence, by methods known in the art, in an appropriate reading frame and then expressing the product. of fusion protein by methods known in the art. Alternatively, such a fusion protein can be prepared by synthetic protein techniques, e.g. using a peptide synthesizer. Thus, for example, a region of additional amino acids, particularly charged amino acids, can be added to the N-terminus of the polypeptide to improve stability and persistence in the host cell, during purification or during subsequent handling and storage. Likewise, peptide fractions can be added to the polypeptide to facilitate its purification. Such regions can be removed before the final preparation of the polypeptide. The vision of peptide portions to the peptides to generate secretion or excretion, to improve stability and facilitate purification, among other things, are familiar and routine techniques in this field. In one embodiment, the polynucleotides encoding the neutrokine-alpha and / or neutrocin-alphaSV polypeptides of the present invention can be fused with the pelB signal sequence of the enzyme pectate lyase to increase the efficiency of expression and purification of such polypeptides in gram-negative bacteria. See US Patents Nos. - - ,576,195 and 5,846,818, the content of which is incorporated herein by reference in its entirety. A preferred fusion protein comprises a heterologous immunoglobulin region that is useful for stabilizing and purifying proteins. For example, European Patent EP-A-0, 464, 533 (Canadian counterpart 2045869), discloses fusion proteins comprising several portions of the constant region of immunoglobulin molecules, together with other human proteins or parts thereof. In many cases, the Fc part in a fusion protein is advantageous for use in therapy and diagnosis and, therefore, results, for example, in better pharmacokinetic properties (European Patent EP-A-0232 262). On the other hand, for some uses it would be desirable to be able to remove the Fc part after the fusion protein has been expressed, detected and purified in the advantageous manner described above. This is the case when the Fc portion proves to be an impediment to be used in therapy and diagnosis, for example, when a fusion protein is to be used as an antigen for immunizations. In drug discovery, for example, human proteins such as hIL-5 have been fused with Fc portions for purposes of performing high throughput screening assays, to identify hIL-5 antagonists. See D. Bennett et al. , J. Molecular Recognition 8: 52-58 (1995) and K. Johanson et al. , J. Biol. Chem., 270: 9459-9471 (1995). The polypeptides of the present invention include naturally purified products, products from chemical synthesis processes and products obtained by recombination techniques from prokaryotic or eukaryotic hosts, including for example, bacterial cells, yeasts, higher plants, insects and mammals Depending on the host employed in a recombinant production process, the polypeptides of the present invention may be glycosylated or non-glycosylated. In addition, the polypeptides of the present invention also include an initial modified methionine residue, in some cases as a result of the host mediated process. The polypeptides of the present invention can be chemically synthesized using techniques known in the art (eg, see Creighton, 1983, Proteins: Structures and Molecular Principles, WH Freeman &Co., NY, and Hunkapiller, M., et al., 1984, Nature 310: 105-111). For example, a peptide corresponding to a fragment of the complete neutrokine-alpha or neutrocin-alphaSV polypeptides of the present invention can be synthesized by the use of a peptide synthesizer. In addition, if desired, non-classical amino acids or chemical analogues of amino acids can be introduced as substitutions or additions in the polynucleotide sequence of neutrocine-alpha or neutrocin-alphaSV. Non-classical amino acids include, but are not limited to, the D isomers of the common amino acids, 2,4-diaminobutyric acid, α-aminoisobutyric acid, 4-aminobutyric acid, Abu, 2-aminobutyric acid, g-Abu, e- Ahx, 6-aminohexanoic acid, Aib, 2-aminoisobutyric acid, 3-aminopropionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulin, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, b- alanine, fluroamino acids, designed amino acids such as beta-methylamino acids, Ca-methylamino acids, Na-methylamino acids and amino acid analogues in general. In addition, the amino acid can be D (dextrorotatory) or L (levorotatory). The present invention encompasses neutrokine-alpha or neutrocin-alphaSV polypeptides that are differentially modified during or after translation, eg, by glycosylation, acetylation, phosphorylation, amidation, derivatization by known blocking / blocking groups, proteolytic cleavage, linkage with a antibody molecule or other cellular ligand, etcetera. Any of the numerous chemical modifications can be carried out by known techniques, including but not limited to, specific chemical breakdown with cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH4, acetylation, formylation, oxidation, reduction, metabolic synthesis in the presence of tunicamycin, and so on. Additional post-translational modifications encompassed by the present invention include, for example, N-linked or O-linked carbohydrate chains, N-terminal or C-terminal processing, attachment of chemical moieties to the amino acid structure, chemical modifications of carbohydrate chains N-linked or O-linked and the addition or deletion of an N-terminal methionine residue as a result of expression in prokaryotic host cells. The polypeptides can also be modified with detectable labels, such as for example enzymatic, fluorescent, isotopic or affinity labels, to allow detection and isolation of the protein. In addition, the polypeptides of the present invention can be modified by iodination. In one embodiment, the neutrokine-alpha and / or neutrocine-alphaSV polypeptides of the present invention can also be labeled with biotin. In other related embodiments, the biotinylated neutrokine-alpha and / or neutrokine-alphaSV polypeptides of the present invention can be used, for example, as imaging agents or as a means to identify one or more neutrokine-alpha receptors and / or neutrocin-alphaSV or other coreceptors or associated molecules. Also, the present invention provides chemically modified derivatives of neutrocin-alpha or neutrocin-alphaSV, which may provide additional advantages such as greater solubility, stability and longer circulation time in vivo or in vi tro of the polypeptide, or a decrease in immunogenicity (see U.S. Patent No. 4,179,337). The chemical portions for derivatization can be selected from water-soluble polymers such as polyethylene glycol, ethylene glycol / propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol and the like. The polypeptides can be modified at random positions within the molecule, or at predetermined positions within the molecule, and can include one, two, three or more attached chemical moieties. The polymer can have any molecular weight and can be branched or unbranched. For polyethylene glycol, the preferred molecular weight is between about 1 and about 100 kDa (the term "about" indicates that in polyethylene glycol preparations, some molecules will weigh more, others - less than the established molecular weight), for greater ease of handling and manufacturing. Other sizes may be used, depending on the desired therapeutic profile (eg, the duration of the desired sustained release, the effects, whether it has biological activity, the ease of handling, the degree or lack of antigenicity and other known effects of polyethylene glycol on a protein. or therapeutic analog). For example, polyethylene glycol can have an average molecular weight of about 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000 , 9500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000, 25,000, 30,000, 35,000 , 40,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000 or 100,000 kDa. As noted above, the polyethylene glycol may have a branched structure. Branched polyethylene glycols are described, for example, in U.S. Patent No. 5,643,575; Morpurgo et al. , Appl. Biochem. Biotechnol. 56: 59-72 (nineteen ninety six); Vorobjev et al. , Nucleosides Nucleotides 18: 2745-2750 (1999); and Caliceti et al. , Bioconjug. Chem. 10: 638-646 (1999), the descriptions of which are incorporated herein by reference in their entirety. The molecules of polyethylene glycol (or other chemical portions) must be bound to the protein considering the effects on the functional or antigenic domains of the same. There are a number of joining methods available to those skilled in the art e.g., European Patent EP 0 401 384, which is incorporated herein by reference (coupling of PEG to FEC-G), see also Malik et al. , Exp. Hematol. 20: 1028-1035 (1992) (reporter PEGylation of FEC-GM using tresyl chloride). For example, polyethylene glycol can be covalently linked through amino acid residues, by a reactive group such as a free amino or free carboxyl group. The reactive groups are those with which an activated polyethylene glycol molecule can be attached. Amino acid residues having a free amino group can include, for example, lysine residues and N-terminal amino acid residues; those having a free carboxyl group may include aspartic acid residues, glutamic acid residues and the C-terminal amino acid residue. Sulfhydryl groups can also be used as the reactive group for the attachment of the polyethylene glycol molecules. For therapeutic purposes, attachment to an amino group, for example, N-terminal or lysine-group binding is preferred. As suggested above, polyethylene glycol can be bound to proteins through linkages with any of a number of amino acid residues. For example, polyethylene glycol can be linked to proteins through covalent bonds with lysine, histidine, aspartic acid, glutamic acid or cysteine. One or more chemical reactions can be used to bind the polyethylene glycol to the specific amino acid residues (eg, lysine, histidine, aspartic acid, glutamic acid or cysteine) of the protein or to more than one type of amino acid residues (eg, lysine, histidine, aspartic acid, glutamic acid, cysteine and combinations thereof) of the protein. Chemically modified proteins at the N-terminus could be specifically desired. Using polyethylene glycol as an illustration, one could select from a variety of polyethylene glycol molecules (by molecular weight, branches, etc.) the ratio of polyethylene glycol molecules to the protein (or peptide in the reaction mixture, the type of reaction of PEGylation to be carried out and the method to obtain the pegylated protein at the selected N-terminal end.The method for obtaining the pegylated preparation at the N-terminal end (ie, separation of this - - portion of other monopegylated portions, if necessary) can be by the purification of the PEGylated material at the N-terminal end of a population of PEGylated protein molecules.Selective chemically modified proteins can be obtained at the N-terminus by reductive alkylation, which exploits the differential reactivity of the different Types of primary amino groups (lysine versus N-terminal) available for derivation in a particular protein. Under appropriate reaction conditions, a substantial selective derivation of the protein at the N-terminus with a polymer containing carbonyl groups is achieved. As indicated above, PEGylation of the proteins of the present invention can be achieved by any of a number of media. For example, polyethylene glycol can be bound to the protein either directly, or by an intervening linker. Systems without a linker for linking polyethylene glycol to proteins are described in Delgado et al. , Cri t. Rev. Thera. Drug Carrier Sys. 9: 249-304 (1992); Francis et al. , Intern. J. of Hematol. 68: 1-18 (1998); U.S. Patent No. 4,002,531; U.S. Patent No. 5,349,052; International Publication WO 95/06058; and International Publication WO 98/32466, the disclosures of which are incorporated herein by reference.

- - A system for linking polyethylene glycol directly to amino acid residues of proteins without the use of intervening linkers uses three-fold MPEG, which is produced by the modification of monomethoxypolyethylene glycol (MPEG) with tresyl chloride (C1S02CH2CF3). Upon reaction of the protein with the three-layered MPEG, the polyethylene glycol binds directly to the amino groups of the protein. Thus, the present invention includes protein-polyethylene glycol conjugates produced by reacting the proteins of the present invention with a polyethylene glycol molecule having a 2,2,2, -trifluoroethanesulfonyl group. Polyethylene glycol can also be bound to proteins using a number of different intervening linkers. For example, U.S. Patent No. 5,612,460, the disclosure of which is incorporated herein by reference, discloses urethane linkers for connecting polyethylene glycol with proteins. Protein-polyethylene glycol conjugates may also be produced wherein the polyethylene glycol is bound to the protein by a linker, by reacting the proteins with compounds such as MPEG-succinimidylsuccinate, activated MPEG with 1,1 '-carbonyldiimidazole, MPEG-2,4, 5-trichlorophenylcarbonate, MPEG-p-nitrophenolcarbonate and various derivatives of MPEG-succinate. A further number of polyethylene glycol derivatives and reaction chemistries for linking polyethylene glycol with proteins are described in International Publication WO 98/32466, the disclosure of which is incorporated herein by reference. The PEGylated protein products that are produced using the chemical reactions set forth herein are included within the scope of the present invention. The number of polyethylene glycol moieties attached to each protein of the invention (i.e., the degree of substitution), may also vary. For example, the PEGylated proteins of the present invention may be linked, on average, to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20 or more polyethylene glycol molecules . Similarly, the average degree of substitution varies within ranges such as 1-3, 2-4, 3-5, 4-6, 5-7, 6-8, 7-9, 8-10, 9-11. , 10-12, 11-13, 12-14, 13-15, 14-16, 15-17, 16-18, 17-19 or 18-20 portions of polyethylene glycol per protein molecule. Some methods for determining the degree of substitution are described, for example, in Delgado et al. , Cri t. Rev. Thera. Drug Carrier Sys. 9: 249-304 (1992). The neutrokine-alpha and / or neutrocin-alphaSV polypeptides can be recovered and purified by known methods including, but not limited to, ammonium sulfate or ethanol precipitation, acid extraction, anionic or cationic exchange chromatography, Phosphocellulose, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Preferably, high performance liquid chromatography ("HPLC") is used for purification. Neutrophil-alpha polypeptides Neutrocin-alpha and / or neutrocin-alphaSV polypeptides of the present invention may be monomers or multimers (i.e., dimers, trimers, tetramers and higher multimers). Accordingly, the present invention relates to monomers and multimers of neutrokine-alpha and / or neutrocine-alphaSV polypeptides of the present invention, to their preparation and to compositions (preferably pharmaceutical compositions) containing them. In specific embodiments, the polypeptides of the present invention are monomers, dimers, trimers or tetramers. In additional embodiments, the multimers of the present invention are at least dimers, at least trimers or at least tetramers. The multimers encompassed by the present invention can be homomers or heteromers. As used herein, the term "homomer" refers to a multimer containing only neutrokine-alpha and / or neutrocine-alphaSV polypeptides of the present invention (including fragments), Neutrocin-alpha and / or Neutrocin-alphaSV fusion variants and variants, as described herein). These homomers may contain neutrokine-alpha and / or neutrocin-alphaSV polypeptides having identical or different amino acid sequence. In a specific embodiment, a homomer of the present invention is a multimer containing only neutrokine-alpha and / or neutrocin-alphaSV polypeptides having an identical amino acid sequence. In another specific embodiment, a homomer of the present invention is a multimer containing neutral-alpha and / or neutrocin-alphaSV polypeptides having different amino acid sequences. In specific embodiments, the multimer of the present invention is a homodimer (eg, containing neutral-alpha and / or neutrocin-alphaSV polypeptides with identical or different amino acid sequences) or a homotrimer (eg, containing neutrokine-alpha polypeptides) and / or neutrocin-alphaSV having identical or different amino acid sequences). In a preferred embodiment, the multimer of the present invention is a homotrimer. In further embodiments, the homomeric multimer of the present invention is at least one homodimer, at least one homotrimer or at least one homotetramer. As used herein, the term "heteromer" refers to a multimer containing heterologous polypeptides (ie, polypeptides of a different protein) in addition to the neutrokine-alpha and / or neutrocine-alphaSV polypeptides of the present invention. In a specific embodiment, the multimer of the present invention is a heterodimer, a heterotrimer or a heterotetramer. In additional embodiments, the heteromeric multimer of the present invention is at least one heterodimer, at least one heterotrimer or at least one heterotetramer. In a non-exclusive additional embodiment, the heteromers of the present invention contain CD40 ligand polypeptide sequences or biologically active fragments or variants thereof. The multimers of the present invention may be the result of hydrophobic, hydrophilic, ionic and / or covalent associations, and / or may be indirectly linked, for example, by the formation of liposomes. Thus, in one embodiment, the multimers of the present invention, such as, for example, homodimers or homotrimers, are formed when the polypeptides of the present invention are brought into contact with one another in solution. In another embodiment, the heteromultimers of the present invention, such as for example heterotrimers or heterotetramers, are formed when the polypeptides of the invention come into contact with antibodies against the polypeptides of the invention (including antibodies against the heterologous polypeptide sequence in a fusion protein. of the invention, in solution In other embodiments, the multimers of the present invention are formed by covalent associations with and / or between the neutrokine-alpha and / or neutrocine-alphaSV polypeptides of the present invention. or more amino acid residues contained in the polypeptide sequence (eg, which are cited in SEQ ID NO: 2 or SEQ ID NO: 19 or which are contained in the polypeptide encoded by the clones deposited with reference to this application). In one case, covalent associations are cross-linked between cysteine residues located in the sequences polypeptides that interact in the native polypeptide (i.e., of natural origin). In another case, the covalent associations are the consequence of a chemical or recombinant manipulation. Alternatively, such covalent associations may involve one or more amino acid residues contained in the heterologous polypeptide in a fusion protein of neutrocine-alpha and / or neutrocine-alphaSV. In one example, the covalent associations are between the heterologous sequence contained in a fusion protein of the invention (see e.g., U.S. Patent No. 5,478,925). In a specific example, the covalent associations are between the heterologous sequence contained in a fusion protein of neutrocine-alpha-Fc and / or neutrocin-alphaSV-Fc of the invention (as described herein). In another specific example, the covalent associations of fusion proteins of the invention are between the sequence of the heterologous polypeptide of another ligand / receptor member of the TNF family that is capable of forming covalently associated multimers, such as, for example, osteoprotegerin (see eg International Publication WO 98/49305, the content of which is incorporated herein by reference in its entirety). In another specific example, the covalent associations of the fusion proteins of the invention are between the heterologous CD40L polypeptide sequence or a soluble fragment thereof. In another embodiment, two or more neutrokine-alpha and / or neutrocine-alphaSV polypeptides of the present invention are linked by synthetic linkers (e.g., peptide linkers, carbohydrates or soluble polymers). Some examples include those peptide linkers described in U.S. Patent No. 5,073,627 (incorporated herein by reference). Proteins comprising multiple neutrokine-alpha and / or neutrocine-alphaSV polypeptides separated by peptide linkers can be produced using recombinant DNA technology. Another method for preparing neutrokine-alpha and / or neutrocin-alphaSV polypeptide multimers of the present invention includes the use of neutrokine-alpha and / or neutrocine-alphaSV polypeptides fused to a leucine zipper or a zipper polypeptide sequence of isoleucine. The zipper domains of leucine or isoleucine are polypeptides that promote the multimerization of the proteins in which they are found. Leucine zippers were originally identified in several DNA binding proteins (Landschulz et al., Science 240: 1759 (1988)), and have been found in a variety of different proteins. Among the known leucine or isoleucine zippers, there are peptides of natural origin and derivatives thereof which are dimerized or trimerized. Examples of leucine zipper domains suitable for producing the soluble multimeric neutrocyne-alpha and / or neutrocin-alphaSV proteins are those described in PCT Patent Application WO 94/10308, which is incorporated herein by reference. Recombinant fusion proteins comprising a soluble neutrokine-alpha and / or neutrokine-alphaSV polypeptide fused to a peptide that is dimerized or trimerized in solution, are expressed in suitable host cells and the neutrocine-alpha and / or neutrocytic protein Soluble ultimeric alphaSV is recovered from the culture supernatant by techniques known in this field. Certain members of the TNF family of proteins are thought to exist in trimeric form (Beutler and Hufffel, Science 264: 667, 1994; Banner et al., Cell 73: 431, 1993). Thus, neutrocin-alpha and / or neutrocin-alphaSV trimeric may offer the advantage of increased biological activity. Preferred leucine zipper portions are those which preferentially form trimers. An example is a leucine zipper derived from pulmonary surfactant protein D (PDT), as described in Hoppe et al., (FEBS Letters 344: 191, (1994)) and in the North American Patent Application serial number. 08 / 446,922, which are incorporated herein by reference. Other peptides derived from trimeric proteins of natural origin, can be used in the preparation of neutrocine-alpha and / or neutrocin-alpha-trimeric. In another example, the proteins of the present invention are associated through interactions between the Flag® polypeptide sequence contained in the Flag®-neutrocin-alpha or Flag®-neutrocin-alphaSV fusion proteins of the present invention. In a further embodiment, the proteins of the present invention are associated through interactions between the heterologous polypeptide sequence contained in the Flag®-neutrocin-alpha- or Flag®-neutrocin-alphaSV fusion proteins of the present invention and an anti-HIV antibody. -Flag®. The multimers of the present invention can be generated using the chemical techniques known in the art. For example, polypeptides that are desired to be contained in the multimers of the invention can be cross-linked chemically using linker molecules and techniques for optimizing the length of linker molecules known in the art (see eg US Patent No. 5,478,925; which is incorporated herein by reference in its entirety). Additionally, the multimers of the present invention can be generated using known techniques to form one or more intermolecular crosslinks between the cysteine residues located within the sequence of the polypeptides that are desired to be contained in the multimer (see for example Patent North American No. 5, 478,925, which is incorporated herein by reference in its entirety). In addition, the polypeptides of the present invention can routinely be modified by the addition of cysteine or biotin to the C-terminal or N-terminus of the polypeptide, and known techniques can be applied to generate multimers containing one or more of these modified polypeptides ( see, for example, U.S. Patent No. 5,478,925 which is hereby incorporated by reference in its entirety). Additionally, known techniques can be applied to generate liposomes containing the polypeptide components that are desired to be contained in the multimer of the invention (see, eg, U.S. Patent No. 5,478,925, which is hereby incorporated in its entirety as reference). Alternatively, the multimers of the invention can be generated using known genetic engineering techniques. In one embodiment, the polypeptides contained in the multimers of the invention are produced recombinantly using the fusion protein technology described herein or otherwise known in the art (see, eg, US Patent No. 5,478,925, which is incorporated herein by reference in its entirety). In a specific embodiment, polynucleotides encoding a homodimer of the present invention are generated by ligation of a polynucleotide sequence encoding a polypeptide of the invention with a sequence encoding a linker polypeptide and then with a synthetic polynucleotide encoding for the translated product of the polypeptide in reverse orientation from the original C-terminal end to the N-terminus (without leader sequence) (see, eg, US Patent No. - - ,478,925, which is incorporated herein by reference in its entirety). In another embodiment, the recombinant techniques described herein or otherwise known in the art, are applied to generate recombinant polypeptides of the present invention that contain a transmembrane domain and that can be incorporated by membrane reconstitution techniques in liposomes (see eg, U.S. Patent No. 5,478,925, which is incorporated herein by reference in its entirety). In one embodiment, the present invention provides a neutrocine-alpha polypeptide having an amino acid sequence encoded by the cDNA clone contained in the ATCC with accession number 97768, or the amino acid sequence of Figures IA and IB (SEQ. ID NO: 2) or a polypeptide comprising a portion (ie, a fragment) of the above polypeptides. In another embodiment, the present invention provides an isolated neutrophin-alphaSV polypeptide having the amino acid sequence encoded by the cDNA clone contained in the ATCC with accession number 203518, or the amino acid sequence of Figures 5A and 5B ( SEQ ID NO: 19) or a polypeptide comprising a portion (ie, a fragment) of the above polypeptides. The polypeptide fragments of the present invention include polypeptides comprising or alternatively consisting of, an amino acid sequence contained in SEQ ID NO: 2, encoded by the cDNA contained in the plasmid having the accession number ATCC 97768, or encoded by nucleic acids that hybridize (eg, under stringent hybridization conditions) to the nucleotide sequence contained in the deposited clone, or the strand complementary to the nucleotide sequence shown in Figures 1A-B (SEQ ID NO: 1). Additionally, the polypeptide fragments of the present invention include polypeptides comprising or alternatively consisting of, an amino acid sequence contained in SEQ ID NO: 19, encoded by the cDNA contained in the plasmid having the accession number ATCC 203518, or encoded by nucleic acids that hybridize (eg, under stringent hybridization conditions) to the nucleotide sequence contained in the deposited clone, or the strand complementary to the nucleotide sequence shown in Figures 5A and 5B (SEQ ID NO: 18). Additionally, the polypeptide fragments of the present invention include polypeptides comprising or alternatively consisting of, an amino acid sequence encoded by nucleic acids that hybridize (eg, under stringent hybridization conditions described herein) to the complementary strand of the sequence of nucleotides shown in SEQ ID NO: 21). The polypeptide fragments of the present invention also include polypeptides comprising or alternatively consisting of, an amino acid sequence contained in SEQ ID NO: 23 or encoded by nucleic acids that hybridize (eg, under stringent hybridization conditions described herein) to the complementary strand of the nucleotide sequence shown in SEQ ID NO: 22). In addition, the polypeptide fragments of the present invention include polypeptides comprising or alternatively consisting of, an amino acid sequence contained in SEQ ID NO: 28 or encoded by nucleic acids that hybridize (eg, under stringent hybridization conditions described herein) ) to the complementary chain to the nucleotide sequence shown in SEQ ID NO: 27). Additionally, the polypeptide fragments of the present invention include polypeptides comprising or alternatively consisting of, an amino acid sequence contained in SEQ ID NO: 30 or encoded by nucleic acids that hybridize (eg, under stringent hybridization conditions described herein) ) to the chain complementary to the nucleotide sequence - - shown in SEQ ID NO: 29). The polypeptide fragments of the present invention include polypeptides that comprise or alternatively consist of, an amino acid sequence contained in SEQ ID NO: 2, encoded by the cDNA contained in the clone deposited or encoded by nucleic acids that hybridize (eg, under stringent hybridization conditions) to the nucleotide sequence contained in the deposited clone , or that are shown in Figures IA and IB (SEQ ID NO: 1) or the chain complementary to it. The protein fragments may be "free" or may be comprised within a larger peptide of which this fragment forms a part or a region, preferably in the form of a single continuous region. Representative examples of the polypeptide fragments of the present invention, include for example fragments comprising or alternatively consisting of approximately amino acid residues: from 1 to 50, 51 to 100, 101 to 150, 151 to 200, 201 to 250 and / or 251 to 285 of SEQ ID NO: 2. In addition, the polypeptide fragments can have at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 175 or 200 amino acids in length. In specific embodiments, the polypeptide fragments of the present invention comprise or alternatively consist of, the amino acid residues: from 1 to 46, 31-44, 47-72, 73-285, 73-83, 94-102, 148-152 , 166-181, 185-209, 210-221, 226-237, 244-249, 253-265 and / or 277-284, as illustrated in Figures IA and IB (SEQ ID NO: 2). The polynucleotides encoding these polypeptides are also encompassed by the present invention. One skilled in the art will recognize that mutations directed to neutrokine-alpha polypeptide regions of the present invention encompass the nineteen insertion amino acid residues that are not found in the neutrokine-alphaSV polypeptide sequence (ie, the Amino acid residues of VA1-142 to Lys-160 of the sequence presented in Figures IA and IB and SEQ ID NO: 2), can affect the biological activities observed of the neutrocine-alpha polypeptide. More specifically, a partial, non-limiting and non-exclusive list of such residues of the neutrokine-alpha polypeptide sequence that can be targeted for mutations includes the following amino acid residues of the neutrokine-alpha polypeptide sequence as shown in SEQ ID NO: 2: V-142; T-143; Q-144; D-145; C-146; L-147; Q-148; L-149; 1-150; A-1551; D-152; S-153; E-154; T-155; P-156; T-157; 1-158; Q-159 and K-160. Polynucleotides encoding neutrokine-alpha polypeptides having one or more mutations in the V-142 to K-160 region of SEQ ID NO: 2 are also contemplated. The polypeptides encoded by these polynucleotides are also included in the present invention. The polypeptide fragments can be "free" or may be comprised within a larger polypeptide of which this fragment forms a part or region, preferably in the form of a single continuous region. Representative examples of polypeptide fragments of the present invention include, for example, fragments comprising or alternatively consisting of approximately amino acid residues: from 1 to 15, 16-30, 31-46, 47-55, 56-72, 73- 104, 105-163, 163-188, 186-210 and 210-284 of the amino acid sequence described in SEQ ID NO: 2. Further representative examples of the polypeptide fragments of the present invention, include for example fragments comprising or alternatively they consist of approximately the amino acid residues: from 1 to 143, 1-150, 47-143, 47-150, 73-143, 73-150, 100-150, 140-145, 142-148, 140-150, 140-200, 140-225 and 140-266 of the amino acid sequence described in SEQ ID NO: 19. In addition, the polypeptide fragments can have at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 175 or 200 amino acids in length. In this context the term "approximately" means the ranges particularly cited and ranges larger or smaller in several, a few, 5, 4, 3, 2 or 1 amino acid residues, at either amino terminus and carboxyl terminus. terminal or both. The polynucleotides encoding these polypeptide fragments are also encompassed by the present invention. Additional preferred moieties include polypeptide fragments comprising, or alternatively consisting of, the predicted intracellular domain of neutrokine-alpha (amino acid residues 1 to 46 of SEQ ID NO: 2), the predicted transmembrane domain of neutrokine-alpha ( amino acid residues 47 to 72 of SEQ ID NO: 2), the predicted extracellular domain of neutrokine-alpha (amino acid residues 73 to 285 of SEQ ID NO: 2), the predicted TNF conservative domain of neutrocine -alpha (amino acid residues 191 to 284 of SEQ ID NO: 2) and a polypeptide comprising or alternatively consisting of, the predicted intracellular domain fused to the predicted extracellular domain of neutrokine-alpha (amino acid residues 1 to 46 fused to the amino acid residues 73 to 285 of SEQ ID NO: 2). The polynucleotides encoding these polypeptides are also encompassed by the present invention.

Additional preferred moieties include polypeptide fragments comprising, or alternatively consisting of, the predicted intracellular domain of neutrokine-alphaSV (amino acid residues 1 to 46 of SEQ ID NO: 19), the predicted transmembrane domain of neutrokine-alphaSV ( amino acid residues 47 to 72 of SEQ ID NO: 19), the predicted extracellular domain of neutrokine-alphaSV (amino acid residues 73 to 266 of SEQ ID NO: 19), the predicted TNF conservative domain of neutrocine -alphaSV (amino acid residues 172 to 265 of SEQ ID NO: 19) and a polypeptide comprising or alternatively consisting of the predicted intracellular domain fused to the predicted extracellular domain of neutrokine-alphaSV (amino acid residues 1 to 46 fused to the amino acid residues 73 to 266 of SEQ ID NO: 19). The polynucleotides encoding these polypeptides are also encompassed by the present invention. Certain additional embodiments of the present invention include polypeptide fragments that comprise, or alternatively consist of, the predicted beta sheet regions identified in Figures 7A-I-7A-II. These polypeptide fragments of the present invention, comprise or alternatively consist of the amino acid residues of Gln-144 to Ala-151, Phe-172 to Lys-173, Ala-177 to Glu-179, Asn-183 to Ile-185, Gly-191 to Lys-204, His-210 to Val-219, Leu-226 to Pro-237, Asn-242 to Ala-251, Gly-256 to Ile-263 and / or Val-276 to Leu-284 from SEQ ID NO: 2. In another non-exclusive mode, these polypeptide fragments of the present invention also comprise, or alternatively consist of the amino acid residues Phe-153 to Lys-154, Ala-158 to Glu-160, Asn-164 to Ile-166, Gly-237 to Ile. 244 and / or Val-257 to Leu-265 of SEQ ID NO: 19, and amino acid residues Phe-42 to Lys-43, Ala-47 to Glu-49, Asn-53 to Ile-55, Gly-61 to Pro-74, His-80 to Val-89, Leu-96 to Pro-107, Asn-112 to Ala-121, Gly-126 to Ile-133 and / or Asp-146 to Leu-154 of SEQ ID NO: 23. In non-exclusive additional embodiments, these polypeptide fragments of the present invention also comprise, or alternatively consist of the amino acid residues from Gln-78 to Ala-85; Phe-106 to Lys-107, ala-111 to Glu-113, Asn-117 to Ile-119, Gly-125 to Lys-138, His-144 to Val-153, Leu-160 to Pro-171, Asn- 176 at Ala-185, Gly-190 at Ile-197 and / or Val-210 at Leu-218 of SEQ ID NO: 28, and amino acid residues Gln-78 at Ala-85; Phe-106 to Lys-107, ala-111 to glu-113, Asn-117 to Ile-119, Gly-125 to Lys-138, His-144 to Val-153, Leu-160 to Pro-171, Asn- 176 to Ala-185, Gly-190 to Ile-197 and / or Val-210 to Leu-218 of SEQ ID NO: 30. Polynucleotides encoding these polypeptide fragments are also provided.

- - A partial, non-limiting and exemplary list of the polypeptides of the present invention comprising or alternatively consisting of combinations of the amino acid sequences of the present invention, includes for example [Met-1 to Lys 113] fused with [Leu -114 to Thr-141] fused to [Ile-142 to Lys-160] fused to [Gly-161 to Gln-198] fused to [Val-199 to Ala-248] fused to [Gly-250 to Leu-285 ] of SEQ ID NO: 2; [Met-l to Lys-113] fused to [Ile-142 to Lys-160] fused to [Gly-161 to Gln-198] fused to [Val-199 to Ala-248] fused to [Gly-250 to Leu -285] of SEQ ID NO: 2; or [Met-l to Lys-113] fused to [Leu-114 to Thr-141] fused to [Ile-142 to Lys-160] fused to [Gly-161 to Gln-198] fused to [Gly-250 to Leu-285] of SEQ ID NO: 2. Other combinations may include the polypeptide fragments in an order different from that previously cited (e.g., [Leu-114 to Thr-141] fused with [Val-199 to Ala-248] fused to [Gly-250 to Leu-285]. ] merged with [Ile-142 to Lys-160] of SEQ ID NO: 2). Other combinations may also include heterologous polypeptide fragments as described herein and / or other polypeptides or polypeptide fragments of the present invention (e.g., [Met-1 to Lys-113] fused to [Leu-114 to Thr. -141] - - merged with [Ile-142 to Lys-160] merged with [Gly-161 to Gln-198] merged with [Gly-250 to Leu 285] of SEQ ID NO: 2 merged with a FLAG mark) . Polynucleotides that code for any of these polypeptides are encompassed by the present invention. A partial, non-limiting and exemplary list of the polypeptides of the present invention comprising, or alternatively consisting of combinations of amino acid sequences, includes for example, [Met-1 to Lys-113] fused to [Leu 114 to Thr- 141] fused with [Gly-142 to Gln-179] fused to [Val-180 to Ala-229] fused to [Gly-230 to Leu-266] of SEQ ID NO: 19; [Met-1 to Lys-113] fused to [Gly-142 to Gln-179] fused to [Val-180 to Ala-229] fused to [Gly-230 to Leu-266] of SEQ ID NO: 19; or [Met-l to Lys-113] fused to [Leu-114 to Thr-141] fused to [Gly-142 to Gln-179] fused to [Gly-230 to Leu-266] of SEQ ID NO: 19 Other combinations may include the polypeptide fragments in an order different from that previously described (eg, [Leu-114 to Thr-141] fused to [Val-180 to Ala-229] fused to [gly-230 to Leu-266] fused with [Gly-142 to Gln-179] of SEQ ID NO: 19). Other combinations may also include heterologous polypeptide fragments such as those described herein and / or other polypeptides or polypeptide fragments of the present invention (e.g., [Met-1 to Lys-113] fused to [Leu-114]. to Thr-141] fused to [Gly-142 to Gln-179] fused to [Gly-230 to Leu 266] of SEQ ID NO: 19 merged with a FLAG mark).

Polynucleotides encoding any of these polypeptides are also encompassed by the present invention. A partial, non-limiting and exemplary list of the polypeptides of the present invention comprising, or alternatively consisting of, combinations of amino acid sequences, includes for example [Met-1 to Lys-106] fused to [Leu-107] a Thr-134] fused to [I le-167 to Lys-184] fused to [Gly-185 to Gln-224] fused to [Val-225 to Ala-272] fused to [Gly-273 to Leu-309] of SEQ ID NO: 23; [Met-l to Lys-106] fused to [glu-135 to Asn-165] fused to [Ile-167 to Lys-184] fused to [Gly-185 to Gln-224] fused to [Val-225 to Ala -272] fused to [Gly-273 to Leu-309] of SEQ ID NO: 23; or [Met-l to Lys-106] fused to [Leu-107 to Thr-134] fused to [Glu-135 to Asn-165] fused to [Ile-167 to Lys-184] fused to [Gly-185 to Gln-224] fused to [Gly-273 to Leu-309] of SEQ ID NO: 23. Other - - combinations may include the polypeptide fragments in an order different from the one previously mentioned (eg [Met-1 to Lys-106] fused with [Gly-185 to Gln-224] fused with [Ile-167 to Lys-184] fused with [Val-225 to Ala-272] fused to [Leu-107 to Thr-134] fused to [Gly-273 to Leu-309] of SEQ ID NO: 23. Other combinations may also include heterologous polypeptide fragments such as those described herein and / or other polypeptides or polypeptide fragments of the present invention (eg, [Met-l to Lys-106] fused to [Glu-135 to Asn-165] fused to [Ile-167 to Lys-184] fused to [Gly-185 to Gln-224] fused to Vál-225 to Ala -272] merged with [Gly-273 to Leu-309] of SEQ ID NO: 23 merged with a FLAG mark). The polynucleotides encoding these polypeptides are also encompassed by the present invention. A partial, non-limiting and exemplary list of the polypeptides of the present invention comprising or alternatively consisting of combinations of the amino acid sequences of the present invention, includes for example [Tyr-1 to Lys-47] fused to [Leu 48 a Thr-75] fused to [Ile-76 to Lys-94] fused to [gly-95 to Gln-132] fused to [Val-133 to Ala-182] fused to [Gly- - 183 to Ala 219] of SEQ ID NO: 28; [Tyr-1 to Lys-47] fused to [Leu-48 to Thr-75] fused to [Ile-76 to Lys-94] fused to [Val-133 to Ala-182] of SEQ ID NO: 28; or [Tyr-1 to Lys-47] fused to [Ile-76 to Lys-94] fused to [Val-133 to Ala-182] fused to [Gly-183 to Ala-219] of SEQ ID NO: 28 Other combinations may include the polypeptide fragments in an order different from the one previously mentioned (eg, [Tyr-1 to Lys-47] fused with [Gly-183 to Ala-219] fused to [Val-133 to Ala-182] fused with [Leu-48 to Thr-75] of SEQ ID NO: 28). Other combinations may also include heterologous polypeptide fragments such as those described herein and / or other polypeptides or polypeptide fragments of the present invention (eg, [Leu-48 to Thr-75] fused to [Ile-76 to Lys-94] fused with [Gly-95 to Gln-132] fused to [Val-133 to Ala-182] of SEQ ID NO: 28 fused to a labeled Fc receptor). Polynucleotides encoding any of these polypeptides are also encompassed by the present invention. A partial, non-limiting and exemplary list of the polypeptides of the present invention comprising or alternatively consisting of combinations of the amino acid sequences of the present invention, includes for example [Tyr-1 to Lys-47] fused to [Leu] -48 to Thr-75] fused to [Ile-76 to Lys-94] fused to [Gly-95 to Gln-132] fused to [Val-133 to Ala-182] fused to [Gly-183 to Ala-219 ] of SEQ ID NO: 30; [Tyr-1 to Lys-47] fused to [Leu-48 to Thr-75] fused to [Ile-76 to Lys-94] fused to [Val-133 to Ala-182] of SEQ ID NO: 30; or [Tyr-1 to Lys-47] fused with [Ile-76 to Lys-94] fused with [Val-133 to Ala-182] merged with [Gly-183 to Ala-219] of SEQ ID NO: 30. Other combinations may include the polypeptide fragments in an order different from that previously cited (eg g., [Tyr-1 to Lys-47] fused to [Gly-183 to Ala-219] fused to [Val-133 to Ala -182] fused to [Leu-48 to Thr-75] of SEQ ID NO: 30). Other combinations may also include heterologous polypeptide fragments such as those described herein and / or other polypeptides or polypeptide fragments of the present invention (e.g. [Leu-48 to Thr-75] fused to [Ile-76 to Lys- 94] fused with [Gly-95 to Gln-132] fused to [Val-133 to Ala-182] of SEQ ID NO: 30 fused to a labeled Fc receptor). Polynucleotides encoding any of these polypeptides are also encompassed by the present invention. Additional embodiments of the present invention include neutrokine-alpha and / or neutrocin-alphaSV polypeptide fragments comprising, or alternatively consisting of, functional regions of the polypeptides of the invention, such as the Garnier-Robson alpha regions, beta regions , torsion regions and helical regions, Chou-Fasman alpha regions, beta regions and helical regions, Kyte-Doolittle hydrophilic regions and hydrophobic regions, alpha amphipathic and beta amphipathic regions of Eisenberg, flexible regions of Karplus-Zchulz, formative regions Emini surface and Jameson-Wolf regions of high antigenic index set forth in Figures 3 and 6 and in Table I and as described herein. In a preferred embodiment, the polypeptide fragments of the present invention are antigenic. The data presented in columns VIII, IX, XIII and XIV of Table I, can be used to routinely determine regions of neutrocin-alpha that exhibit a high degree of antigenicity potential. The regions of high antigenicity are determined from the data presented in columns VIII, IX, XIII and / or IV, by selecting values representing regions of the polypeptide that are likely to be exposed on the surface thereof, in an environment in which which can occur the recognition of the antigen in the process of initiation of an immune response. Among - the highly preferred fragments of the present invention, there are those that comprise neutrokine-alpha and / or neutrocin-alphaSV regions that combine several structural characteristics, such as several (e.g., 1, 2, 3 or 4) of the previously established characteristics. The polynucleotides encoding these polypeptides are also encompassed by the present invention. In another embodiment, the present invention provides a polypeptide comprising or alternatively consisting of, an epitope-carrying portion of a polypeptide of the invention. The polynucleotides encoding these polypeptides are also encompassed by the present invention. The epitope of this polypeptide portion is an immunogenic or antigenic epitope of a polypeptide of the invention. The term "immunogenic epitope" is defined as a part of a protein that induces an antibody response when the entire protein is the immunogen. On the other hand, a region of a protein molecule to which an antibody can be attached is defined as an "antigenic epitope". The number of immunogenic epitopes of a protein is generally less than the number of antigenic epitopes. See, for example, Geysen et al. , Proc. Nat 'l Acad. Sci. USA 81: 3998-4002 (1983).

- - As for the selection of polypeptides carrying an antigenic epitope (ie, containing a region of a protein molecule to which an antibody can bind), it is well known in the art that relatively short synthetic peptides that mimic of a protein sequence, they are routinely capable of inducing an antiserum that reacts with the partially imitated protein. See, for example, Sutcliffe, JG Shinnick, TM, Green, N and Learner, RA (1983) "Antibodies that react with predetermined sites of proteins", Science, 219: 660-666. Peptides capable of inducing sera that react with the proteins that are often represented in the primary sequence of a protein, can be characterized by a set of simple chemical rules, and are not confined to immunodominant regions of intact proteins (ie, immunogenic epitopes) or to amino-terminal or carboxyl-terminal. The peptides and polypeptides carrying the antigenic epitope of the present invention, therefore, are useful for inducing antibodies, including monoclonal antibodies, that specifically bind to a polypeptide of the present invention. See, for example, Wilson et al. , Cell 37: 767-778 (1984) to 777. The peptides and polypeptides carrying the antigenic epitope of the present invention, preferably - contain a sequence of at least 4, at least 5, at least 6, at least 7, preferably at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 25, at least 30, at least 40, at least 50, and more preferably between about 15 and about 30 amino acids contained within the amino acid sequence of a polypeptide of the invention. Preferred polypeptides comprising immunogenic or antigenic epitopes have at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 Amino acid residues in length. Preferred non-exclusive antigenic epitopes include the antigenic epitopes described herein, as well as portions thereof. Non-limiting examples of antigenic polypeptides or peptides that can be used to generate specific antibodies against neutrocin-alpha and / or neutrocin-alphaSV, include: a polypeptide comprising or alternatively consisting of the amino acid residues from about Phe-115 to about 147 of Figures IA and IB (SEQ ID NO: 2); a polypeptide comprising or alternatively consisting of the amino acid residues of about Ile-150 to about Tyr-163 of Figures IA and IB (SEQ ID NO: 2), a polypeptide which comprises or alternatively consists of the amino acid residues from about Ser-171 to about Phe-194 of Figures IA and IB (SEQ ID NO: 2); a polypeptide comprising or alternatively consisting of the amino acid residues from about Glu-223 to about Tyr-246 of Figures IA and IB (SEQ ID NO: 2); and a polypeptide comprising or alternatively consisting of the amino acid residues from about Ser-271 to about Phe-278 of Figures IA and IB (SEQ ID NO: 2). In this context, the term "approximately" means the ranges particularly mentioned and ranges greater or lesser in several, a few, 5, 4, 3, 2 or 1 amino acid residues at either or both amino-terminal or carboxyl-terminal ends . It has been determined that these polypeptide fragments are carriers of antigenic epitopes of the neutrokine-alpha polypeptide, by analysis of the Jameson-Wolf antigenic index, as shown in Figure 3 and in Table I, above. Non-limiting examples of antigenic polypeptides or peptides that can be used to generate specific antibodies against neutrokine-alpha and / or neutrocin-alphaSV, include: a polypeptide comprising or alternatively consisting of the amino acid residues from about Pro-32 to about 47 of Figures 5A and 5B (SEQ - - ID NO: 19); a polypeptide comprising or alternatively consisting of the amino acid residues from about Glu-116 to about Ser-143 of Figures 5A and 5B (SEQ ID NO: 19); a polypeptide comprising or alternatively consisting of the amino acid residues from about Phe-153 to about Tyr-173 of Figures 5A and 5B (SEQ ID NO: 19); a polypeptide comprising or alternatively consisting of the amino acid residues from about Pro-218 to about Tyr-227 of Figures 5A and 5B (SEQ ID NO: 19); a polypeptide comprising or alternatively consisting of the amino acid residues from about Ala-232 to about Gln-241 of Figures 5A and 5B (SEQ ID NO: 19); a polypeptide comprising or alternatively consisting of the amino acid residues from about Ile-244 to about Ala-249 of Figures 5A and 5B (SEQ ID NO: 19); and a polypeptide comprising or alternatively consisting of the amino acid residues of about Ser-252 to about Val-257 of Figures 5A and 5B (SEQ ID NO: 19). In this context, the term "approximately" means the ranges particularly mentioned and ranges greater or lesser in several, a few, 5, 4, 3, 2 or 1 amino acid residues at either or both amino-terminal or carboxyl-terminal ends . The polynucleotides that code for these polypeptides are also encompassed by the present invention. It has been determined that these polypeptide fragments are carriers of antigenic epitopes of the neutrokine-alphaSV polypeptide by analysis of the Jameson-Wolf antigenic index, as shown in Figure 6 and a tabular representation of the data presented in Figure 6, generated by the "Protean" component of the DNA * STAR computer program as stated above). The epitope-bearing peptides and polypeptides of the present invention can be produced by any conventional means. See e.g. Houghten, R. A. (1985) General methods for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen-antibody interaction at the level or findividual amino acids. Proc. Nat 'l Acad. Sci. USA 82: 5131-5135; This "Simultaneous Multiple Peptide Synthesis (SMPS)" process is also described in US Patent No. 4,631,211 to Houghten et al. (1986). The epitope-bearing peptides and polypeptides of the present invention have uses that include, but are not limited to, use for inducing antibodies in accordance with methods known in the art. See, for example, Sutcliffe et al., Supra; Wilson et al., Supra; Chow, M. et al. , Proc. Nat 'l Acad. Sci. USES. 82: 910-914; and Bittle, F.J. - et al. , J. Gen. Virol. 66: 2347-2354 (1985). The immunogenic epitope-carrying peptides of the present invention, i.e. those parts of a protein that induce an antibody response when the entire protein is the immunogen, are identified in accordance with methods known in the art. See, for example, Geysen et al. , supra. In addition, the US Patent US ,194,392 to Geysen (1990) describes a general method for detecting or determining the sequence of monomers (amino acids or other compounds) which is a topological equivalent of an epitope ie, a "mimotope") which is complementary to a particular paratope (site). antigen binding) of an antibody of interest. More generally, US Pat. No. 4,433,092 to Geysen (1989) describes a method for detecting or determining a monomer sequence that is a topographic equivalent of a ligand that is complementary to the ligand binding site of a particular receptor of interest. Similarly, U.S. Patent No. 5,480,971 to Houghten, R.A. et al. (1996) on mixtures of peralkylated oligopeptides, describes peralkylated Cl-C7-alkyl oligopeptides and sets and libraries of such peptides, as well as methods for using the oligopeptide assemblies and libraries to determine the sequence of a peralkylated oligopeptide that preferentially binds to a receptor-molecule of interest. Thus, non-peptide analogues of the epitope-bearing peptides of the present invention can be prepared routinely by these methods. The present invention includes polypeptides comprising or alternatively consisting of an epitope of the polypeptide having an amino acid sequence of SEQ ID NO: 2 or an epitope of the polypeptide sequence encoded by a polynucleotide sequence contained in the ATCC deposit No. 97768 or encoded by a polynucleotide that hybridizes with the complement of the sequence of SEQ ID NO: 1 or the cDNA sequence contained in the ATCC deposit No. 97768 (eg, under stringent hybridization conditions described herein). The present invention further includes polynucleotide sequences comprising or alternatively consisting of a sequence encoding an epitope of a polypeptide sequence of the invention (such as, for example, the sequence described in SEQ ID NO: 1), polynucleotide sequences of the complementary strand of a polynucleotide sequence that codes for an epitope of the invention and polynucleotide sequences that hybridize with the complementary strand (eg, under stringent hybridization conditions described herein).

- The present invention also encompasses polypeptides comprising or alternatively consisting of an epitope of the polypeptide having an amino acid sequence of SEQ ID NO: 19 or an epitope of the polypeptide sequence encoded by a polynucleotide sequence contained in the ATCC deposit No. 203518 or encoded by a polynucleotide that hybridizes with the complement of the sequence of SEQ ID NO: 18 or the cDNA sequence contained in the ATCC deposit No. 203518 (eg, under stringent hybridization conditions described herein). The present invention further includes polynucleotide sequences comprising or alternatively consisting of a sequence encoding an epitope of a polypeptide sequence of the invention (such as, for example, the sequence described in SEQ ID NO: 18), polynucleotide sequences of the complementary strand of a polynucleotide sequence that codes for an epitope of the invention and polynucleotide sequences that hybridize to the complementary strand (eg, under stringent hybridization conditions described herein). The term "epitopes" as used herein, refers to portions of a polypeptide that have antigenic or immunogenic activity in an animal, preferably a mammal, and more preferably in a human-being. A preferred embodiment of the present invention includes a polypeptide comprising an epimole, as well as the polynucleotide that codes for that polypeptide. The term "immunogenic epitope" as used herein, is defined as a portion of a protein that induces an antibody response in an animal, determined by any method known in the art, for example by methods for generating described antibodies infra (see for example, Geysen et al., Proc. Nat'l Acad. Sci. USA 81: 3998-4002 (1983)). The term "antigenic epitope" as used herein, is defined as a portion of a protein to which an antibody can be bound in an immunospecific manner, as determined by any method known in the art, for example by immunoassays described herein. Immunospecific binding excludes non-specific binding, but does not necessarily exclude cross-reactions with other antigens. The antigenic epitopes do not necessarily have to be immunogenic. Fragments that function as epitopes can be produced by any conventional method (See e.g., Houghten, Proc. Nat'l Acad. Sci. USA 82: 5131-5135 (1985), further described in the US Patent.

No. 4,631,211). In the present invention, the antigenic epitopes preferably contain a sequence of at least 4, at least 5, at least 6, at least 7, preferably at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 25, at least 30, at least 40, at least 50, and more preferably between about 15 and about 30 amino acids. Preferred polypeptides comprising immunogenic or antigenic epitopes have at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 Amino acid residues in length. Additional non-exclusive preferred antigenic epitopes include the antigenic epitopes described herein, as well as portions thereof. Antigenic epitopes are useful, for example, for inducing antibodies, including monoclonal antibodies, that bind specifically to the epitope. Preferred antigenic epitopes include the antigenic epitopes described herein, as well as any combination of two, three, four, five or more of these antigenic epitopes. Antigenic epitopes can be used as target molecules in immunoassays (see for example, Wilson et al., Cell 37: 767-778 (1984), Sutcliffe et al., Science 219: 660-666 (1983)). Similarly, immunogenic epitopes can be used, for example, to induce antibodies in accordance with methods known in the art (see for example, Sutcliffe et al., Supra, Wilson et al., Supra).; Chow et ai., Proc. Nat 'l Acad. Sci. USA 82: 910-914; and Bittle et al. , J. Gen. Virol. 66: 2347-2354 (1985). Preferred immunogenic epitopes include the immunogenic epitopes described herein, as well as any combination of two, three, four, five or more of these immunogenic epitopes. Polypeptides comprising one or more immunogenic epitopes can be presented to induce an antibody response together with a carrier protein, such as albumin, in an animal system (such as in rabbits or mice) or, if the polypeptide is of sufficient length (at least about 25 amino acids), the polypeptide can be presented without a carrier. However, it has been demonstrated that immunogenic epitopes comprising an amount as small as 8 to 10 amino acids are sufficient to induce the production of antibodies capable of binding to at least linear epitopes on a denatured polypeptide (eg, in an analysis of Western-type immunoblotting). The epitope-bearing polypeptides of the present invention can be used to induce antibodies in accordance with methods known in the art, including but not limited to, in vivo immunization, in vitro immunization and phage display methods. See e.g., Sutcliffe et al., Supra; Wilson et al., Supra, and Bittle et al., J. Gen. Virol. 66: 2347-2354 (1985). If immunization is used in vivo, animals can be immunized with the free peptide; however, the antibody titer against any peptide can be enhanced by coupling the peptide with a macromolecular carrier, such as limpet hemocyanin (KLH) or tetanus toxoid. For example, peptides containing cysteine residues can be coupled to a carrier using a linker sequence, such as the maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), while other peptides can be coupled with carriers using a more general linker, such as, for example, glutaraldehyde. Animals such as rabbits, rats and mice are immunized with the free peptide or with the peptide coupled with a carrier, for example, by intraperitoneal and / or intradermal injection of emulsions containing approximately 100 μg of the peptide or carrier protein and Freund's adjuvant or any other adjuvant known to stimulate an immune response. Several booster injections may be necessary, for example, at intervals of about two weeks, to obtain a useful titer of the antipeptide antibody, which can be detected for example by ELISA assays using the free peptide adsorbed to a solid surface. The titer of anti-peptide antibodies in the serum of an immunized animal can be increased by the selection of antypeptide antibodies, for example, by adsorbing the peptide on a solid support and eluting the selected antibodies in accordance with methods known in the art. As will be observed by a person skilled in the art and as described above, the polypeptides of the present invention comprising an immunogenic or antigenic epitope can be fused with other polypeptide sequences. For example, the polypeptides of the present invention can be fused to the constant domain of immunoglobulins (IgA, IgE, IgG, IgM) or portions thereof (CH1, CH2, CH3 or any combinations thereof and portions thereof) , obtaining chimeric polypeptides. Such fusion proteins can facilitate purification and can increase the half-life in vivo. This has been demonstrated for chimeric proteins consisting of the first two domains of the human CD4 polypeptide and several domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. See e.g., European Patent EP 394,827; Traunecker et al. , Nature, 331: 84-86 (1988). A greater distribution of an antigen through the epithelial barrier to the immune system has been demonstrated, for antigens (e.g., insulin) conjugated to an FcRn binding partner such as IgG or Fc fragments (see e.g., PCT International Publications WO 96/22024 and WO 99/04813). IgG fusion proteins that have a dimeric structure with disulfide bridges due to the disulfide bonds of the IgG portion, have been shown to be more efficient in inhibiting and neutralizing other molecules, compared to monomeric polypeptides or fragments thereof by themselves. See e.g., Fountoulakis et al., J. Biochem. 270: 3958-3964 (1995). The nucleic acids encoding the above epitopes can also be recombined with a gene of interest in the form of an epitope tag (eg, the hemagglutinin tag ("HA") or the flag mark) to aid in the detection and purification of the expressed polypeptide. For example, a system described by Janknecht et al., Allows easy purification of non-denatured fusion proteins expressed in human cell lines (Janknecht et al., 1991, Proc. Nat'l Acad. Sci. USA 88: 8972-897 ). In this system, the gene of interest is subcloned into a vaccinia recombination plasmid, such that the open reading frame of the gene is fused to the translation with an amino-terminal tag consisting of 6 histidine residues. The tag serves as the matrix binding domain for the fusion protein. Extracts from cells infected with the recombinant vaccinia virus are placed on a Ni ~ + nitriloacetic acid-agarose column and the histidine-labeled proteins can be eluted selectively with buffer solutions containing imidazole. In another embodiment, the neutrokine-alpha and / or neutrocine-alphaSV polypeptides of the present invention and the epitope-bearing fragments thereof, are fused to a heterologous antigen (e.g., a polypeptide, carbohydrate, phospholipid or nucleic acid). In specific embodiments, the heterologous antigen is an immunogen. In a more specific embodiment, the heterologous antigen is the HIV gpl20 protein or a fragment thereof. The polynucleotides encoding these polypeptides are also encompassed by the present invention. In another embodiment, the neutrokine-alpha and / or neutrocine-alphaSV polypeptides of the present invention and the epitope-bearing fragments thereof, are fused to polypeptide sequences of another member of the TNF ligand family (or biologically active fragments or variants thereof). In a specific embodiment, the neutrokine-alpha and / or neutrocine-alphaSV polypeptides of the present invention are fused to a sequence of the CD40L polypeptide. In a preferred embodiment, the sequence of the CD40L polypeptide is soluble. The technique of gene entrainment, portion entrainment, exon entrainment and / or codon entrainment (collectively referred to as "DNA entrainment") can be used to modulate the activity of neutrocin-alpha and / or neutrocin-alphaSV, thus generating agonists and antagonists of neutrocine-alpha and / or neutrocin-alphaSV. See generally, U.S. Patent Nos. 5,605,793, 5,811,238, 5,830,721, 5,834,252 and 5,837,458 and Patten, P.A., et al. , Curr. Opinion Biotechnol. 8: 724-33 (1997); Harayama, S. Trends Biotechnol. 16 (2): 76-82 (1998); Hansson, L. O., et al., J. Mol. Biol. 287: 265-76 (1999); and Lorenzo, M. M. and Blasco, R. Biotechniques 24 (2): 308-13 (1998) (where each of these patents and publications is incorporated herein by reference). In one embodiment, the alteration of the neutrokine-alpha and / or neutrocine-alphaSV polynucleotides and the corresponding polypeptides can be achieved by DNA entrainment. DNA entrainment involves the assembly of two or more DNA segments in a desired neutrokine-alpha and / or neutrokine-alphaSV molecule, by homologous recombination or site-specific recombination.

In another embodiment, the neutrokine-alpha and / or neutrocine-alphaSV polynucleotides and the corresponding polypeptides can be altered by subjecting them to random mutagenesis by error-prone PCR, random insertion of nucleotides or other methods prior to recombination. In another modality, one or more components, portions, sections, parts, domains, fragments, etc. of neutrocin-alpha and / or neutrocin-alphaSV, can be recombined with one or more components, portions, sections, parts, domains, fragments, etc. of one or more heterologous molecules. In preferred embodiments, the heterologous molecules are, for example, TNF-alpha, lymphotoxin-alpha (LT-alpha, also known as TNF-beta), LT-beta (found in the form of a heterotrimeric complex, LT-alpha-2-beta ), OPGL, FasL, CD27L; CD30L; CD40L, 4-1BBL, DcR3, OX40L, TNF-gamma (International Publication WO 996/14328); AIM-I (International Publication WO 97/33899); AIM-II (International Publication WO 97/34911), APRIL (J. Exp. Med. 188 (6): 1185-1190); endocina-alpha (International Publication WO 98/07880); OPG, OX40 and neural growth factor (FCN) and soluble forms of fas, CD-0, CD27, CD40 and 4-IBB, TR2 (International Publication WO 96/34095), DR3 (International Publication WO 97/33904), DR4 (International Publication WO 98/32856), TR5 (International Publication WO 98/30693), TR6 (International Publication WO 98/30694), TR7 (International Publication WO 98/41629), TRANK, TR9 (International Publication WO 98/56892) , TRIO (International Publication WO 98/54202), 312C2 (International Publication WO 98/06842), TR12, CAD and v-FLIP. In additional embodiments, the heterologous molecules are any member of the TNF family. In preferred embodiments, the neutrokine-alpha and / or neutrocine-alphaSV polypeptides of the present invention (including biologically active fragments or variants thereof), are fused to soluble CD40L polypeptides, or biologically active fragments or variants thereof. To improve or alter the characteristics of the neutrokine-alpha and / or neutrocine-alphaSV polypeptides, protein engineering can be employed. Recombinant DNA technology known to those skilled in the art can be used to create new mutant proteins or "muteins" including substitutions, deletions, additions of single or multiple amino acids, or fusion proteins. Such modified polypeptides may show, e.g., increased activity or increased stability. In addition, they can be purified in high yields and show a better solubility than the corresponding natural polypeptide, at least under certain purification and storage conditions. For example, for many proteins, including the extracellular domain of the mature forms of a secreted protein, it is known in the art that one or more amino acids can be removed from the N-terminal or C-terminus without substantially losing biological function. For example, Ron et al., J. Biol. Chem., 268: 2984-2988 (1993) reported modified KGF proteins that had heparin binding activity, even if 3, 8 or 27 amino acid residues at the amino terminus were removed. In the present case, since the protein of the invention is a member of the TNF polypeptide family, the N-terminal amino acid deletions up to the residue Gly (G) at position 191 of Figures IA and IB (SEQ ID NO. : 2) could retain some biological activity, for example, the ability to stimulate the proliferation, differentiation and / or activation of lymphocytes (eg, B cells) and cytotoxicity against appropriate target cells. Polypeptides that underwent additional N-terminal deletions, including the Gly (G) residue, would not be expected to retain biological activity, because it is known that this residue in the TNF-related polypeptides is the carrier of the conservative domain required for the activity biological However, even if the deletion of one or more amino acids from the N-terminus of a protein results in the modification or loss of one or more biological functions thereof, other functional activities could still be retained. Thus, the ability of the shortened protein to induce and / or bind antibodies that recognize the total molecule or the extracellular domain of the protein will generally be retained at least from most residues of the entire protein or the extracellular domain. of it are removed from the N-terminal end. The fact that if a particular polypeptide lacking the N-terminal residues of a complete protein retains the immunological activity, it can be easily determined by routine methods described herein and otherwise known in the art. In accordance with the above, the present invention further provides polypeptides that underwent the deletion of one or more amino terminal residues of the amino acid sequence of neutrocin-alpha shown in Figures IA and IB (SEQ ID NO: 2), to the glycine residue at position 191 (residue Gly-191 of the amino-terminal end) and polynucleotides encoding such polypeptides. In particular, the present invention provides polypeptides comprising, or alternatively consisting of the amino acid sequence of residues nx-285 of SEQ ID NO: 2, wherein n1 is an integer in the range of the amino acid position of the Amino acid residues 2-190 of the amino acid sequence of SEQ ID NO: 2. The polynucleotides encoding these polypeptides are also encompassed by the present invention. More particularly, the present invention provides polynucleotides that encode polypeptides that comprise or alternatively consist of an amino acid sequence that is selected from the group consisting of residues 2-285, 3-285, 4-285, 5-285, 6. -285, 7-285, 8-285, 9-285, 10-285, 11-285, 12-285, 13-285, 14-285, 15-285, 16-285, 17-285, 18-285 , 19-285, 20-285, 21-285, 22-285, 23-285, 24-285, 25-285, 26-285, 27-285, 28-285, 29-285, 30-285, 31 -285, 32-285, 33-285, 34-285, 35-285, 36-285, 37-285, 38-285, 39-285, 40-285, 41-285, 42-285, 43-285 , 44-285, 45-285, 46-285, 47-285, 48-285, 49-285, 50-285, 51-285, 52-285, 53-285, 54-285, 55-285, 56 -285, 57-285, 58-285, 59-285, 60-285, 61-285, 62-285, 63-285, 64-285, 65-285, 66-285, 67-285, 68-285 , 69-285, 70-285, 71-285, 72-285, 73-285, 74-285, 75-285, 76-285, 77-285, 78-285, 79-285, 80-285, 81 -285, 82-285, 83-285, 84-285, 85-285, 86-285, 87-285, 88-285, 89-285, 90-285, 91-285, 92-285, 93-285 , 94-285, 95-285, 96-285, 97-285, 9 8-285, 99-285, 100-285, 101-285, 102-285, 103-285, 104-285, 105-285, 106-285, 107-285, 108-285, 109-285, 110- 285, 111-285, 112-285, 113-285, 114-285, 115-285, 116-285, 117-285, 118-285, 119-285, 120-285, 121-285, 122-285, 123-285, 124-285, 125-285, 126-285, 127-285, 128-285, 129-285, 130-285, 131-285, 132-285, 133-285, 134-285, 135- 285, 136-285, 137-285, 138-285, 139-285, 140-285, 141-285, 142-285, 143-285, 144-285, 145-285, 146-285, 147-285, 148-285, 149-285, 150-285, 151-285, 152-285, 153-285, 154-285, 155-285, 156-285, 157-285, 158-285, 159-285, 160- 285, 161-285, 162-285, 163-285, 164-285, 165-285, 166-285, 167-285, 168-285, 169-285, 170-285, 171-285, 172-285, 173-285, 174-285, 175-285, 176-285, 177-285, 178-285, 179-285, 180-285, 181-285, 182-285, 183-285, 184-285, 185- 285, 186-285, 187-285, 188-285, 189-285 and 190-285 of SEQ ID NO: 2. The polypeptides encoded by these polynucleotides are also encompassed by the present invention. The present invention also relates to nucleic acid molecules comprising, or alternatively consisting of, a polynucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99 %, identity to the polynucleotide sequence coding for the neutrocine-alpha and / or neutrocine-alphaSV polypeptides described above. The present invention also encompasses the above polynucleotide sequences fused to a heterologous polynucleotide sequence. Polypeptides encoded by these nucleic acids and / or polynucleotides are also encompassed by the present invention, as well as polypeptides that comprise or alternatively consist of an amino acid sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identity to the sequence of amino acids described above and polynucleotides encoding such polypeptides. In addition, since the predicted extracellular domain of the neutrokine-alpha polypeptides of the present invention can itself induce a biological activity, deletions of N-terminal and C-terminal amino acid residues from the predicted extracellular region of the polypeptide (positions extension Gln-73 to Leu-285 of SEQ ID NO: 2) may retain part of the biological activity, such as, for example, ligand binding, stimulation of proliferation, differentiation and / or activation of lymphocytes (eg, B cells) and modulation of cell replication or modulation of target cell activity. However, even if the deletion of one or more amino acids from the N-terminal end of the predicted extracellular domain of a neutrokine-alpha polypeptide results in the modification or loss of one or more biological functions of the polypeptide, other activities may still be retained functional Thus, the ability of the shortened polypeptides to induce and / or bind antibodies that recognize the complete or mature polypeptide or the extracellular domains of the polypeptides will generally be retained at least from most residues of the complete or mature polypeptide or the extracellular domains of the polypeptides are removed from the N-terminus. The fact that a particular polypeptide lacking the N-terminal residues of a complete polypeptide retains the immunological activity, can easily be determined by routine methods described herein and known in some manner or other in the art. . In accordance with the foregoing, the present invention further provides polypeptides that underwent the deletion of one or more residues from the amino terminal end of the amino acid sequence of the neutrocin-alpha shown in SEQ ID NO: 2, to the glycine residue in position number 280, and polynucleotides encoding such polypeptides. In particular, the present invention provides polypeptides comprising or alternatively consisting of the amino acid sequence of residues N2-285 of SEQ ID NO: 2, wherein N2- is an integer in the range of the amino acid position of the amino acid residues 73-280 of SEQ ID NO: 2 and 73 is the position of the first N-terminal residue residue of the predicted extracellular domain of the neutrocine-alpha polypeptide (described in SEQ ID NO: 2). The polynucleotides encoding these polypeptides are also encompassed by the present invention. More particularly, in certain embodiments, the present invention provides polynucleotides that encode polypeptides that comprise or alternatively consist of an amino acid sequence that selects the group consisting of residues from Q-73 to L-285; G-74 to L-285; D-75 to L-285; L-76 to L-285; A-77 to L-285; S-78 to L-285; L-79 to L-285; R-80 to L-285; A-81 to L-285; E-82 to L-285; L-83 to L-285; Q-84 to L-285; G-85 to L-285; H-86 to L-285; H-87 to L-285; A-88 to L-285; E-89 to L-285; K-90 to L-285; L-91 to L-285; P-92 to L-285; A-93 to L-285; G-94 to L-285; A-95 to L-285; G-96 to L-285; A-97 to L-285; P-98 to L-285; K-99 to L-285; A-100 to L-285; G-101 to L-285; L-102 to L-285; E-103 to L-285; E-104 to L-285; A-105 to L-285; P-106 to L-285; A-107 to L-285; V-108 to L-285; T-109 to L-285; A-110 to L-285; G-111 to L-285; L-112 to L-285; K-113 to L-285; 1-114 to L-285; F-115 to L-285; E-116 to L-285; P-117 to L-285; P-118 to L-285; A-119 to L-285; P-120 to L-285; G-121 to L-285; E-122 to L-285; G-123 to L-285; N-124 to L-285; S-125 to L-285; S-126 to L-285; Q-127 to L-285; N-128 to L-285; S-129 to L-285; R-130 to L-285; N-131 to L-285; K-132 to L-285; R-133 to L-285; A-134 to L-285; V-135 to L-285; Q-136 to L-285; G-137 to L-285; P-138 to L-285; E-139 to L-285; E-140 to L-285; T-141 to L-285; V-142 to L-285; T-143 to L-285; Q-144 to L-285; D-145 to L-285; C-146 to L-285; L-147 to L-285; Q-148 to L-285; L-149 to L-285; 1-150 to L-285; A-151 to L-285; D-152 to L-285; S-153 to L-285; E-154 to L-285; T-155 to L-285; P-156 to L-285, T-157 to L-285; 1-158 to L-285; Q-159 to L-285 K-160 to L-285; ' G-161 to L-285; S-162 to L-285; Y-163 to L-285 T-164 to L-285; F-165 to L-285; V-166 to L-285; P-167 to L-285 W-168 to L-285; L-169 to L-285; L-170 to L-285; S-171 to L-285 F-172 to L-285. K-173 to L-285; R-174 to L-285; G-175 to L-285 S-176 to L-285, A-177 to L-285; L-178 to L-285; E-179 to L-285 E-180 to L-285; K-181 to L-285; E-182 to L-285; N-183 to L-285 K-184 to L-285; 1-185 to L-285; L-186 to L-285; V-187 to L-285 K-188 to L-285. E-189 to L-285; T-190 to L-285; G-191 to L-285 Y-192 to L-285, F-193 to L-285; F-194 to L-285; 1-195 to L-285 Y-196 to L-285, G-197 to L-285; Q-198 to L-285; V-199 to L-285 L-200 to L-285; Y-201 to L-285; T-202 to L-285; d-203 to L-285 K-204 a L-285; T-205 to L-285; Y-206 to L-285; A-207 to L-285 M-208 to L-285. G-209 to L-285; H-210 to L-285; L-211 to L-285 1-212 a L-285. Q-213 to L-285; R-214 to L-285; K-215 to L-285 K-216 to L-285. V-217 to L-285; H-218 to L-285; V-219 to L-285 F-220 to L-285. G-221 to L-285; D-222 to L-285; E-223 to L-285 L-224 a L-285. S-225 to L-285; L-226 to L-285; V-227 to L-285 T-228 to L-285. L-229 to L-285; F-230 to L-285; R-231 to L-285 C-232 to L-285. 1-233 to L-285; Q-234 to L-285; N-235 to L-285 M-236 to L-285, • P-237 to L-285; E-238 to L-285; T-239 to L-285 L-240 to L-285, • P-241 to L-285; N-242 to L-285; N-243 to L-285 S-244 a L-285, • C-245 to L-285; Y-246 to L-285; S-247 to L-285 A-248 a L-285, • g-249 to L-285; 1-250 to L-285; A-251 to L-285 K-252 a L-285, L-253 to L-285; E-254 to L-285; E-255 to L-285; TG-256 to L-285; D-257 to L-285; E-258 to L-285; L-259 to L-285; Q-260 to L-285; L-261 to L-285; A-262 to L-285; 1-263 to L-285; P-264 to L-285; R-265 to L-285; E-266 to L-285; N-267 to L-285; A-268 a-L-285; Q-269 to L-285; 1-270 to L-285; S-271 to L-285; L-272 to L-285; D-273 to L-285; G-274 to L-285; D-275 to L-285; V-276 to L-285; T-277 to L-285; F-278 to L-285; F-279 to L-285; and G-280 to L-285 of SEQ ID NO: 2. The polypeptides encoded by these polynucleotides are also encompassed by the present invention. The present invention also relates to nucleic acid molecules comprising, or alternatively consisting of, polynucleotide sequences with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identity to the polynucleotide sequence coding for the neutrokine-alpha and / or neutrocine-alphaSV polypeptides described above. the present invention also includes the above polynucleotide sequences fused to a heterologous polynucleotide sequence. Polypeptides encoded by these nucleic acids and / or polynucleotide sequences are also encompassed by the present invention, as are polypeptides that comprise or alternatively consist of an amino acid sequence with at least 80%, 85%, 90%, 92% 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence described above, and polynucleotides encoding such polypeptides. Hi preferred embodiments of the present invention refer to nucleic acid molecules comprising, or alternatively consisting of a polynucleotide having a nucleotide sequence with at least 80%, 85%, 90% identity and more preferably with at least 95% identity. %, 96%, 97%, 98%, 99% or 100% identity to a polynucleotide sequence encoding the neutrokine-alpha polypeptide having the amino acid sequence at positions 134-285 of Figures IA and IB (SEQ ID NO: 2). Preferred embodiments of the invention refer to nucleic acid molecules that comprise or alternatively consist of a polynucleotide having a nucleotide sequence with at least 90% identity to a polynucleotide sequence encoding the neutrocine-alpha polypeptide having the amino acid sequence of positions 134-285 of Figures IA and IB (SEQ ID NO: 2). More preferred embodiments of the present invention refer to nucleic acid molecules comprising or alternatively consisting of a polynucleotide having a nucleotide sequence with at least 95% identity to a polynucleotide sequence encoding the neutrocine-alpha polypeptide having the amino acid sequence of positions 134-285 of Figures IA and IB (SEQ ID NO: 2). More preferred embodiments of the present invention, refer to nucleic acid molecules comprising or alternatively consisting of a polynucleotide having a nucleotide sequence with at least 96% identity to a polynucleotide sequence encoding the neutrokine-alpha polypeptide having the amino acid sequence of positions 134-285 of figures IA and IB (SEQ ID NO: 2). Additionally, more preferred embodiments of the present invention relate to nucleic acid molecules comprising or alternatively consisting of a polynucleotide having the nucleotide sequence with at least 97% identity to a polynucleotide sequence encoding the neutrocytic polypeptide. alpha having the amino acid sequence of positions 134-285 of FIGS. A and IB (SEQ ID NO: 2). In addition, more preferred embodiments of the present invention relate to nucleic acid molecules that comprise or alternatively consist of a polynucleotide having a nucleotide sequence with at least 98% identity to a polynucleotide sequence encoding the neutrokine-alpha polypeptide having the amino acid sequence of positions 134-285 of Figures IA and IB (SEQ ID NO : 2) . Additionally, more preferred embodiments of the present invention refer to nucleic acid molecules comprising or alternatively consisting of a polynucleotide having a nucleotide sequence with at least 99% identity to a polynucleotide sequence encoding the neutrocytic polypeptide. alpha having the amino acid sequence of positions 134-285 of Figures IA and IB (SEQ ID NO: 2). In specific embodiments, a polypeptide comprising or alternatively consisting of one of the following polypeptide fragments deleted at the N-terminus of neutrokine-alpha and / or neutrocine-alphaSV, are preferred: the amino acid residues of Ala-71 to Leu -285, amino acid residues from Ala-81 to Leu-285, amino acid residues from Leu-112 to Leu-285, amino acid residues from Ala-134 to Leu-285, amino acid residues from Leu-147 to Leu-285 and amino acid residues of Gly-161 to Leu-285 of SEQ ID NO: 2. The polynucleotides encoding these polypeptides are also encompassed by the following invention. Similarly, many examples of muteins with C-terminal deletions that are biologically functional are known. For example, interferon gamma shows up to ten times greater activity by eliminating 8 to 10 amino acid residues from the carboxyl-terminal end of the protein (Dóbeli et al., J. Biotechnology 7: 199-216 (1988)). present protein is a member of the TNF polypeptide family, C-terminal amino acid deletions up to the leucine residue at position 284, are expected to retain most, if not all, of the biological activity, e.g. ligand binding , the ability to stimulate the proliferation, differentiation and / or activation of lymphocytes (eg, B cells) and the modulation of cellular replication Polypeptides that suffered from lesions of up to 10 additional C-terminal residues (ie, up to the glycine residue at position 274), they could also retain some of the activity, such as binding to the receptor, although such polypeptides would lack a portion of the conserved TNF domain extending to approximately the Leu-284 position of SEQ ID NO: 2. However, even if the deletion of one or more amino acids from the C-terminal end of a protein results in the modification or loss of one or more biological functions thereof, other activities may still be retained functional Thus, the ability of the shortened protein to induce and / or bind antibodies that recognize the complete or mature protein will generally be retained when at least the majority of the complete or mature protein residues are removed from the C-terminus. The fact that if a particular polypeptide lacking the C-terminal residues of the entire protein retains the immunological activity, it can be easily determined by the routine methods described herein and known in some way or other in the art. In accordance with the foregoing, the present invention further provides polypeptides that underwent the deletion of one or more carboxyl-terminal residues of the amino acid sequence of the neutrocine-alpha polypeptide shown in Figures IA and IB (SEQ ID NO: 2), to the glycine residue at position 274 (Gly-274) and polynucleotides encoding such polypeptides. In particular, the present invention provides polypeptides comprising or alternatively consisting of the amino acid sequence of the 1-m1 residues of the amino acid sequence of SEQ ID NO: 2, wherein m1 is an integer in the range of the position of amino acid of amino acid residues 274-284 of SEQ ID NO: 2. Polynucleotides encoding these polypeptides are also encompassed by the present invention. More particularly, the present invention provides polynucleotides that encode polypeptides that comprise or alternatively consist of an amino acid sequence that is selected from the group consisting of residues 1-274, 1-275, 1-276, 1-277, 1 -278, 1-279, 1-280, 1-281, 1-282, 1-283 and 1-284 of SEQ ID NO: 2. The polypeptides encoded by these polynucleotides are also encompassed by the present invention. The present invention also relates to nucleic acid molecules comprising or alternatively consisting of a polynucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99 % identity to the polynucleotide sequence coding for the neutrokine-alpha and / or neutrocine-alphaSV polypeptides described above. The present invention also includes the above polynucleotide sequences fused to a heterologous polynucleotide sequence. The polypeptides encoded by these nucleic acids and / or polynucleotide sequences are also encompassed by the following invention, just as polypeptides that comprise or alternatively consist of an amino acid sequence with at least 80%, 85%, 90%, 92 %, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence described above, and polynucleotides encoding such polypeptides. Polypeptides are also provided which comprise or alternatively consist of one or more amino acid deletions of both the amino terminal and the carboxyl terminus, which can generally be described as having residues n1-m1 of SEQ ID NO: 2, wherein n1 and m1 are integers like those previously defined. Also included is a nucleotide sequence encoding a polypeptide comprising or alternatively consisting of a portion of the amino acid sequence of the complete neutrokine-alpha encoded by the cDNA clone deposited with accession number ATCC 97768, wherein this portion it excludes from 1 to 190 amino acids from the amino-terminal end or from 1 to 11 amino acids from the C-terminal end of the complete amino acid sequence (or any combination of these N-terminal and C-terminal deletions) encoded by the cDNA clone that it is found in the deposited plasmid. The polynucleotides encoding all of the above deletion polypeptides, are encompassed by the present invention. Similarly, deletions of C-terminal amino acid residues from the predicted extracellular domain of neutrokine-alpha, to the leucine residue at position 79 of SEQ ID NO: 2, could retain some biological activity, such as, for example, Ligand binding, stimulation of proliferation, differentiation and / or activation of lymphocytes (eg, B cells) and modulation of cell replication or modulation of target cell activities. Polypeptides subjected to additional C-terminal deletions, including Leu-79 of SEQ ID NO: 2, would not be expected to retain biological activity. However, even if the deletion of one or more amino acids from the C-terminal end of a polypeptide results in the modification or loss of one or more biological functions thereof, other functional activities may still be retained. Thus, the ability of the cut polypeptide to induce and / or go to antibodies that recognize the complete, mature or extracellular form of the polypeptide will generally be retained when at least the majority of the residues of the complete, mature or extracellular form of the polypeptide are removed from the C-terminal end. The fact that a particular polypeptide lacking C-terminal residues of the predicted extracellular domain retains the immunological activity, can be easily determined by methods described herein and known in some way or other in the art. In accordance with the above, the present invention further provides polypeptides that underwent the deletion of one or more carboxyl-terminal residues of the amino acid sequence of the predicted extracellular domain of the neutrocine-alpha polypeptide shown in SEQ ID NO: 2, to the leucine residue at position 79 of SEQ ID NO: 2, and polynucleotides encoding such polypeptides. In particular, the present invention provides polypeptides comprising or alternatively consisting of the amino acid sequence of residues 73-? Rr * of the amino acid sequence of SEQ ID NO: 2, wherein m2 is an integer in the range of the amino acid position of amino acid residues 79-285 of the amino acid sequence of SEQ ID NO: 2, and residue 78 is the position of the first residue at the C-terminus of the predicted extracellular domain of the neutrocytic polypeptide. alpha (described in SEQ ID NO: 2). The polypeptides encoded by these polynucleotides are also encompassed by the present invention. More particularly, in certain embodiments, the present invention provides polynucleotides that encode polypeptides that comprise or alternatively consist of an amino acid sequence that is selected from the group consisting of residues Q-73 to Leu-285; Q-73 to L-284; Q-73 to K-283; Q-73 to L-282; Q-73 to A-281; Q-73 to G-280; Q-73 to F-279; Q-73 to F-278; Q-73 to t-277; Q-73 to V-276; Q-73 to D-275; Q-73 to G-274; Q-73 to D-273; Q-73 to L-272; Q-73 to S-271; Q-73 to 1-270; Q-73 to Q-269; Q-73 to A-268; Q-73 to N-267; Q-73 to E-266; Q-73 to R-265; Q-73 to P-264; Q-73 to I-263; Q-73 to A-262; q-73 to L-261; Q-73 to Q-260; Q-73 to L-259; Q-73 to E-258; Q-73 to D-257; q-73 to G-256; Q-73 to E-255; Q-73 to E-254; Q-73 to L-253; Q-73 to K-252; Q-73 to A- - 2 - 251; Q-73 to 1-250; Q-73 to G-249; Q-73 to A-248; Q-73 to S-247; Q-73 to Y-246; Q-73 to C-245; Q-73 to S-244; Q-73 to N-243; Q-73 to N-242; Q-73 to P-241; Q-73 to L-240; Q-73 to T-239; Q-73 to E-238; Q-73 to P-237; Q-73 to M-236; Q-73 to N- 235; Q-73 to Q-234; Q-73 to 1-233; Q-73 to C-232; Q-73 to R- 231; Q-73 to F-230; Q-73 to L-229; Q-73 to T-228; Q-73 to v- 227; Q-73 to L-226; Q-73 to S-225; Q-73 to L-224; Q-73 to E-223; Q-73 to D-222; Q-73 to G-221; Q-73 to F-220; Q-73 to v- 219; Q-73 to H-218; Q-73 to V-217; Q-73 to K-216; Q-73 to K-215; Q-73 to R-214; Q-73 to Q-213; Q-73 to 1-212; Q-73 to L- 211; Q-73 to H-210; Q-73 to G-209; Q-73 to M-208; Q-73 to A-207; Q-73 to Y-206; Q-73 to T-205; Q-73 to K-204; Q-73 to D- 203; Q-73 to T-202; Q-73 to Y-201; Q-73 to L-200; Q-73 to V- 199; Q-73 to Q-198; Q-73 to G-197; Q-73 to Y-196; Q-73 to I- 195; Q-73 to F-194; Q-73 to F-193; Q-73 to Y-192; Q-73 to G- 191; Q-73 to T-190; Q-73 to E-189; Q-73 to K-188; q-73 to V- 187; Q-73 to L-186; Q-73 to 1-185; Q-73 to K-184; Q-73 to N- 183; Q-73 to E-182; Q-73 to K-181; Q-73 to E-180; Q-73 to E- 179; Q-73 to L-178; Q-73 to A-177; Q-73 to S-176; Q-73 to G-175; Q-73 to R-174; Q-73 to K-173; Q-73 to F-172; Q-73 to s-171; Q-73 to L-170; Q-73 to L-169; Q-73 to W-168; Q-73 to P- 167; Q-73 to V-166; Q-73 to F-165; Q-73 to T-164; Q-73 to Y- 163; Q-73 to S-162; Q-73 to G-161; Q-73 to K-160; Q-73 to Q- 159; Q-73 to 1-158; Q-73 to T-157; Q-73 to P-156; Q-73 to T-155; Q-73 to E-154; Q-73 to S-153; Q-73 to D-152; Q-73 to A-151; Q-73 to 1-150; Q-73 to L-149; Q-73 to Q-148; Q-73 to L-147; Q-73 to C-146; Q-73 to D-145; Q-73 to Q-144; Q-73 to T-143; Q-73 to V-142; Q-73 to T-141; Q-73 to E-140; Q-73 to E-139; Q-73 to P-138; Q-73 to G-137; Q-73 to Q-136; Q-73 to V-135; Q-73 to A-134; Q-73 to R-133; Q-73 to K-132; Q-73 to N-131; Q-73 to R-130; Q-73 to S-129; Q-73 to N-128; Q-73 to Q-127; Q-73 to S-126; Q-73 to S-125; Q-73 to N-124; Q-73 to G-123; Q-73 to E-122; Q-73 to G-121; Q-73 to P-120; Q-73 to A-119; Q-73 to P-118; Q-73 to P-117; Q-73 to E-116; Q-73 to F-115; Q-73 to 1-114; Q-73 to K-113; Q-73 to L-112; Q-73 to G-111; Q-73 to A-110; Q-73 to T-109; Q-73 to v-108; Q-73 to A-107; Q-73 to P-106; Q-73 to A-105, Q-73 to E-104; Q-73 to E-103; Q-73 to L-102; Q-73 to G-101; Q-73 to A-100; Q-73 to K-99; Q-73 to P-98; Q-73 to A-97; Q-73 to G-96; Q-73 to A-95; Q-73 to G-94; Q-73 to A-93; Q-73 to P-92; Q-73 to L-91; Q-73 to K-90; Q-73 to E-89; Q-73 to A-88; q-73 to H-87; Q-73 to H-86; Q-73 to G-85; Q-73 to Q-84; Q-73 to L-83; Q-73 to E-82; Q-73 to A-81; Q-73 to R-80; and Q-73 to L-79 of SEQ ID NO: 2. The polypeptides encoded by these polynucleotides are also encompassed by the following invention. The present invention also relates to nucleic acid molecules comprising or alternatively consisting of a polynucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99 % identity to the polynucleotide sequence coding for the neutrokine-alpha and / or neutrocine-alphaSV polypeptides described above. The present invention also includes the above polynucleotide sequences fused to a heterologous polynucleotide sequence. The polypeptides encoded by these nucleic acids and / or polynucleotide sequences are also encompassed by the following invention, just as polypeptides that comprise or alternatively consist of an amino acid sequence with at least 80%, 85%, 90%, 92 %, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence described above, and polynucleotides encoding such polypeptides. The present invention also provides polypeptides that underwent the deletion of one or more amino acids from the amino terminal or the carboxyl terminal end of the predicted extracellular domain of neutrokine-alpha, which can generally be described as having n2-m2 residues of SEQ ID NO: 2, where n2 and m2, are integers as previously defined. In another embodiment, a nucleotide sequence encoding a polypeptide consisting of a portion of the extracellular domain of the amino acid sequence neutrocin-alpha encoded by the plasmid cDNA contained in the deposit having the accession number ATCC 97768, wherein this portion excludes from one to about 206 amino acids of the amino terminal end of the extracellular domain of the amino acid sequence encoded by the plasmid cDNA contained in the deposit having the accession number ATCC 97768, or from one to about 206 amino acids of the carboxyl-terminal end of the extracellular domain of the amino acid sequence encoded by the plasmid cDNA contained in the deposit having the accession number ATCC 97768, or any combination of the aforementioned amino-terminal and carboxyl-terminal deletions, of the extracellular domain complete of the amino acid sequence encoded by the plasmid cDNA contained in the deposit having the accession number ATCC 97768. As mentioned above, even if deletion of one or more amino acids from the N-terminus of a polypeptide results in the modification or loss of one or more functional activities (eg activ biological diversity), other biological functions or activities may still be retained. Thus, the ability of a shortened neutrokine-alpha mutein to induce and / or bind antibodies that recognize the full length or mature protein or the extracellular domain of the polypeptide will generally be retained at least from most of the residues of the Full-length or mature protein or the extracellular domain of the polypeptide are removed from the N-terminus. The fact whether a particular polypeptide lacking N-terminal residues of a complete polypeptide has immunological activity, can be easily determined by routine methods described herein and known in some way or other in the art. It is not unlikely that a neutrokine-alpha mutein with a large number of lesions of N-terminal amino acid residues can retain any functional (e.g., biological or immunogenic) activity. In fact, peptides composed of an amount as small as six amino acid residues of neutrocine-alpha, can often elicit an immune response. In accordance with the above, the present invention further provides polypeptides that underwent the deletion of one or more amino terminal residues of the predicted full-length amino acid sequence of the neutrocin-alpha shown in SEQ ID NO: 2, up to the residue glycine at position number 280 of the sequence shown in SEQ ID NO: 2 and polynucleotides encoding such polypeptides. In particular, the present invention provides polypeptides comprising the amino acid sequence of residues n3-285 of the sequence shown in SEQ ID NO: 2, wherein n3 is an integer in the range of the amino acid position of the residues of amino acid 1 to 280 of the amino acid sequence of SEQ ID NO: 2. More particularly, the present invention provides polynucleotides that encode polypeptides comprising or alternatively consist of an amino acid sequence that selects the group consisting of the residues of D-2 to L-285; D-3 to L-285; S-4 to L-285; T-5 to L-285; E-6 to L-285; R-7 to L-285; E-8 to L-285; Q-9 to L-285; S-10 to L-285; r-11 to L-285; L-12 to L-285; T-13 to L-285; S-14 to L-285; C-15 to L-285; L-16 to L-285; K-17 to L-285; K-18 to L-285; R-19 to L-285; E-20 to L-285; E-21 to L-285; M-22 to L-285; K-23 to L-285; L-24 to L-285; K-25 to L-285; E-26 to L-285; C-27 to L-285; V-28 to L-285; S-29 to L-285; 1-30 to L-285; L-31 to L-285; P-32 to L-285; R-33 to L-285; K-34 to L-285; E-35 to L-285; S-36 to L-285; P-37 to L-285; S-38 to L-285; V-39 to L-285; R-40 to L-285; S-41 to L-285; S-42 to L-285; K-43 to L-285; D-44 to L-285; G-45 to L-285; K-46 to L-285; L-47 to L-285; L-48 to L-285; A-49 to L-285; A-50 to L-285; T-51 to L-285; L-52 to L-285; L-53 to L-285; L-54 to L-285; A-55 to L-285; L-56 to L-285; L-57 to L-285; S-58 to L-285; c-59 to L-285; C-60 to L-285; L-61 to L-285; T-62 to L-285; V-63 to L-285; v-64 to L-285; S-65 to L-285; F-66 to L-285; Y-67 to L-285; Q-68 to L-285; V-69 to L-285; A-70 to L-285; A-71 to L-285; L-72 to L-285; Q-73 to L-285; G-74 to L-285; D-75 to L-285; L-76 to L-285 A-77 to L-285; S-78 to L-285; L-79 to L-285; R-80 to L-285 A-81 to L-285; E-82 to L-285; L-83 to L-285; Q-84 to L-285 G-85 to L-285; H-86 to L-285; H-87 to L-285; A-88 to L-285 E-89 to L-285; K-90 to L-285; L-91 to L-285; P-92 to L-285 A-93 to L-285; G-94 to L-285; A-95 to L-285; G-96 to L-285 A-97 to L-285; P-98 to L-285 KI-99 to L-285; a-100 to L-285; G-101 to L-285; L-102 to L-285; E-103 to L-285; E-104 to L-285; A-105 a L-285 P-106 to L-285; A-107 to L-285; V-108 to L-285; T-109 to L-285 A-10 to L-285; G-111 to L-285; L-112 to L-285; K-113 to L-285 1-114 to L-285; F-115 to L-285; E-116 to L-285; P-117 to L-285 P-118 to L-285; A-19 to L-285; P-120 to L-285; G-121 to L-285 E-122 to L-285; G-123 to L-285; N-124 to L-285; S-125 to L-285 S-126 to L-285; Q-127 to L-285; N-128 to L-285; S-129 to L-285 R-130 to L-285; N-131 to L-285; K-132 to L-285; R-133 to L-285 A-134 to L-285; V-135 to L-285; q-136 to L-285; G-137 to L-285 P-138 to L-285; E-139 to L-285; E-140 to L-285; t-141 to L-285 V-142 to L-285; T-143 to L-285; Q-144 to L-285; D-145 to L-285 C-146 to L-285; L-147 to L-285; Q-148 to L-285; L-149 to L-285 1-150 to L-285; A-151 to L-285; D-152 to L-285; S-153 to L-285 E-154 to L-285; T-155 to L-285; P-156 to L-285; T-157 to L-285 1-158 to L-285; Q-159 to L-285; K-160 to L-285; G-161 to L-285 s-162 to L-285; Y-163 to L-285; T-164 to L-285; F-165 to L-285 V-166 to L-285; P-167 to L-285; w-168 to L-285; L-169 to L-285 L-170 to L-285; s-171 to L-285; F-172 to L-285; K-173 to L-285; r-174 to L-285; G-175 to L-285; S-176 to L-285; a-177 a L-285; ' L-178 to L-285; E-179 to L-285; E-180 to L-285; K-181 a L-285; E-182 to L-285; N-183 to L-285; K-184 to L-285; 1-185 a L-285; L-186 to L-285; V-187 to L-285; K-188 to L-285; E-189 a L-285; T-190 to L-285; G-191 to L-285; Y-192 to L-285; F-193 a L-285; F-194 to L-285; 1-195 to L-285; Y-196 to L-285; G-197 a L-285; Q-198 to L-285; V-199 to L-285; L-200 to L-285; Y-201 a L-285; T-202 to L-285; D-203 to L-285; K-204 to L-285; T-205 a L-285, Y-206 to L-285; A-207 to L-285; M-208 to L-285; G-209 a L-285, H-210 to L-285; L-211 to L-285; 1-212 to L-285; Q-213 a L-285; R-214 to L-285; K-215 to L-285; K-216 to L-285; V-217 a L-285, H-218 to L-285; V-219 to L-285; F-220 to L-285; G-221 a L-285. D-222 to L-285; e-223 to L-285; L-224 to L-285; s-225 a L-285 • L-226 to L-285; V-227 to L-285; T-228 to L-285; L-229 a L-285 • F-230 to L-285; r-231 to L-285; C-232 to L-285; 1-233 a L-285, Q-234 to L-285; N-235 to L-285; M-236 to L-285; P-237 a L-285 • E-238 to L-285; T-239 to L-285; L-240 to L-285; P-241 a L-285 • N-242 to L-285; N-243 to L-285; S-244 to L-285; c-245 a L-285, • Y-246 to L-285; s-247 to L-285; A-248 to L-285; g-249 a L-285 • 1-250 to L-285; A-251 to L-285; K-252 to L-285; L-253 a L-285, • E-254 to L-285; E-255 to L-285; G-256 to L-285; D-257 a L-285, E-258 to L-285; L-259 to L-285; q-260 to L-285; L-261 a L-285, a-262 to L-285; 1-263 to L-285; P-264 to L-285; R-265 a L-285, E-266 to L-285; N-267 to L-285; a-268 to L-285; q-269 a L-285, 1-270 to L-285; S-271 to L-285; L-272 to L-285; D-273 to L-285; G-274 to L-285; D-275 to L-285; V-276 to L-285; T-277 to L-285; F-278 to L-285; F-279 to L-285; and G-280 to L-285 of SEQ ID NO: 2. The present application also relates to nucleic acid molecules comprising or alternatively consisting of a polynucleotide sequence with at least 80, 85, 90, 92, 95, 96, 97, 98, or 99% identity to the polynucleotide sequence encoding the neutrokine-alpha and / or neutrocine-alphaSV polypeptides described above. The present invention also includes polynucleotide sequences fused to a heterologous polynucleotide sequence. The polypeptides encoded by these nucleic acids and / or polynucleotide sequences are also encompassed by the present invention, as are polypeptides comprising an amino acid sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence described above, and polynucleotides encoding such polypeptides. As mentioned above, even if the deletion of one or more amino acids from the C-terminal end of a protein results in the modification or loss of one or more functional activities (eg biological activity) thereof, other activities may still be retained functional Thus, the ability of a shortened Neutrocin-alpha mutein to induce and / or bind antibodies that recognizes the complete or mature form or extracellular domain of the polypeptide, will generally be retained when at least the majority of the residues of the complete or mature form or of the extracellular domain of the polypeptide are removed from the C-terminal end. The fact that a particular polypeptide lacking C-terminal residues of a complete polypeptide retains immunological activity can be easily determined by routine methods described herein and otherwise known in the art. It is not unlikely that a Neutrocin-alpha mutein that has undergone the deletion of a large number of C-terminal amino acid residues, may retain some functional activity (e.g., biological or immunogenic). In fact, peptides composed of as little as 6 amino acid residues of neutrocine-alpha can often elicit an immune response. In accordance with the foregoing, the present invention further provides, in another embodiment, polypeptides that underwent the deletion of one or more carboxyl-terminal residues of the amino acid sequence of neutrocin-alpha shown in SEQ ID NO: 2, to the glutamic acid residue at position number 6 and polynucleotides encoding such polypeptides. In particular, the present invention provides polypeptides comprising the amino acid amino acid sequence of residues lm ° of SEQ ID NO: 2, wherein m3 is an integer in the range of amino acid position of amino acid residues 6 -284 of the amino acid sequence of SEQ ID NO: 2. More particularly, the present invention provides polynucleotides that encode polypeptides that comprise, or alternatively consist of, an amino acid sequence that is selected from the group consisting of M1 residues. to L-284; M-1 to K-283; M-1 to L-282; M-1 to A-281; M-1 to G-280; M-1 to F-279; M-1 to F-278; M-1 to T-277; M-1 to V-276; M-1 to D-275; M-1 to G-274; M-1 to D-273; M-1 to L-272; M-1 to S-271; M-1 to 1-270; M-1 to Q-269; M-1 a-268; M-1 to N-267; M-1 to E-266; m-1 to R-265; M-1 to P-264; M-1 a 1-263; M-1 to A-262; M-1 to L-261; M-l to q-260; M-1 to L-259; M-1 to E-258; M-1 to D-257; M-1 to G-256; M-l to E-255; M-1 to E-254; M-1 to L-253; M-1 to K-252; M-1 to A-251; M-1 to 1-250; M-1 to G-249; M-1 to A-248; M-1 to S-247; M-1 to Y-246; M-1 to C-245; M-1 to S-244; M-1 to N-243; M-1 to N-242; M-1 to P-241; M-1 to L-240; M-l to T-239; M-1 to E-238; M-1 to P-237; M-1 to M-236; M-1 to N-235; M-1 to Q-234; M-1 to 1-233; M-1 to C-232; M-1 to R-231; M-1 to F-230; M-1 to L-229; M-1 to T-228; M-1 to V-227; M-1 to L-226; M-1 to S-225; M-1 to L-224; M-1 to E-223; M-1 to D-222; M-1 to G-221; M-1 to F-220; M-1 to V.219; M-1 to H-218; M-1 to V-217; M-1 to K-216; M-1 to K-215; M-1 to R-214; M-1 to Q-213; M-1 a 1-212; M-1 to L-211; M-1 to H-210; M-1 to G-209; M-1 to M-208; M-1 to A-207; M-1 to Y-206; M-l to T-205; M-l to K-204; M-1 to D-203; M-1 to T-202; M-l to Y-201; M-1 to L-200; M-1 to V-199; M-1 to Q-198; M-1 to G-197; M-1 to Y-196; M-1 to 1-195; M-1 to F-194; M-1 to F-193; M-l a Y-192; M-1 to G-191; M-l to T-190; M-l to e-189; M-1 to K-188; M-1 to V-187; M-1 to L-186; M-1 to 1-185; M-1 to K-184; M-1 to N-183; M-l to E-182; M-1 to K-181; M-1 to E-180; M-1 to E-179; M-L to L-178; M-1 to A-177; M-1 to S-176; M-1 to G-175; M-1 to R-174; M-1 to K-173; M-1 to F-172; M-1 to S-171; M-1 to L-170; M-1 to L-169; M-1 to W-168; M-1 to P-167; M-1 to V-166; M-1 to F-165; M-l to T-164; M-l to Y-163; M-1 to S-162; M-1 to G-161; M-1 to K-160; M-1 to Q-159; M-1 to 1-158; M-l to T-157; M-1 to P-156; M-l to T-155; M-1 to E-154; m-1 to s-153; M-1 to D-152; M-1 to A-151; M -1 to 1-150; M-1 to L-149; M-1 to Q-148; M-l a L-147; M-1 to C-146; M-1 to D-145; M-1 to Q-144; M-l to T-143; M-1 to V-142; M-l to T-141; M-1 to E-140; M-1 to E-139; M-1 to P-138; M-1 to G-137; M-1 to Q-136; M-1 to V-135; M-1 a-134; M-1 to R-133; M-1 to K-132; M-1 to N-131; M-1 to R-130; M-1 a-129; M-1 to N-128; M-l to q-127; M-1 to S-126; M-1 to S-125; M-1 to N-124; M-1 to G-123; M-1 to E-122; M-1 to G-121; M-1 to P-120; M-1 to A-119; M-1 to P-118; M-1 to P-117; M-1 to E-116; M-1 to F-115; M-1 to 1-114; M-1 to K-113; M-1 to L-112; M-1 to G-111; M-1 a-110; M-1 to T-109; M-1 to V-108; M-l to A-l 07; M-1 to P-106; M-1 to A-105; M-1 to E-104; M-1 to E-103; M-1 to L-102; M-1 to G-101; M-l to a-100; M-1 to K-99; M-l to P-98; M-1 to A-97; M-1 to G-96; M-L to A-95; M-1 to G-94; M-1 to A-93 M-1 to P-92; M-1 to L-91; M-l to K-90; M-1 to E-89; M-1 a-88 M-1 to H-87; M-1 to H-86; M-1 to G-85; M-1 to Q-84; M-1 to L-83 M-1 to E-82; M-l to A-81; M-1 to R-80; M-L to L-79; M-1 to S-78 M-1 to A-77; M-1 to L-76; M-1 to D-75; M-1 to G-74; M-1 to Q-73 M-1 to L-72; M-l a a-71; M-l to A-70; M-l to v-69; M-l to q-68 M-l to Y-67; M-1 to F-66; M-1 to S-65; M-1 to V-64; M-1 to V-63 M-1 to T-62; M-1 to L-61; M-1 to C-60; M-1 to C-59; M-1 to S-58 M-1 to L-57; M-L to L-56; M-1 to A-55; M-1 to L-54; M-1 to L-53 M-1 to L-52; M-l to T-51; m-1 to A-50; M-l to A-49; M-1 to L-48 M-1 to L-47; M-l to K-46; M-l to G-45; M-1 to D-44; M-1 to K-43 M-1 to S-42; M-1 to S-41; m-1 to R-40; M-1 to V-39; M-1 to S-38 M-1 to P-37; M-1 to S-36; M-1 to E 4-35; M-l to K-34; M-1 to R-33; M-1 to P-32; M-1 to L-31; M-1 to 1-30; M-1 to S-29; M-1 to V-28; M-1 to C-27; M-l to E-26; M-l to K-25; M-1 to L-24; M-l to K-23; M-l to M-22; M-l to E-21; M-l to E-20; M-1 to R-19; M-l to K-18; M-l to K-17; M-1 to L-16; M-1 to C-15; M-1 to S-14; M-l to T-13; M-1 to L-12; M-1 to R-11; M-1 to S-10; M-l to Q-9; M-l to E-8; M-1 to R-7; and Ml to E-6 of SEQ ID NO: 2. The present application also relates to nucleic acid molecules comprising or alternatively consisting of a polynucleotide sequence with at least 80, 85, 90, 92, 95, 96, 97, 98, or 99 percent identity to the polynucleotide sequence encoding the above-described neutrokine-alpha and / or neutrocine-alphaSV polypeptides. The present invention also includes the above polynucleotide sequences fused to a heterologous polynucleotide sequence. Polypeptides encoded by these nucleic acids and / or polynucleotide sequences are also encompassed by the present invention, as are polypeptides comprising an amino acid sequence with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% identity the amino acid sequence described above and polynucleotides encoding such polypeptide. The present invention also provides polypeptides that underwent deletion of one or more amino acids from both the amino terminus and the carboxyl terminus of a neutrocine-alpha polypeptide, which can generally be described as having the n3-m3 residues of SEQ ID NO: 2 where n3 and m3 are integers as previously defined. In addition, since the predicted extracellular domain of the neutrokine-alphaSV polypeptides of the present invention per se can induce a functional activity (e.g., biological activity) deletions of N-terminal and C-terminal amino acid residues of the predicted extracellular region of the polypeptide at positions Gln-73 to Leu-266 of SEQ ID NO: 19 could retain some functional activity, such as example ligand binding, stimulation of proliferation, differentiation and / or activation of lymphocytes (eg, B cells), modulation of cell replication, modulation of target cell activity and / or immunogenicity. However, even if the deletion of one or more amino acids from the N-terminal end of the predicted extracellular domain of a neutrokine-alphaSV polypeptide results in the modification or loss of one or more functional activities thereof, other activities may still be retained. functional Thus, the ability of the shortened polypeptides to induce and / or bind antibodies that recognize the complete or mature polypeptide or the extracellular domains of the polypeptides will generally be retained at least from most of the complete or mature polypeptide residues or from the extracellular domains of the polypeptides are removed from the N-terminus. The fact that a particular polypeptide lacking N-terminal residues of the complete polypeptide retains the biological activity can easily be determined by routine methods described herein and otherwise known in the art. In accordance with the foregoing, the present invention further provides polypeptides that underwent the deletion of one or more amino terminal residues of the amino acid sequence of neutrocine-alphaSV shown in SEQ ID NO: 19, up to the glycine residue in the position number 261, and polynucleotide encoding such polypeptides. In particular, the present invention provides polypeptides comprising the amino acid sequence of residues n4-266 of SEQ ID NO: 19, wherein n4 is an integer in the range of the amino acid position of amino acid residues 73- 261 of the amino acid sequence of SEQ ID NO: 19 and 261 is the position of the first residue of the N-terminal predicted extracellular domain of the neutrocine-alphaSV polypeptide (shown in SEQ ID NO: 19). More particularly, in certain embodiments, the present invention provides polynucleotides that encode polypeptides comprising or alternatively consisting of, an amino acid sequence that is selected from the group consisting of residues from Q-73 to L-266; G-74 to L-266; D-75 to L-266; L-76 to L-266; A-77 to L-266; S-78 to L-266; L-79 to L-266; R-80 to L-266; A-81 to L-266; E-82 to L-266; L-83 to L-266; Q-84 to L-266; G-85 to L-266; H-86 to L-266; H-87 to L-266; A-88 to L-266; E-89 to L-266; K-90 to L-266; L-91 to L-266; P-92 to L-266; A-93 to L-266; G-94 to L-266; A-95 to L-266; G-96 to L-266; A-97 to L-266; P-98 to L-266; K-99 to L-266; A-100 to L-266; G-101 to L- 266; L-102 to L-266; E-103 to L-266; E-104 to L-266; A-105 a -L-266; P-106 to L-266 A-107 to L-266 V-108 to L-266; T-109 a L-266; A-110 to L-266 G-111 to L-266 L-112 to L-266; K-113 a L-266; 1-114 to L-266 F-115 to L-266 E-116 to L-266; P-117 to L-266; P-118 to L-266 A-119 to L-266 P-120 to L-266; G-121 to L-266; E-122 to L-266 G-123 to L-266 N-124 to L-266; S-125 a L-266; S-126 to L-266 Q-127 to L-266 N-128 to L-266; S-129 a L-266; R-130 to L-266 N-131 to L-266 K-132 to L-266; R-133 a L-266; A-134 to L-266 V-135 to L-266 Q-136 to L-266; G-137 to L-266; P-138 to L-266 E-139 to L-266 E-140 to L-266; T-141 a L-266; G-142 to L-266 S-143 to L-266 Y-144 to L-266; T-145 a L-266; F-146 to L-266 V-147 to L-266 P-148 to L-266; W-149 a L-266; L-150 to L-266 L-151 to L-266 S-152 to L-266; F-153 a L-266; K-154 to L-266 R-155 to L-266 G-156 to L-266; S-157 to L-266; A-158 to L-266 L-159 to L-266 E-160 to L-266; E-161 a L-266; K-162 to L-266 E-163 to L-266 N-164 to L-266; K-165 a L-266; 1-166 to L-266 L-167 to L-266 V-168 to L-266; K-169 a L-266; E-170 to L-266 T-171 to L-266 G-172 to L-266; Y-173 a L-266; F-174 to L-266 F-175 to L-266 1-176 to L-266; Y-177 to L-266; G-178 to L-266 Q-179 to L-266 V-180 to L-266; L-181 a L-266; Y-182 to L-266 T-183 to L-266 D-184 to L-266; K-185 a L-266; T-186 to L-266 Y-187 to L-266 A-188 to L-266; M-189 a L-266; G-190 to L-266 H-191 to L-266 L-192 to L-266; 1-193 a L-266; Q-194 to L-266 R-195 to L-266 K-196 to L-266; K-197 to L-266; V-198 to L-266 H-199 to L-266 V-200 to L-266; F-201 to L-266; G-202 to L-266; D-203 to L-266; E-204 to L-266; L-205 to L-266; S-206 to L-266; L-207 to L-266; V-208 to L-266; T-209 to L-266; L-210 to L-266; F-211 to L-266; R-212 to L-266; C-213 to L-266; 1-214 to L-266; Q-215 to L-266; N-216 to L-266; M-217 to L-266; P-218 to L-266; E-219 to L-266; T-220 to L-266; L-221 to L-266; P-222 to L-266; N-223 to L-266; N-224 to L-266; S-225 to L-266; C-226 to L-266; Y-227 to L-266; S-228 to L-266; A-229 to L-266; G-230 to L-266; 1-231 to L-266; A-232 to L-266; K-233 to L-266; L 234 to L-266; E-235 to L-266; E-236 to L-266; G-237 to L-266; D-238 to L-266; E-239 to L-266; L-240 to L-266; Q-241 to L-266; L-242 to L-266; A-243 to L-266; 1-244 to L-266; P-245 to L-266; R-246 to L-266; E-247 to L-266; N-248 to L-266; A-249 to L-266; Q-250 to L-266; 1-251 to L-266; S-252 to L-266; L-253 to L-266; D-254 to L-266; G-255 to L-266; D-256 to L-266; V-257 to L-266; T-258 to L-266; F-259 to L-266; F-260 to L-266; and G-261 to L-266 of SEQ ID NO: 19. The present application also relates to nucleic acid molecules comprising or alternatively consisting of a polynucleotide sequence with at least 80, 85, 90, 92, 95, 96, 97, 98, or 99 identity to the polynucleotide sequence coding for the neutrokine-alpha and / or neutrocine-alphaSV polypeptides described above. The present invention also includes polynucleotide sequences fused to a heterologous polynucleotide sequence. The polypeptides encoded by these nucleic acids and / or polynucleotide sequences are also encompassed by the present invention, as are polypeptides comprising an amino acid sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence described above, and polynucleotides encoding such polypeptides. Similarly, the deletions of C-terminal amino acid residues from the predicted extracellular domain of neutrokine-alphaSV, up to the leucine residue at position 79 of SEQ ID NO: 19, may retain some functional activity, such as, for example, the binding to the ligand, the ability to stimulate the proliferation, differentiation and / or activation of lymphocytes (eg, B cells), modulation of cell replication, modulation of activities in the target cell and / or immunogenicity. Polypeptides subjected to additional C-terminal deletions including residue Leu-79 of SEQ ID NO: 19, would not be expected to retain biological activity. However, even if the deletion of one or more amino acids from the C-terminal end of a polypeptide results in the modification or loss of one or more functional activities (e.g., the biological activity) of it, other functional activities could still be retained. Thus, the ability of the polypeptide shortened to induce and / or bind antibodies that recognize the complete, mature or extracellular form of the polypeptide will generally be retained at least from most residues of the complete, mature or extracellular domain of the polypeptide. polypeptide are removed from the C-terminal end. The fact that a particular polypeptide lacking C-terminal residues of the predicted extracellular domain retains immunological activity can easily be determined by routine methods described herein and otherwise known in the art. In accordance with the foregoing, the present invention further provides polypeptides that underwent the deletion of one or more carboxyl-terminal residues of the amino acid sequence of the predicted extracellular domain of the neutrokine-alphaSV shown in SEQ ID NO: 19, up to the Leucine residue at position 79 of SEQ ID NO: 19, and polynucleotides encoding such polypeptides. In particular, the present invention provides polypeptides having the amino acid sequence of residues 73-m4 of the amino acid sequence of SEQ ID NO: 19, wherein m4 is an integer in the range of amino acid position of amino acid residues 79-266 of the amino acid sequence of SEQ ID NO: 19. More particularly, in certain embodiments, the present invention provides polynucleotides that encode polypeptides that comprise or alternatively consist of an amino acid sequence that is selected from group consisting of waste from Q-73 to L-265; Q-73 to K-264; Q-73 to L-263; Q-73 to A-262; Q-73 to G-261; Q-73 to F-260; Q-73 to F-259; Q-73 to T-258; Q-73 to V-257; Q-73 to D-256; Q-73 to G-255; Q-73 to D-254; Q-73 to L-253; Q-73 to S-252; Q-73 to 1-251; Q-73 to Q-250; Q-73 to A-249; Q-73 to N-248; Q-73 to E-247; Q-73 to R-246; Q-73 to P-245; Q-73 to 1-244; Q-73 to A-243; Q-73 to L-242; Q-73 to Q-241; Q-73 to L-240; Q-73 to E-239; Q-73 to D-238; Q-73 to G-237; Q-73 to E-236; Q-73 to E-235; Q-73 to L-234; Q-73 to K-233; Q-73 to A-232; Q-73 to 1-231; Q-73 to G-230; Q-73 to A-229; Q-73 to S-228; Q-73 to Y-227; Q-73 to C-226; Q-73 to S-225; Q-73 to N-224; Q-73 to N-223; Q-73 to P-222; Q-73 to L-221; Q-73 to T-220; Q-73 to E-219; Q-73 to P-218; Q-73 to M-217; Q-73 to N-216; Q-73 to Q-215; Q-73 to 1-214; Q-73 to C-213; Q-73 to R-212; Q-73 to F-211; Q-73 to L-210; Q-73 to T-209; Q-73 to V-208; Q-73 to L-207; Q-73 to S-206; Q-73 to L-205; Q-73 to E-204; Q-73 to D-203; Q-73 to G-202; Q-73 to F-201; Q-73 to V-200; Q-73 to H-199; Q-73 to V-198; Q-73 to K-197; Q-73 to K-196; Q-73 to R-195; Q-73 to Q-194; Q-73 to I-193; Q-73 to L-192; Q-73 to H-191; Q-73 to G-190; Q-73 to Q-7389; Q-73 to A-188; Q-73 to Y-187; Q-73 to T-186; Q-73 to K-185; Q-73 to D-184; Q-73 to T-183; Q-73 to Y-182; Q-73 to L- 181; Q-73 to V-180; Q-73 to Q-179; Q-73 to G-178; Q-73 to Y- 177; Q-73 to 1-176; Q-73 to F-175; Q-73 to F-174; Q-73 to Y- 173; Q-73 to G-172; Q-73 to T-171; Q-73 to E-170; Q-73 to K- 169; Q-73 to V-168; Q-73 to L-167; Q-73 to 1-166; Q-73 to K-165; Q-73 to N-164; Q-73 to E-163; Q-73 to K-162; Q-73 to E-161; Q-73 to E-160; Q-73 to L-159; Q-73 to A-158; Q-73 to S-157; Q-73 to G-156; Q-73 to R-155; Q-73 to K-154; Q-73 to F- 153; Q-73 to S-152; Q-73 to L-151; Q-73 to L-150; Q-73 to W- 149; Q-73 to P-148; Q-73 to V-147; Q-73 to F-146; Q-73 to T-145; Q-73 to Y-144; Q-73 to S-143; Q-73 to G-142; Q-73 to T-141; Q-73 to E-140; Q-73 to E-139; Q-73 to P-138; Q-73 to G-137; Q-73 to Q-136; Q-73 to V-135; Q-73 to A-134; Q-73 to R-133; Q-73 to K-132; Q-73 to N-131; Q-73 to R-130; Q-73 to S-129; Q-73 to N-128; Q-73 to Q-127; Q-73 to S-126; Q-73 to S-125; Q-73 to N-124; Q-73 to G-123; 'Q-73 to E-122; Q-73 to G-121; Q-73 to P-120; Q-73 to A-119; Q-73 to P-118; Q-73 to P- 117; Q-73 to E-116; Q-73 to F-115; Q-73 to 1-114; Q-73 to K-113; Q-73 to L-112; Q-73 to G-111; Q-73 to A-110; Q-73 to T-109; Q-73 to V-108; Q-73 to A-107; Q-73 to P-106; Q-73 to A-105, Q-73 to E-104; Q-73 to E-103; Q-73 to L-102; Q-73 to G-101; Q-73 to A-100; Q-73 to K-99; Q-73 to P-98; Q-73 to A-97; Q-73 to G-96; Q-73 to A-95; Q-73 to G-94; Q-73 to A-93; Q-73 a P-92; Q-73 to L-91; Q-73 to K-90; Q-73 to E-89; Q-73 to A-88; Q-73 to H-87; Q-73 to H-86; Q-73 to G-85; Q-73 to Q-84; Q-73 to L-83; Q-73 to E-82; Q-73 to A-81; Q-73 to R-80; Q-73 to L-79 and Q-73 to S-78 of SEQ ID NO: 19. The present application also relates to nucleic acid molecules comprising or alternatively consisting of a polynucleotide sequence with at least 80, 85 , 90, 92, 95, 96, 97, 98, or 99% identity to the polynucleotide sequence coding for the neutrokine-alpha and / or neutrocine-alphaSV polypeptides described above. The present invention also includes polynucleotide sequences fused to a heterologous polynucleotide sequence. The polypeptides encoded by these nucleic acids and / or polynucleotide sequences are also encompassed by the present invention, as are polypeptides comprising an amino acid sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence described above, and polynucleotides encoding such polypeptides. The present invention also provides polypeptides that underwent the deletion of one or more amino acids both at the amino terminus and at the carboxyl terminus of the predicted extracellular domain of neutrokine-alphaSV, which can generally be described as having residues n4 -m4 of SEQ ID NO: 29, where n4 and m4, are integers as previously defined. In another embodiment, a nucleotide sequence encodes a polypeptide consisting of a portion of the extracellular domain of the amino acid sequence neutrocin-alphaSV encoded by the cDNA clone contained in the deposit with accession number ATCC 203518, wherein this portion excludes of one 206 amino acids from the amino terminal end of the extracellular domain of the amino acid sequence encoded by the cDNA contained in the deposit having the accession number ATCC 203518, or from one to about 1 to 187 amino acids of the carboxyl terminus of the domain extracellular of the amino acid sequence encoded by the cDNA clone contained in the deposit having the accession number ATCC 203518, or any combination of the above amino-terminal and carboxyl-terminal deletions of the complete extracellular domain of the amino acid sequence encoded by the cDNA clone contained in the deposit that has the ATCC access number 2 03518. As mentioned above, even if the deletion of one or more amino acids from the N-terminus of a polypeptide results in the modification or loss of one or more functional activities (eg, biological activity thereof, they could still be retained). other functional activities. Thus, the ability of a shortened neutrokine-alphaSV mutein to induce and / or bind antibodies that recognize the full-length or mature forms or the extracellular domain of the polypeptide will generally be retained at least from most of the residues of the Mature or complete length form, or the extracellular domain of the polypeptide are removed from the N-terminal end. The fact that a particular polypeptide lacking N-terminal residues of a complete polypeptide retains immunological activity can be readily determined by routine methods described herein and otherwise known in the art. It is not unlikely that a neutrokine-alphaSV mutein with a large number of lesions of N-terminal amino acid residues can retain functional (e.g., immunogenic) activities. In fact, peptides composed of an amount as small as six amino acid residues of neutrocine-alphaSV, can often elicit an immune response. Accordingly, the present invention further provides polypeptides that underwent the deletion of one or more amino-terminal residues of the predicted full-length amino acid sequence of the neutrokine-alphaSV shown in SEQ ID NO: 19, to the glycine residue at position number 261 of the sequence shown in SEQ ID NO: 19, and polynucleotides encoding such polypeptides. In particular, the present invention provides polypeptides comprising the amino acid sequence of residues n5-266 of the sequence shown in SEQ ID NO: 19, where n5 is an integer in the range of the amino acid position of the residues of amino acid 1 to 261 of the amino acid sequence of SEQ ID NO: 19. More particularly, the present invention provides polynucleotides that encode polypeptides comprising or alternatively consisting of, an amino acid sequence that is selected from the group consisting of the residues from D-2 to L-266; D-3 to L-266; S-4 to L-266; T-5 to L-266; E-6 to L-266; R-7 to L-266; E-8 to L-266; Q-9 to L-266; S-10 to L-266; R-ll to L-266; L-12 to L-266; T-13 to L-266; S-14 to L-266; C-15 to L-266; L-16 to L-266; K-17 to L-266; K-18 to L-266; R-19 to L-266; E-20 to L-266; E-21 to L-266; M-22 to L-266; K-23 to L-266; L-24 to L-266; K-25 to L-266; E-26 to L-266; C-27 to L-266; V-28 to L-266; S-29 to L-266; 1-30 to L-266; L-31 to L-266; P-32 to L-266; R-33 to L-266; K-34 to L-266; E-35 to L-266; S-36 to L-266; P-37 to L-266; S-38 to L-266; V-39 to L-266; R-40 to L-266; S-41 to L-266; S-42 to L-266; K-43 to L-266; D-44 to L-266; G-45 to L-266; K-46 to L-266; L-47 to L-266; L-48 to L-266; A-49 to L-266; A-50 to L-266; T-51 to L-266; L-52 to L-266; L-53 to L-266; L-54 to L-266; A-55 to L-266; L-56 to L-266; L-57 to L-266; S-58 to L-266; C-59 to L-266; C-60 to L-56; L-61 to L-266; T-62 to L-266; V-63 to L-266; V-64 to L-266; S-65 to L-266; F- 66 to L-266; Y-67 to L-266; Q-68 to L-266; V-69 to L-266; A-70 to L-266; A-71 to L-266; L-72 to L-266; Q-73 to L-266; G-74 to L-266; D-75 to L-266; L-76 to L-266; A-77 to L-266; S-78 to L-266; L-79 to L-266; R-80 to L-266; A-81 to L-266; E-82 to L-266; L-83 to L-266; Q-84 to L-266; G-85 to L-266; H-86 to L- 266; H-87 to L-266; A-88 to L-266; E-89 to L-266; K-90 to L-266; L-91 to L-266; T-92 to L-266; A-93 to L-266; G-94 to L-266; A-95 to L-266; G-96 to L-266; A-97 to L-266; P-98 to L-266; K-99 to L-266; A-100 to L-266; G-101 to L-266; L-102 to L-266; E-103 to L-266; E-104 to L-266; A-105 to L-266; P-106 a L-266; A-107 to L-266; V-108 to L-266; T-109 to L-266; A-110 to L-266; G-111 to L-266; L-112 to L-266; K-113 to L-266; 1-114 to L-266; F-115 to L-266; E-116 to L-266; P-117 to L-266; P-118 to L-266; A-119 to L-266; P-120 to L-266; G-121 to L-266; E-122 to L-266; G-123 to L-266; N-124 to L-266; S-125 to L-266; S-126 a L-266; Q-127 to L-266; N-128 to L-266; S-129 to L-266; R-130 to L-266; N-131 to L-266; K-132 to L-266; R-133 to L-266; A-134 to L-266; V-135 to L-266; Q-136 to L-266; G-137 to L-266; P-138 to L-266; E-139 to L-266; E-140 to L-266; T-141 to L-266; G-142 to L-266; S-143 to L-266; Y-144 to L-266; T-145 to L-266; F-146 a L-266; V-147 to L-266; P-148 to L-266; W-149 to L-266; L-150 to L-266; L-151 to L-266; S-152 to L-266; F-153 to L-266; K-154 to L-266; R-155 to L-266; G-156 to L-266; S-157 to L-266; A-158 to L-266; L-159 to L-266; E-160 to L-266; E-161 to L-266; K-162 to L-266; E-163 to L-266; N-164 to L-266; K-165 to L-266; 1-166 to L-266, L-167 to L-266. V-168 to L-266; K-169 to L-266; E-170 a L-266 • T-171 to L-266 • G-172 to L-266; Y-173 to L-266; F-174 a L-266. F-175 to L-266,. 1-176 to L-266; Y-177 to L-266; G-178 a L-266. Q-179 to L-266. V-180 to L-266; L-181 to L-266; Y-182 to L-266 • T-183 to L-266, • D-184 to L-266; K-185 to L-266; T-186 a L-266, • Y-187 to L-266, 'A-188 to L-266; M-189 to L-266; G-190 to L-266. H-191 to L-266, • L-192 to L-266; 1-193 to L-266; Q-194 a L-266 • R-l 95 to L-266, • K-196 to L-266; K-197 to L-266; V-198 a L-266, • H-199 to L-266, • V-200 to L-266; F-201 to L-266; G-202 to L-266, • D-203 to L-266, • E-204 to L-266; L-205 to L-266; S-206 a L-266, • L-207 to L-266, V-208 to L-266; T-209 to L-266; L-210 a L-266, • F-211 to L-266, R-212 to L-266; C-213 to L-266; 1-214 a L-266, • Q-215 to L-266, N-216 to L-266; M-217 to L-266; P-218 a L-266, • E-219 to L-266, T-220 to L-266; L-221 to L-266; P-222 a L-266, • N-223 to L-266, N-224 to L-266; S-225 to L-266; C-226 a L-266, • Y-227 to L-266, S-228 to L-266; A-229 to L-266; G-230 a L-266, • 1-231 to L-266, A-232 to L-266; K-233 to L-266; L-234 a L-266, E-235 to L-266, E-236 to L-266; G-237 to L-266; D-238 a L-266, • E-239 to L-266, L-240 to L-266; Q-241 to L-266; L-242 a L-266, • A-243 to L-266, 1-244 to L-266; P-245 to L-266; R-246 a L-266, E-247 to L-266, N-248 to L-266; A-249 to L-266; Q-250 to L-266, 1-251 to L-266; S-252 to L-266; L-253 to L-266; D-254 a L-266, G-255 to L-266, D-256 to L-266; V-257 to L-266; T-258 a L-266, F-259 to L-266; F-260 to L-266; and G-261 to L-266 of the SEQ II and NO: 19. The present invention also relates to nucleic acid molecules comprising or alternatively consisting of a polynucleotide sequence with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% of identity to the polynucleotide sequence coding for the neutrokine-alpha and / or neutrocine-alphaSV polypeptides described above. The present invention also includes the above polynucleotide sequences fused to a heterologous polynucleotide sequence. Polypeptides encoded by these nucleic acids and / or polynucleotide sequences are also encompassed by the present invention, as are polypeptides comprising an amino acid sequence with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% identity to the above-described amino acid sequence and polynucleotides encoding such polypeptides. Likewise, as mentioned above, even if the deletion of one or more amino acids from the C-terminal end of a protein results in the modification or loss of one or more functional activities (e.g., biological activities) thereof, other functional activities may still be retained. Thus, the ability of a shortened neutrokine-alphaSV mutein to induce and / or bind antibodies that recognize the mature or complete form or the extracellular domain of the polypeptide will generally be retained at least from most residues of the complete form or mature or from the extracellular domain of the polypeptide are removed from the C-terminal end. Whether a particular polypeptide lacking C-terminal residues of a complete polypeptide retains immunological activity, can be easily determined by routine methods described herein and known in some other way in the art. It is not unlikely that a neutrokine-alphaSV mutein with a large number of deletions of C-terminal amino acid residues can retain any functional (e.g., immunogenic) activity. In fact, peptides composed of a number as small as six amino acid residues of neutrocine-alphaSV, can often elicit an immune response. In accordance with the foregoing, the present invention further provides, in another embodiment, polypeptides that underwent the deletion of one or more carboxyl-terminal residues of the amino acid sequence of neutrocine-alphaSV shown in SEQ ID NO: 19, to the glutamic acid residue at position 6, and polynucleotides encoding such polypeptides. In particular, the present invention provides polypeptides comprising the amino acid sequence of residues 1-m5 of SEQ ID NO: 19, wherein m5 is an integer in the range of the amino acid position of amino acid residues 6 to 265 of the amino acid sequence of SEQ ID NO: 19. More particularly, the present invention provides polynucleotides that encode polypeptides comprising or alternatively consisting of, an amino acid sequence that is selected from the group consisting of the residues of Ml a L-265; M-1 to K-264; M-1 to L-263; M-1 to A-262; M-1 to G-261; M-1 to F-260; M-1 to F-259; M-l to T-258; M-1 to V-257; M-1 to D-256; M-1 to G-255; M-1 to D-254; M-1 to L-253; M-1 to S-252; M-1 to 1-251; M-l to Q-250; M-1 to A-249; M-1 to N-248; M-1 to E-247; M-1 to R-246; M-1 P-245; M-1 to 1-244; M-1 to A-243; M-1 to L-242; M-1 to Q-241; M-1 to L-240; M-1 to E-239; M-1 to D-238; M-1 to G-237; M-1 to E-236; M-1 to E-235; M-1 to L-234; M-1 to K-233; M-l to A-232; M-1 to 1-231; M-1 to G-230; M-1 to A-229; M-1 to S-228; M-1 to Y-227; M-1 to C-226; M-1 to S-225; M-1 to N-224; M-1 to N-223; M-1 to P-222; M-1 to L-221; M-l to T-220; M-1 to E-219; M-1 to P-218; M-1 to M-217; M-1 to N-216; M-1 to Q-215; M-1 to I-214; M-1 to C-213; M-1 to R-212; M-1 to F-211; M-1 to L-210; M-1 to T-209; M-1 to V-208; M-1 to L-207; M-1 to S-206; M-1 to L-205; M-1 to E-204; M-1 to D-203; M-1 to G-202; M-1 to F-201; M-1 to V-200; M-1 to H-199; M-1 to V-198; M-1 to K-197; M-1 to K-196; M-1 to R-195; M-1 to K-194; M-1 to 1-193; M-1 to L-192; M-1 to H-191; M-1 to G-190; M-1 to M-189; M-1 to A-188; M-1 to Y-187; M-l to T-186; M-l to K-185; M-1 to D-184; M-l to T-183; M 1 to Y-182; M-1 to L-181; M-1 to V-180; M-1 to Q-179; M-l to G 178; M-l to Y-177; M-1 to 1-176; M-1 to F-175; M-1 to F-174; M 1 to Y-173; M-1 to G-172; M-1 to T-171; M-1 to E-170; M-l to K 169; M-1 to V-168; M-1 to L-167; M-1 to 1-166; M-1 to K-165; M ' 1 to N-l 64; M-1 to E-163; M-1 to K-162; M-l to E-161; M-1 to E-160; M-1 to L-159; M-1 to A-158; M-1 to S-157; M-1 to G-156; M 1 to R-155; M-1 to K-154; M-1 to F-153; M-1 to S-152; M-l to L ' 151; M-1 to L-150; M-l to W-149; M-1 to P-148; M-1 to V-147; M-1 to F-146; M-l to T-145; M-l to Y-144; M-1 to S-143; M-1 to G-142; M-l to T-141; M-1 to E-140; M-1 to E-139; M-1 to P-138; M-1 to G-137; M-1 to Q-136; M-1 to V-135; M-1 to A-134; M-1 to R-133; M-1 to K-132; M-1 to N-131; M-1 to R-130; M-1 to S-129; M-1 to N-128; M-l to Q-127; M-1 to S-126; M-1 to S-125; M-1 to N-124; M-1 to G-123; M-1 to E-122; M-1 to G-121; M-1 to P-120; M- 1 to A-119; M-1 to P-118; M-1 to P-117; M-1 to E-116; M-1 to F-115; M-1 to 1-114; M-1 to K-113; M-1 to L-112; M-1 to G-111; M- 1 to A-110; M-1 to T-109; M-1 to V-108; M-l to A-l 07; M-1 to P-106; M-1 to A-105; M-1 to E-104; M-1 to E-103; M-1 to L-102; M-1 to G-101; M-l to A-100; M-1 to K-99; M-l to P-98; M-l to A-97 M-1 to G-96; M-l to A-95; M-1 to G-94; M-l to A-93; M-l to P-92 M-1 to L-91; M-l to K-90; M-1 to E-89; M-1 to A-88; M-l to H-87 M-1 to H-86; M-1 to G-85; M-1 to Q-84; M-L to L-83; M-l to E-82 M-l to A-81; M-1 to R-80; M-L to L-79; M-1 to S-78; M-1 to A-77 M-1 to L-76; M-1 to D-75; M-1 to G-74; M-l to Q-73; M-1 to L-72 M-1 to A-71; M-l to A-70; M-1 to V-69; M-1 to Q-68; M-1 to Y-67 M-1 to F-66; M-1 to S-65; M-1 to V-64; M-1 to V-63; M-l to T-62 M-l to L-61; M-1 to C-60; M-1 to C-59; M-1 to S-58; M-1 to L-57 M-1 to L-56; M-1 to A-55; M-1 to L-54; M-L to L-53; M-1 to L-52 M-1 to T-51; M-l to A-50; M-l to A-49; M-1 to L-48; M-l to L-47 M-l to K-46; M-l to G-45; M-1 to D-44; M-l to K-43; M-1 to S-42 M-1 to S-41; M-1 to R-40; M-1 to V-39; M-1 to S-38; M-1 to P-37 M-1 to S-36; M-l to E-35; M-l to K-34; M-1 to R-33; M-1 to P-32 M-1 to L-31; M-1 to 1-30; M-1 to S-29; M-1 to V-28; M-1 to C-27 M-1 to E-26; M-l to K-25; M-1 to L-24; M-l to K-23; M-1 to M-22 M-1 to E-21; M-l to E-20; M-1 to R-19; M-l to K-18; M-l to K-17 M-l to L-16; M-1 to C-15; M-1 to S-14; M-l to T-13; M-1 to L-12 M-1 to R-11; M-1 to S-10; M-l to Q-9; M-l to E-8; M-1 to R-7; and Ml to E-6 of SEQ ID NO: 19. The present application also relates to nucleic acid molecules comprising or alternatively consisting of a polynucleotide sequence with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% identity to the polynucleotide sequence coding for the neutrokine-alpha and / or neutrocine-alphaSV polypeptides described above. The present invention also includes the above polynucleotide sequences fused to a heterologous polynucleotide sequence. Polypeptides encoded by these nucleic acids and / or polynucleotide sequences are also encompassed by the present invention, as are polypeptides comprising an amino acid sequence with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% identity to the above-described amino acid sequence and polynucleotides encoding such polypeptides. The present invention also provides polypeptides that underwent the deletion of one or more amino acids from both the amino terminus and the carboxyl terminus of a neutrocine-alphaSV polypeptide, which can generally be described as having the n5-m5 residues of SEQ ID NO: 19, where n5 and m5 are integers as previously defined. In additional embodiments, the present invention provides polypeptides comprising the amino acid sequence of residues 134-m6 of SEQ ID NO: 2, wherein m6 is an integer from 140 to 285, which corresponds to the position of the amino acid residue in SEQ ID NO: 2. For example, the present invention provides polynucleotides that encode polypeptides comprising or alternatively consisting of, an amino acid sequence that is selected from the group consisting of the residues of A-134 to Leu-285; A-134 to L-284; A-134 to K-283; A-134 to L-282; A-134 to A-281; A-134 to G-280; A-134 to F-279; A-134 to F-278; A-134 to 1-211; A-134 to V-276; A-134 to D-275; A-134 to G-274; A-134 to D-273; A-134 to L-272; A-134 to S-271, - A-134 to 1-270,. A-134 to Q-269; A-134 to A-268; A-134 a N-267, • A-134 to E-266,. A-134 to R-265; A-134 to P-264; A-134 a 1-263, • A-134 to A-262,. A-134 to L-261. A-134 to Q-260; A- 134 a L-259, • A-134 to E-258, • A-134 to D-257, A-134 to G-256; A-134 a E-255 • A-134 to E-254 • A-134 to L-253, A-134 to K-252; A-134 a A-251, • A-134 to 1-250, • A-134 to G-249. A-134 to A-248; A-134 a S-247,. A-134 to Y-246,. A-134 to C-245. A-134 to S-244; A-134 a N-243 • A-134 to N-242 • A-134 to P-241 • A-134 to L-240; A- 134 a T-239, • A-134 to E-238, • A-134 to P-237, • A-134 to M-236; A- 134 a N-235, • A-134 to Q-234, • A-134 to 1-233, • A-134 to C-232; A-134 a R-231-A-134 to F-230 • A-134 to L-229 • A-134 to T-228; A-134 a V-227 A-134 to L-226. A-134 to S-225 • A-134 to L-224; A-134 a E-223, • A-134 to D-222, • A-134 to G-221, • A-134 to F-220; A-134 a V-219 • A-134 to H-218 • A-134 to V-217, • A-134 to K-216; A-134 a K-215. A-134 to R-214. A-134 to Q-213, • A-134 to 1-212; A-134 a L-211. A-134 to H-210, • A-134 to G-209, • A-134 to M-208; A-134 a A-207, • A-134 to Y-2T6, • A-134 to T-205, • A-134 to K-204; A-134 a D-203 • A-134 to T-202, • A-134 to Y-201, • A-134 to L-200; A-134 a V-199; A-134 to Q-198, - A-134 to G-197, • A-134 to Y-196; A-134 a 1-195 • A-134 to F-194, • A-134 to F-193, 'A-134 to Y-192; A-134 a G-191 • A-134 to T-190, A-134 to E-189, A-134 to K-188; A-134 a V-187 • A-134 to L-186, • A-134 to 1-185, A-134 to K-184; A-134 a N-183 • A-134 to E-182, • A-134 to K-181, A-134 to E-180; A- 134 a E-179 • A-134 to L-178, 'A-134 to A-177, A-134 to S-176; A-134 a G-175, • A-134 to R-174, A-134 to K-173, A-134 to F-172; A- 134 to s- -171; A-134 to L-170; A-134 to L-169; A-134 to W-168; A-134 a P- -167; A-134 to V-166; A-134 to F-165; A-134 to T-164; A-134 a Y- -163; A-134 to S-162; A-134 to G-161; A-134 to K-160; A-134 a Q- -159; A-134 to 1-158; A-134 to T-157; A-134 to P-156; A-134 a T- -155; A-134 to E-154; A-134 to S-153; A-134 to D-152; A-134 a A- -151; A-134 to 1-150; A-134 to L-149; A-134 to Q-148; A-134 a L- -147; A-134 to C-146; A-134 to D-145; A-134 to Q-144; A-134 a T- -143; A-134 to V-142; A-134 to T-141; and A-134 to E-140 of the SEQ ID NO: 2. The present application also relates to nucleic acid molecules comprising or alternatively consisting of a polynucleotide sequence with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% identity to the polynucleotide sequence coding for the neutrokine-alpha and / or neutrocine-alphaSV polypeptides described above. The present invention also includes the above polynucleotide sequences fused to a heterologous polynucleotide sequence. Polypeptides encoded by these nucleic acids and / or polynucleotide sequences are also encompassed by the present invention, as are polypeptides comprising an amino acid sequence with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% identity to the above-described amino acid sequence and polynucleotides encoding such polypeptides.

Additional preferred polypeptide fragments of the present invention, comprise or alternatively consist of an amino acid sequence that is selected from the group consisting of the residues of M-1 to C-15; D-2 to L-16; D-3 to K-17; S-4 to K-18; T-5 to R-19; E-6 to E-20; R-7 to E-21; E-8 to M-22; Q-9 to K-23; S-10 to L-24; R-11 to K-25; L-12 to E-26; T-13 to C-27; S-14 to V-28; C-15 to S-29; L-16 to 1-30; K-17 to L-31; K-18 to P-32; R-19 to R-33; E-20 to K-34; E-21 to E-35; M-22 to S-36; K-23 to P-37; L-24 to S-38; K-25 to V-39; E-26 to R-40; C-27 to S-41; V-28 to S-42; S-29 to K-43; 1-30 to D-44; L-31 to G-45; P-32 to K-46; R-33 to L-47; K-34 to L-48; E-35 to A-49; S-36 to A-50; P-37 to T-51; S-38 to L-52; V-39 to L-53; R-40 to L-54; S-41 to A-55; S-42 to L-56; K-43 to L-57; D-44 to S-58; G-45 to C-59; K-46 to C-60; L-47 to L-61; L-48 to T-62; A-49 to V-63; A-50 to V-64; T-51 to S-65; L-52 to F-66; L-53 to Y-67; L-54 to Q-68; A-55 to V-69; L-56 to A-70; L-57 to A-71; S-58 to L-72; C-59 to Q-73; C-60 to G-74; L-61 to D-75; T-62 to L-76; V-63 to A-77; V-64 to S-78; S-65 to L-79; F-66 to R-80; Y-67 to A-81; Q-68 to E-82; V-69 to L-83; A-70 to Q-84; A-71 to G-85; L-72 to H-86; Q-73 to H-87; G-74 to A-88; D-75 to E-89; L-76 to K-90; A-77 to L-91; S-78 to P-92; L-79 to A-93; R-80 to G-94; A-81 to A-95; E-82 to G-96; L-83 to A-97; Q-84 to P-98; G-85 to K-99; H-86 to A-100; H-87 to G-101; A-88 to L-102; E-89 to E-103; K-90 to E-104; L-91 to A-105; P-92 to P-106; A-93 to A-107; G-94 to V-108; A-95 to T-109; G-96 to A-110; A-97 to G-111; P-98 to L-112; K- 99 to K-113; A-100 to I-114; G-101 to F-115; L-102 to E-116; E-103 to P-117; E-104 a P-118 A-105 to A-119; P-106 to P-120 A-107 to G-121; V-108 to E-122 T-109 to G-123; A-110 to N-124 G-111 to S-125; L-112 to S-126 K-113 to Q-127; 1-114 to N-128 F-115 to S-129; E-116 to R-130 P-117 to N-131; P-118 to K-132 A-119 to R-133; P-120 to A-134 G-121 to V-135; E-122 to Q-136 G-123 to G-137; N-124 to P-138 S-125 to E-139; S-126 to E-140 Q-127 to T-141; N-128 to V-142 S-129 to T-143; R-130 to Q-144 N-131 to D-145; K-132 to C-146 R-133 to L-147; A-134 to Q-148 V-135 to L-149; Q-136 to 1-150 G-137 to A-151; P-138 to D-152 E-139 to S-153; E-140 to E-154 T-141 to T-155; V-142 to P-156 T-143 to T-157; Q-144 to 1-158 D-145 to Q-159; C-146 to K-160 L-147 to G-161; Q-148 to S-162 L-149 to Y-163; 1-150 to T-164 A-151 to F-165; D-152 to V-166 S-153 to P-167; E-154 to W-168 T-155 to L-169; P-156 to L-170 T-157 to S-171; 1-158 to F-172 Q-159 to K-173; K-160 to R-174 G-161 to G-175; S-162 to S-176 Y-163 to A-177; T-164 to L-178 F-165 to E-179; V-166 to E-180 P-167 to K-181; W-168 to E-182 L-169 to N-183; L-170 to K-184 S-171 to 1-185; F-172 to L-186 K-173 to V-187; R-174 to K-188 G-175 to E-189; S-176 to T-190 A-177 to G-191; L-178 to Y-192, E-179 to F-193; E-180 to F-194 K-181 to 1-195; E-182 to Y-196, N-183 to G-197; K-184 to Q-198 1-185 to V-199; L-186 to L-200, V-187 to Y-201; K-188 to T-202 E-189 to D-203; T-190 to K-204, G-191 to T-205; Y-192 to Y-206 F-193 to A-207; F-194 to M-208, 1-195 to G-209; Y-196 to H-210; G-197 to L-211; Q-198 to 1-212; V-199 to Q-213; L-200 to R-214; Y-201 to K-215; T-202 to K-216; D-203 to V-217; K-204 to H-218; T-205 to V-219; Y-206 to F-220; A-207 to G-221; M-208 to D-222; G-209 to E-223; H-210 to L-224; L-211 to S-225; 1-212 to L-226; Q-213 to V-227; R-214 to T-228; K-215 to L-229; K-216 to F-230; V-217 to R-231; H-218 to C-232; V-219 to 1-233; F-220 to Q-234, G-221 to N-235; D-222 to M-236; E-223 to P-237; L-224 to E-238; S-225 to T-239; L-226 to L-240; V-227 to P-241; T-228 to N-242; L-229 to N-243; F-230 to S-244; R-231 to C-245; C-232 to Y-246; 1-233 to S-247; Q-234 to A-248; N-235 to G-249; M-236 to 1-250; P-237 to A-251; E-238 to K-252; T-239 to L-253; L-240 to E-254; P-241 to E-255; N-242 to G-256; N-243 to D-257; S-244 to E-258; C-245 to L-259; Y-246 to Q-260; S-247 to L-261; A-248 to A-262; G-249 to 1-263; 1-250 to P-264; A-251 to R-265; K-252 to E-266; L-253 to N-267; E-254 to A-268; E-255 to Q-269; G-256 to 1-270; D-257 to S-271; E-258 to L-272; L-259 to D-273; Q-260 to G-274; 1-261 to D-275; A-262 to V-276; 1-263 to T-277; P-264 to F-278; R-265 to F-279; E-266 to G-280; N-267 to A-281; A-268 to L-282; Q-269 to K-283; 1-270 to L-284; and S-271 to L-285 of SEQ ID NO: 2. Preferably, these polypeptide fragments have one or more functional activities (eg, biological activity, antigenicity and immunogenicity) of the neutrokine-alpha and / or neutrocine polypeptides. -alphaSV of the present invention and can be used, for example, to generate or select antibodies, in the manner that will be described later. The present invention also relates to polypeptides comprising or alternatively consisting of an amino acid sequence with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% identity to a previously described amino acid sequence. The present invention also includes the above amino acid sequences fused to a heterologous amino acid sequence, in the manner described herein. The polynucleotides encoding these polypeptides are also encompassed by the present invention. Additional preferred polypeptide fragments of the present invention, comprise or alternatively consist of an amino acid sequence that is selected from the group consisting of the residues of M-1 to C-15; D-2 to L-16; D-3 to K-17; S-4 to K-18; T-5 to R-19; E-6 to E-20; R-7 to E-21; E-8 to M-22; Q-9 to K-23; S-10 to L-24; R-11 to K-25; L-12 to E-26; T-13 to C-27; S-14 to V-28; C-15 to S-29; L-16 to I-30; K-17 to L-31; K-18 to P-32; R-19 to R-33; E-20 to K-34; E-21 to E-35; M-22 to S-36; K-23 to P-37; L-24 to S-38; K-25 to V-39; E-26 to R-40; C-27 to S-41; V-28 to S-42; S-29 to K-43; I-30 to D-44; L-31 to G-45; P-32 to K-46; R-33 to L-47; K-34 to L-48; E-35 to A-49; S-36 to A-50; P-37 to T-51; S-38 to L-52; V-39 to L-53; R-40 to L-54; S-41 to A-55; S-42 to L-56; K-43 to L-57; D-44 to S-58; G-45 to c-59; K-46 to C-60; L-47 to L-61; L- 48 to T-62; A-49 to V-63; A-50 to V-64; T-51 to S-65; L-52 to F-66; L-53 to Y-67; L-54 to Q-68; A-55 to V-69; L-56 to A-70; L-57 to A-71; S-58 to L-72; C-59 to Q-73; C-60 to G-74; L-61 to D-75; T-62 to L-76; V-63 to A-77; V-64 to S-78; S-65 to L-79; F-66 to R-80; Y-67 to A-81; Q-68 to E-82; V-69 to L-83; A-70 to Q-84; A-71 to G-85; L-72 to H-86; Q-73 to H-87; G-74 to A-88; D-75 to E-89; L-76 to K-90; A-77 to L-91; S-78 to P-92; L-79 to A-93; R-80 to G-94; A-81 to A-95; E-82 to G-96; L-83 to A-97; Q-84 to P-98; G-85 to K-99; H-86 to A-100; H-87 to G-101; A-88 to L-102; E-89 to E-103; K-90 to E-104; L-91 to A-105; P-92 to P- 106; A-93 to A-107; G-94 to V-108; A-95 to T-109; G-96 to A-110; A-97 to G-111; P-98 to L-112; K-99 to K-113; A-100 to I-114; G-101 to F-115; L-102 to E-116; E-103 to P-117; E-104 to P-118; A-105 to A-119; P-106 to P-120; A-107 to G-121; V-108 to E-122; T-109 to G-123; A-110 to N-124; G-111 to S-125; L-112 a S-126; K-113 to Q-127; 1-114 to N-128; F-115 to S-129; E-116 to R-130; P-117 to N-131; P-118 to K-132; A-119 to R-133; P-120 to A-134; G-121 to V-135; E-122 to Q-136; G-123 to G-137; N-124 to P-138; S-125 to E-139; S-126 to E-140; Q-127 to T-141; N-128 to G-142; S-129 to S-143; R-130 to Y-144; N-131 to T-145; K-132 a F-146; R-133 to V-147; A-134 to P-148; V-135 to W-149; Q-136 to L-150; G-137 to L-151; P-138 to S-152; E-139 to F-153; E-140 to K-154; T-141 to R-155; G-142 to G-156; S-143 to S-157; Y-144 to A-158; T-145 to L-159; F-146 to E-160; V-147 to E-161; P-148 to K-162; W-149 to E-163; L-150 to N-164; L-151 to K-165; S-152 to 1-166; F-153 to L-167; K-154 to V-168; R-155 to K-169; G-156 a E-170. S-157 to T-171. A-158 to G-172; L-159 to Y-173; E-160 a F-174. E-161 to F-175, K-162 to 1-176; E-163 to Y-177; N-164 a G-178; K-165 to Q-179; 1-166 to V-180; L-167 to L-181; V-168 a Y-182 K-169 to T-183. E-170 to D-184. T-171 to K-185; G-172 a T-186 • Y-173 to Y-187. F-174 to A-l 88. F-175 to M-189; 1-176 a G-190 Y-177 to H-191; G-178 to L-192. Q-179 to 1-193; V-180 a Q-194. L-181 to R-195. Y-182 to K-196 • T-183 to K-197; D-184 a V-198, • K-185 to H-199. T-186 to V-200, • Y-187 to F-201; A-188 a G-202,. M-189 to D-203. G-190 to E-204, • H-191 to L-205; L-192 a S-206 • 1-193 to L-207, q-194 to V-208 • R-195 to T-209; K-196 a L-210, • K-197 to F-211, V-198 to R-212, • H-199 to C-213; V-200 a 1-214, • F-201 to Q-215. G-202 to N-216, • D-203 to M-217; E-204 a P-218, • L-205 to E-219, • S-206 to T-220, • L-207 to L-221; V-208 to P-222, • T-209 to N-223 • L-210 to N-224, • F-211 to S-225; R-212 a C-226, • C-213 to Y-227. 1-214 to S-228, - Q-215 to A-229; N-216 a G-230, • M-217 to 1-231,. P-218 to A-232, • E-219 to K-233; T-220 a L-234 • L-221 to E-235 • P-222 to E-236, N-223 to G-237; N-224 a D-238, • S-225 to E-239, -C-226 to L-240, Y-227 to Q-241; S-228 a L-242 • A-229 to A-243, • G-230 to 1-244, • 1-231 to P-245; A-232 to R-246, • K-233 to E-247, • L-234 to N-248, E-235 to A-249; E-236 a Q-250, • G-237 to 1-251, • D-238 to S-252, E-239 to L-253; L-240 a D-254, • Q-241 to G-255, • L-242 to D-256, A-243 to V-257; 1-244 a T-258, P-245 to F-259, R-246 to F-260, E-247 to G-261; N-248 a A-262, A-249 to L-263, Q-250 to K-264; 1-251 to L-265; and S-252 to L-266 of SEQ ID NO: 19. Preferably, these polypeptide fragments have one or more functional activities (eg, biological activity, antigenicity and immunogenicity) of the neutrokine-alpha and / or neutrocine polypeptides. -alphaSV of the present invention and can be used, for example, to generate or select antibodies, in the manner that will be described later. The present invention also relates to polypeptides comprising or alternatively consisting of an amino acid sequence with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% identity to a previously described amino acid sequence. The present invention also includes the above amino acid sequences fused to a heterologous amino acid sequence, in the manner described herein. The polynucleotides encoding these polypeptides are also encompassed by the present invention. Additional preferred polypeptide fragments of the present invention, comprise or alternatively consist of an amino acid sequence that is selected from the group consisting of the residues of M-1 to F-15; D-2 to C-16; E-3 to S-17; S-4 to E-18; A-5 to K-19; K-6 to G-20; T-7 to E-21; L-8 to D-22; P-9 to M-23; P-10 to K-24; P-ll to V-25; C-12 to G-26; L-13 to Y-27; C-14 to D-28; F-15 to P-29; C-16 to 1-30; S-17 to T-31; E-18 to P-32; K-19 to Q-33; G-20 to K-34; E-21 to E-35; D-22 to E-36; M-23 to G-37; K-24 to A-38; V-25 to W-39; ' G-26 to F-40; Y-27 to G-41; D-28 to 1-42; P-29 to C-43; 1-30 to R-44; T-31 to D-45; P-32 to G-46; Q-33 to R-47; K-34 to L-48; E-35 to L-49; E-36 to A-50; G-37 to A-51; A-38 to T-52; W-39 to L-53; F-40 to L-54; G-41 to L-55; 1-42 to A-56; C-43 a L-57; R-44 to L-58; d-45 to S-59; G-46 to S-60; $ -47 to S-61; L-48 to F-62; L-49 to T-63; A-50 to A-64; A-51 to M-65; T-52 to S-66; L-53 to L-67; L-54 to Y-68; L-55 to Q-69; A-56 to L-70; L-57 to A-71; L-58 to A-72; S-59 to L-73; S-60 to Q-74; S-61 to A-75; F-62 to D-76; T-63 to L-77; A-74 to M-78; M-65 to N-79; S-66 to L-80; L-67 to R-81; Y-68 to M-82; Q-69 to E-83; L-70 to L-84; A-71 to Q-85; A-72 to S-86; L-73 to Y-87; Q-74 to R-88; A-75 to G-89; D-76 to S-90; L-77 to A-91; M-78 to T-92; N-79 to P-93; L-80 to A-94; R-81 to A-95; M-82 to A-96; E-83 to G-97; L-84 to A-98; Q-85 to P.99; S-86 to E-100; Y-87 to L-101; R-88 to T-102; G-89 to A-103; S-90 to G-104; A-91 to V-105; T-92 to K-106; P-93 to L-107; A-94 to L-108; A-95 to T-109; a-96 to P-110; G-97 to A-III; A-98 to A-112; P-99 to P-113; E-100 to R-114; L-101 to P-115; T-102 to H-116; A-103 to N-117; G-104 to S-118; V-105 to S-119; K-106 to R-120; L-107 to G-121; L-108 a H-122; T-109 to R-123; P-110 to N-124; A-III to R-125; A-112 to R-126; P-113 to A-127; R-114 to F-128; P-115 to Q-129; H-116 to G-130; N-117 to P-131; S-118 to E-132; S-119 to E-133; R-120 to t-134; G-121 to E-135; H-122 to Q-136; R-123 to D-137; N-124 to V-138; R-125 to D-139; R-126 to L-140; A-127 to S-141; F-128 to A-142. Q-129 to P-143; G-130 to P-144; P-131 to A-145; E-132 a P-146, E-133 to C-147; T-134 to L-148; E-135 to P-149; Q-136 a G-150 D-137 to C-151; V-138 to R-152; D-139 to H-153; L-140 a S-154; S-141 to Q-155; A-142 to H-156; P-143 to D-157; P-144 a D-158, A-145 to N-159, P-146 to G-160; C-147 to M-161; L-148 a N-l 62. P-149 to L-163, G-150 to R-164; C-151 to N-l 65; R-152 a 1-166, • H-153 to 1-167. S-154 to Q-168; Q-155 to D-169; H-156 a C-170, • D-157 to L-171, D-158 to Q-172; N-159 to L-173; G-160 a 1-174, • M-161 to A-175. N-162 to D-176; L-163 to S-177; R-164 a D-178, • N-165 to T-179,. 1-166 to P-180; 1-167 to A-181; Q-168 a L-182, • D-169 to E-183. C-170 to E-184; L-171 to K-185; Q-172 a E-186, • L-173 to N-187. 1-174 to K-188; A-175 to 1-189; D-176 a V-190, • S-177 to V-191,. D-178 to R-192; T-179 to Q-193; P-180 a T-194, • A-181 to G-195, • L-182 to Y-196; E-183 to F-197; E-184 a F-198, • K-185 to 1-199, • E-186 to Y-200; N-187 to S-201; K-188 a Q-202, • 1-189 to V-203, • V-190 to L-204; V-191 to Y-205; R-192 a T-206, • Q-193 to D-207,. t-194 to P-208; G-195 to 1-209; Y-196 a F-210, • F-197 to A-211, -F-198 to M-212; 1-199 to G-213; Y-200 a H-214, • S-201 to V-215, • Q-202 to 1-216; V-203 to Q-217; L-204 a R-218, 'Y-205 to K-219, • T-206 to K-220; D-207 to V-221; P-208 to H-222, • 1-209 to V-223, • F-210 to F-224; A-211 to G-225; M-212 a D-226, G-213 to E-227, • H-214 to L-228; V-215 to S-229; 1-216 a L-230, • Q-217 to V-231, R-218 to T-232; K-219 to L-233; K-220 a F-234, • V-221 to R-235, • H-222 to C-236; V-223 to 1-237; F-224 a Q-238, G-225 to N-239, D-226 to M-240; E-227 to P-241; L-228 to K-242; S-229 to T-243; L-230 to L-244; V-231 to P-245; T-232 to N-246; L-233 to N-247; F-234 to S-248; R-235 to C-249; C-236 to Y-250; 1-237 to S-251; Q-238 to A-252; N-239 to G-253; M-240 to 1-254; P-241 to A-255; K-242 to R 256; T-243 to L-257; 1-244 to E-258; P-245 A E-259; N-246 to G-260; N-247 to D-261; S-248 a E-262; C-249 to 1-263; Y-250 to Q-264; S-251 to L-265; A-252 to A-266; G-253 to 1-267; 1-254 to P-278; A-255 to R-269; R-256 to E-270; L-257 to N-271; E-258 to A-272; E-259 to Q-273; G-260 to 1-274; D-261 to S-275; E-262 to R-276; 1-263 to N-277; Q-264 to G-278; L-265 to D-279; A-266 to D-280; 1-267 to T-281; P-268 to F-282; R-269 to F-283; E-270 to G-284; N-271 to A-285; A-272 to L-286; Q-273 to K-287; 1-274 to L-288; and S-275 to L-289 of SEQ ID NO: 38. Preferably, these polypeptide fragments have one or more functional activities (eg, biological activity, antigenicity and immunogenicity) of the neutrokine-alpha and / or neutrocine polypeptides. -alphaSV of the present invention and can be used, for example, to generate or select antibodies, in the manner that will be described later. The present invention also relates to polypeptides comprising or alternatively consisting of an amino acid sequence with at least 80, 85, 90, 92, 95, 96, 97, 98 or 99% identity to a previously described amino acid sequence. The present invention also includes the above amino acid sequences fused to a heterologous amino acid sequence, in the manner described herein. The polynucleotides encoding these polypeptides are also encompassed by the present invention. One skilled in the art will recognize that some amino acid sequences of the neutrokine-alpha and neutrocin-alphaSV polypeptides can vary without significantly affecting the structure or function of the polypeptide. If such sequence differences are taken into account, it should be remembered that there will be critical areas in the polypeptide that determine the activity. Thus, the present invention further includes variations of the neutrokine-alpha polypeptide that exhibit a neutral-alpha polypeptide functional activity (e.g., biological activity) or that include neutrokine-alpha polypeptide regions such as the polypeptide fragments described herein. The present invention also includes variations of the neutrocyl-alphaSV polypeptide that show a neutrocyl-alphaSV polypeptide functional activity (e.g., biological activity) or that include neutrocin-alphaSV polypeptide regions such as the polypeptide fragments described herein. Such mutants include deletions, insertions, inversions, repeats and type substitutions that are selected in accordance with the general rules that are known in the art to have little effect on activity. For example, some guidelines concerning how to prepare phenotypically silent amino acid substitutions are provided in Bowie, JU et al., "Deciphering the Message in Protein Sequences: Tolerance to Amino Acid Substitutions" Science 247: 1306-1310 (1990), in where the authors indicate that there are two main approaches to study the tolerance of an amino acid sequence to changes. The first method is based on the process of evolution, in which mutations are accepted or rejected by natural selection. The second approach uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene and selections or searches to identify sequences that maintain functionality. As the authors state, these studies have revealed that proteins are surprisingly tolerant to amino acid substitutions. The authors also indicate which amino acid changes are likely to be permissible at a certain position of the protein. For example, the most buried amino acid residues require non-polar side chains, while some features of the surface side chains are generally retained. Other phenotypically silent substitutions are described in Bowie J. U. et al., Supra, and the references cited therein. The conservative substitutions typically observed are replacements between aliphatic amino acids Ala, Val, Leu e lie; exchange of hydroxyl residues between Ser and Thr, exchanges of acid residues of Asp and Glu, substitutions between the amide residues of Asn and Gln, exchange of basic residues of Lys and Arg, and replacements between aromatic residues Phe, Tyr. Thus, the fragment, derivative or analog of the polypeptide of Figures IA and IB (SEQ ID NO: 2) or that encoded by the deposited cDNA plasmid, can be (i) one in which one or more amino acid residues are substituted by conserved or non-conserved amino acid residues (preferably a conserved amino acid residue) and such a substituted amino acid residue may or may not be encoded by the genetic code, or (ii) one in which one or more amino acid residues includes a substituent group or (iii) one in which the extracellular domain of the polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide (e.g., polyethylene glycol) or (iv) one in which the additional amino acids are they fuse with the extracellular domain of the polypeptide, such as an IgG Fc fusion region or a peptide or leader or secretory sequence, or a sequence that is used for the purification of the extracellular domain the polypeptide or a protein sequence. Such fragments, derivatives and analogs are considered within the scope of those skilled in the art from the teachings herein. In addition, the fragment derived or analogue of the polypeptide of Figures 5A and 5B (SEQ ID NO: 19) or that encoded by the deposited cDNA plasmid, can be (i) one in which one or more amino acid residues are replaced by conserved or non-conserved amino acid residues (preferably a conserved amino acid residue) and such substituted amino acid residue may or may not be encoded by the genetic code, or (ii) one in which one or more amino acid residues includes a substituent group or (iii) one in which the extracellular domain of the polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide (eg, polyethylene glycol) or (iv) one in which the additional amino acids are fused with the extracellular domain of the polypeptide, such as a soluble biologically active fragment of another member of the TNF ligand family (eg, the CD40 ligand), an IgG Fc fusion region, a pep sequence thimeric or leader or secretory, or a sequence that is used for the purification of the extracellular domain of the polypeptide or a protein sequence. Such fragments, derivatives and analogs are considered within the scope of those skilled in the art from the teachings herein. Thus, the neutrokine-alpha and / or neutrocine-alphaSV polypeptides of the present invention may include one or more substitutions, deletions or additions of amino acids either by natural mutations, or, by human manipulation. As indicated, preference changes are minor in nature, such as conservative amino acid substitutions that do not significantly affect the conformation or activity of the protein (see Table II). TABLE II. Substitutions of Amino Acids Conservatives Aromatics Phenylalanine Tryptophan Tyrosine Hydrophobic Leucine Isoleucine Valine Polar Glutamine Asparagine Basics Arginine Lysine Histidine Acids Aspartic acid Glutamic acid Small Alanine Serine Threonine Methionine Glycine In one embodiment of the present invention, the polypeptide comprises or alternatively consists of the amino acid sequence of a neutrocine-alpha or neutrocin-alphaSV polypeptide having an amino acid sequence that contains at least one conservative amino acid substitution, but no more than 50 conservative amino acid substitutions, preferably no more than 40 conservative amino acid substitutions, still more preferably no more than 30 conservative amino acid substitutions and even more preferably no more than 20 conservative amino acid substitutions. Of course, in ever-increasing preference order, it is highly preferable for a peptide or polypeptide to have an amino acid sequence comprising the amino acid sequence of a neutrocine-alpha polypeptide containing at least one, but not more than 10, 9, 8, 7, 6, , 4, 3, 2 or 1 conservative amino acid substitutions. For example, site-directed changes can be made at the amino acid level of neutrokine-alpha, replacing a particular amino acid with a conservative substitution. Preferred conservative substitution mutations of the amino acid sequence of neutrocin-alpha provided in SEQ ID NO: 2 include: Ml replaced by A, G, I, L, S, T or V; D2 replaced by E; D3 replaced by E; S4 replaced by A, G, I, L, T, M or V; T5 replaced by A, G, I, L, S, M or V; E6 replaced by D; R7 replaced by H, or K; E8 replaced by D; Q9 replaced by N; S10 replaced by A, G, I, L, T, M or V; Rll replaced by H, or K; L12 replaced by A, G, I, S, T, M or V; T13 replaced by A, G, I, L, S, M or V; S14 replaced by A, G, I, L, T, M or V; L16 replaced by A, G, I, S, T, M or V; K17 replaced by H, or R; K18 replaced by H, or R; R19 replaced by H, or K; E20 replaced by D; E21 replaced by D; M22 replaced by A, G, I; L, S, T or V; K23 replaced by H, or R; L24 replaced by A, G, I, S, T, M or V; K25 replaced by H, or R; E26 replaced by D; V28 replaced by A, G, I; L, S, T, or M; S29 replaced by A, G, I, L, T, M or V; 130 replaced by A, G, L, S, T, M or V; L31 replaced by A, G, I, S, T, M or V; R33 replaced by H, or K; K34 replaced by H, or R; E35 replaced by D; S36 replaced by A, G, I, L, T, M or V; S38 replaced by A, G, I, L, T, M or V; V39 replaced by A, G, I; L, S, T, or M; R40 replaced by H, or K; S41 replaced by A, G, I, L, T, M or V; S42 replaced by A, G, I, L, T, M or V; K43 replaced by H, or R; D44 replaced by E; G45 replaced by A, I, L, S, T, M or V; K46 replaced by H, or R; L47 replaced by A, G, I, S, T, M or V L48 replaced by A, G, I, S, T, M or V; A49 replaced by G, I, L, S, T, M or V; A50 replaced by G, I, L, S, T, M or V; T51 replaced by A, G, I, L, S, M or V; L52 replaced by A, G, I, S, T, M or V; L53 replaced by A, G, I, S, T, M or V; L54 replaced by A, G, I, S, T, M or V; A55 replaced by G, I, L, S, T, M or V; L56 replaced by A, G, I, S, T, M or V; L57 replaced by A, G, I, S, T, M or V; S58 replaced by A, G, I, L, T, M or V; L61 replaced by A, G, I, S, T, M or V; T62 replaced by A, G, I, L, S, M or V; V63 replaced by A, G, I; L, S, T, or M; V64 replaced by A, G, I; L, S, T, or M; S65 replaced by A, G, I, L, T, M or V; F66 replaced by W, or Y; Y67 replaced by F, or W; Q68 replaced by N; V69 replaced by A, G, I; L, S, T, or M; A70 replaced by G, I, L, S, T, M or V; A71 replaced by G, I, L, S, T, M or V; L72 replaced by A, G, I, S, T, M or V; Q73 replaced by N; G74 replaced by A, I, L, S, T, M or V; D75 replaced by E; L76 replaced by A, G, I, S, T, M or V; A77 replaced by G, I, L, S, T, M or V; S78 replaced by A, G, I, L, T, M or V; L79 replaced by A, G, I, S, T, M or V; R80 replaced by H, or K; A81 replaced by G, I, L, S, T, M or V; E82 replaced by D; L83 replaced by A, G, I, S, T, M or V; Q84 replaced by N, G85 replaced by A, I, L, S, T, M or V; H86 replaced by K, or R; H87 replaced by K, or R; A88 replaced by G, I, L, S, T, M or V; E89 replaced by D; K90 replaced by H, or R; L91 replaced by A, G, I, S, T, M or V; A93 replaced by G, I, L, S, T, M or V; G94 replaced by A, I, L, S, T, M or V; A95 replaced by G, I, L, S, T, M or V; G96 replaced by A, I, L, S, T, M or V; A97 replaced by G, I, L, S, T, M or V; K99 replaced by h; or R; A100 'replaced by G, I, L, S, T, M or V; G101 replaced by A, I, L, S, T, M or V; L102 replaced by A, G, I, S, T, M or V; E103 replaced by d; E104 replaced by D; A105 replaced by G, I, L, S, T, M or V; A107 replaced by G, I, L, S, T, M or V; V108 replaced by A, G, I; L, S, T, or M; T109 replaced by A, G, I, L, S, M or V; A110 replaced by G, I, L, S, T, M or V; Glll replaced by A, I, L, S, T, M or V; L112 replaced by A, G, I, S, T, M or V; K113 replaced by H, or R; 1114 replaced by A, G, L, S, T, M or V; F115 replaced by W, or Y; E116 replaced by D; A119 replaced by G, I, L, S, T, M or V; G121 replaced by A, I, L, S, T, M or V; E122 replaced by d; G123 replaced by A, I, L, S, T, M or V; N124 replaced by Q, S125 replaced by A, G, I, L, T, M or V; S126 replaced by A, G, I, L, T, M or V; Q127 replaced by N, N128 replaced by Q; S129 replaced by A, G, I, L, T, M or V; R130 replaced by H, or K; N131 replaced by Q; K132 replaced by H, or R; R133 replaced by H, or K; A134 replaced by G, I, L, S, T, M or V; VI35 replaced by A, G, I; L, S, T, or M; Q136 replaced by N, G137 replaced by A, I, L, S, T, M or V; E139 replaced by D; E140 replaced by D, T141 replaced by A, G, I, L, S, M or V; V142 replaced by A, G, I; L, S, T, or M; T143 replaced by A, G, I, L, S, M or V; Q144 replaced by N, D145 replaced by E; L147 replaced by A, G, I, S, T, M or V; Q148 replaced by N; L149 replaced by A, G, I, S, T, M or V; 1150 replaced by A, G, L, S, T, M or V; A151 replaced by G, I, L, S, T, M or V; D152 replaced by E; S153 replaced by A, G, I, L, T, M or V; E154 replaced by D; T155 replaced by A, G, I, L, S, M or V; T157 replaced by A, G, I, L, S, M or V; 1158 replaced by A, G, L, S, T, M or V; Q159 replaced by N; K160 replaced by H, or R; G161 replaced by A, I, L, S, T, M or V; S62 replaced by A, G, I, L, T, M or V; Y163 replaced by F; or W; TI64 replaced by A, G, I, L, S, M or V; F165 replaced by w; or Y; VI66 replaced by A, G, I; L, S, T, or M; W168 replaced by F, or Y; L169 replaced by A, G, I, S, T, M or V; L170 replaced by A, G, I, S, T, M or V; S171 replaced by A, G, I, L, T, M or V; F172 replaced by W; or Y; K173 replaced by H, or R; R174 replaced by H, or K; G175 replaced by A, I, L, S, T, M or V; S176 replaced by A, G, I, L, T, M or V; A177 replaced by G, I, L, S, T, M or V; L178 replaced by A, G, I, S, T, M or V; E179 replaced by D; E180 replaced by D; K181 replaced by H, or R; E182 replaced by D; N183 replaced by Q; K184 replaced by H, or R; 1185 replaced by A, G, L, S, T, M or V; L186 replaced by A, G, I, S, T, M or V; V187 replaced by A, G, I; L, S, T, or M; K188 replaced by H, or R; E189 replaced by D; T190 replaced by A, G, I, L, S, M or V; G191 replaced by A, I, L, S, T, M or V; Y192 replaced by F, or W; F193 replaced by W, or Y, F194 replaced by W, or Y; 1195 replaced by A, G, L, S, T, M or V; Y196 replaced by F, or W; G197 replaced by A, I, L, S, T, M or V; Q198 replaced by N, V199 replaced by A, G, I; L, S, T, or M; L200 replaced by A, G, I, S, T, M or V; Y201 replaced by F; or W; T202 replaced by A, G, I, L, S, M or V; D203 replaced by E; K204 replaced by H, or R; T205 replaced by A, G, I, L, S, M or V; Y206 replaced by F, or W; A207 replaced by G, I, L, S, T, M or V; M208 replaced by A, G, I; L, S, T or V; G209 replaced by A, I, L, S, T, M or V; H210 replaced by K, or R; L211 replaced by A, G, I, S, T, M or V; 1212 replaced by A, G, L, S, T, M or V; Q213 replaced by N; R214 replaced by H, or K; K215 replaced by H, or R; K216 replaced by H, or R; V217 replaced by A, G, I; L, S, T, or M; H218 replaced by K, or R; V219 replaced by A, G, I; L, S, T, or M; F220 replaced by W, or Y; G221 replaced by A, I, L, S, T, M or V; D222 replaced by E; E223 replaced by D; L224 replaced by A, G, I, S, T, M or V; S225 replaced by A, G, I, L, T, M or V; L226 replaced by A, G, I, S, T, M or V; V227 replaced by A, G, I; L, S, T, or M; T228 replaced by A, G, I, L, S, M or V; L229 replaced by A, G, I, S, T, M or V; F230 replaced by W, or Y; R231 replaced by H, or K; 1233 replaced by A, G, L, S, T, M or V; Q234 replaced by N; N235 replaced by Q; M236 replaced by A, G, I; L, S, T or V; E238 replaced by D; T239 replaced by A, G, I, L, S, M or V; L240 replaced by A, G, I, S, T, M or V; N242 replaced by Q; N243 replaced by Q; S244 replaced by A, G, I, L, T, M or V; Y246 replaced by F; or W; S247 replaced by A, G, I, L, T, M or V; A248 replaced by G, I, L, S, T, M or V; G249 replaced by A, I, L, S, T, M or V; 1250 replaced by A, G, L, S, T, M or V; A251 replaced by G, I, L, S, T, M or V; K252 replaced by H, or R; L253 replaced by A, G, I, S, T, M or V; E254 replaced by D; E255 replaced by D; G256 replaced by A, I, L, S, T, M or V; D257 replaced by E; E258 replaced by D; L259 replaced by A, G, I, S, T, M or V; Q260 replaced by N; L261 replaced by A, G, I, S, T, M or V; A262 replaced by G, I, L, S, T, M or V; 1263 replaced by A, G, L, S, T, M or V; R265 replaced by H, or K; E266 replaced by D; N267 replaced by Q; A268 replaced by G, I, L, S, T, M or V; Q269 replaced by N; I270 replaced by A, G, L, S, T, M or V; S271 replaced by A, G, I, L, T, M or V; L272 replaced by A, G, I, S, T, M or V; D273 replaced by E; G274 replaced by A, I, L, S, T, M or V; D275 replaced by E; V276 replaced by A, G, I; L, S, T, or M; T277 replaced by A, G, I, L, S, M or V; F278 replaced by W, or Y; F279 replaced by W, or Y; G280 replaced by A, I, L, S, T, M or V; A281 replaced by G, I, L, S, T, M or V; L282 replaced by A, G, I, S, T, M or V; K283 replaced by H, or R; L284 replaced by A, G, I, S, T, M or V; and / or L285 replaced by A, G, I, S, T, M or V. The polynucleotides encoding these polypeptides are also encompassed by the present invention. The resulting neutrokine-alpha proteins of the present invention can be routinely selected with respect to their functional activity and / or physical properties of neutrocine-alpha and / or neutrocine-alphaSV (such as, for example, greater or lesser stability and / or solubility). Preferably, the resulting proteins of the present invention have a higher and / or lower functional activity of neutrocine-alpha and / or neutrocine-alphaSV. Preferably, the neutrokine-alpha and / or neutrocine-alphaSV proteins resulting from the present invention have more than one functional activity and / or physical property of neutrokine-alpha and / or neutrocine-alphaSV increased and / or decreased. - In another embodiment, site-directed changes at the amino acid level of neutrokine-alphaSV can be made by replacing a particular amino acid with a conservative substitution. Preferably, mutations by conservative substitution of the amino acid sequence of neutrokine-alphaSV provided in SEQ ID NO: 19, include: Ml replaced by A, G, I, L, S, T or V; D2 replaced by E; D3 replaced by E; S4 replaced by A, G, I, L, T, M or V; T5 replaced by A, G, I, L, S, M or V; E6 replaced by D; R7 replaced by H, or K; E8 replaced by D; Q9 replaced by N; S10 replaced by A, G, I, L, T, M or V; Rll replaced by H, or K; L12 replaced by A, G, I, S, T, M or V; T13 replaced by A, G, I, L, S, M or V; S14 replaced by A, G, I, L, T, M or V; L16 replaced by A, G, I, S, T, M or V; K17 replaced by H, or R; K18 replaced by H, or R; R19 replaced by H, or K; E20 replaced by D; E21 replaced by D; M22 replaced by A, G, I, L, S, T or V; K23 replaced by H, or R; L24 replaced by A, G, I, S, T, M or V; K25 replaced by H, or R; E26 replaced by D; V28 replaced by A, G, I, L, S, T, or M; S29 replaced by A, G, I, L, T, M or V; 130 replaced by A, G, L, S, T, M or V; L31 replaced by A, G, I, S, T, M or V; R33 replaced by H, or K; K34 replaced by H, or R; E35 replaced by D; S36 replaced by A, G, I, L, T, M or V; S38 replaced by A, G, I, L, T, M or V; V39 replaced by A, G, I, L, S, T, or M; R40 replaced by H, or K; S41 replaced by A, G, I, L, T, M or V; S42 replaced by A, G, I, L, T, M or V; K43 replaced by H, or R; D44 replaced by E; G45 replaced by A, I, L, S, T, M or V; K46 replaced by H, or R; L47 replaced by A, G, I, S, T, M or V; L48 replaced by A, G, I, S, T, M or V; A49 replaced by G, I, L, S, T, M or V; A50 replaced by G, I, L, S, T, M or V; T51 replaced by A, G, I, L, S, M or V; L52 replaced by A, G, I, S, T, M or V; L53 replaced by A, G, I, S, T, M or V; L54 replaced by A, G, I, S, T, M or V; A55 replaced by G, I, L, S, T, M or V; L56 replaced by A, G, I, S, T, M or V; L57 replaced by A, G, I, S, T, M or V; S58 replaced by A, G, I, L, T, M or V; L61 replaced by A, G, I, S, T, M or V; T62 replaced by A, G, I, L, S, M or V; V63 replaced by A, G, I; L, S, T, or M; V64 replaced by A, G, I, L, S, T, or M; S65 replaced by A, G, 'I, L, T, M or V; F66 replaced by W, or Y; Y67 replaced by F, or W; Q68 replaced by N; V69 replaced by A, G, I, L, S, T, or M; A70 replaced by G, I, L, S, T, M or V; A71 replaced by G, I, L, S, T, M or V; L72 replaced by A, G, I, S, T, M or V; Q73 replaced by N; G74 replaced by A, I, L, S, T, M or V; D75 replaced by E; L76 replaced by A, G, I, S, T, M or V; A77 replaced by G, I, L, S, T, M or V; S78 replaced by A, G, I, L, T, M or V; L79 replaced by A, G, I, S, T, M or V; R80 replaced by H, or K; A81 replaced by G, I, L, S, T, M or V; E82 replaced by D; L83 replaced by A, G, I, S, T, M or V; Q84 replaced by N, G85 replaced by A, I, L, S, T, M or V; H86 replaced by K, or R; H87 replaced by K, or R; A88 replaced by G, I, L, S, T, M or V; E89 replaced by D; K90 replaced by H, or R; L91 replaced by A, G, I, S, T, M or V; A93 replaced by G, I, L, S, T, M or V; G94 replaced by A, I, L, S, T, M or V; A95 replaced by G, I, L, S, T, M or V; G96 replaced by A, I, L, S, T, M or V; A97 replaced by G, I, L, S, T, M or V; K99 replaced by H; or R; Al00 replaced by G, I, L, S, T, M or V; G101 replaced by A, I, L, S, T, M or V; L102 replaced by A, G, I, S, T, M or V; E103 replaced by D; E104 replaced by D; A105 replaced by G, I, L, S, T, M or V; A107 replaced by G, I, L, S, T, M or V; V108 replaced by A, G, I, L, S, T, or M; T109 replaced by A, G, I, L, S, M or V; A110 replaced by G, I, L, S, T, M or V; Glll replaced by A, I, L, S, T, M or V; L112 replaced by A, G, I, S, T, M or V; K113 replaced by H, or R; 1114 replaced by A, G, L, S, T, M or V; F115 replaced by W, or Y; E116 replaced by D; A119 replaced by G, I, L, S, T, M or V; G121 replaced by A, I, L, S, T, M or V; E122 replaced by D; G123 replaced by A, I, L, S, T, M or V; N124 replaced by Q, S125 replaced by A, G, I, L, T, M or V; S126 replaced by A, G, I, L, T, M or V; Q127 replaced by N, N128 replaced by Q; S129 replaced by A, G, I, L, T, M or V; R130 replaced by H, or K; N131 replaced by Q; K132 replaced by H, or R; R133 replaced by H, or K; A134 replaced by G, I, L, S, T, M or V; V135 replaced by A, G, I, L, S, T, or M; Q136 replaced by N, G137 replaced by A, I, L, S, T, M or V; E139 replaced by D; E140 replaced by D, T141 replaced by A, G, I, L, S, M or V; G142 replaced by A, I, L, S, T, M or V; S143 replaced by A, G, I, L, T, M or V; Y144 replaced by F, or W; T145 replaced by A, G, I, L, S, M or V; F146 replaced by W, or Y; V147 replaced by A, G, I, L, S, T or M; W149 replaced by F, or Y, L150 replaced by A, G, I, S, T, M or V; L151 replaced by A, G, I, S, T, M or V; S152 replaced by A, G, I, L, T, M or V; F153 replaced by W, or Y; K154 replaced by H, or R; R155 replaced by H, or K; G156 replaced by A, I, L, S, T, M or V; S157 replaced by A, G, I, L, T, M or V; A158 replaced by G, I, L, S, T, M or V; L159 replaced by A, G, I, S, T, M or V; E160 replaced by D; E161 replaced by D; K162 replaced by H, or R; El63 replaced by D; NI64 replaced by Q; K165 replaced by H; or R; 1166 replaced by A, G, L, S, T, M or V; L167 replaced by A, G, I, S, T, M or V; VI68 replaced by A, G, I, L, S, T or M; K169 replaced by H, or R; E170 replaced by D; T171 replaced by A, G, I, L, S, M or V; G172 replaced by A, I, L, S, T, M or V; Y173 replaced by F, or W; F174 replaced by W, or Y; F175 replaced by W, or Y; 1176 replaced by A, G, L, S, T, M or V; &177 replaced by F, or W; G178 replaced by A, I, L, S, T, M or V; Q179 replaced by N; V180 replaced by A, G, I, L, S, T or M; L181 replaced by A, G, I, S, T, M or V; Y182 replaced by F, or W; T183 replaced by A, G, I, L, S, M or V; D184 replaced by E; K185 replaced by H, or R; T186 replaced by A, G, I, L, S, M or V; Y187 replaced by F, or W; A188 replaced by G, I, L, S, T, M or V; M189 replaced by A, G, I, L, S, T or V; G190 replaced by A, I, L, S, T, M or V; H191 replaced by K, or R; L192 replaced by A, G, I, S, T, M or V; 1193 replaced by A, G, L, S, T, M or V; Q194 replaced by N; R195 replaced by H, or K; K196 replaced by H, or R; K197 replaced by H, or R; VI98 replaced by A, G, I, L, S, T or M; H199 replaced by K, or R; V200 replaced by A, G, I, L, S, T or M; F201 replaced by W, or Y; G202 replaced by A, I, L, S, T, M or V; D203 replaced by E; E204 replaced by D; L205 replaced by A, G, I, S, T, M or V; S206 replaced by A, G, I, L, T, M or V; L207 replaced by A, G, I, S, T, M or V; V208 replaced by A, G, I, L, S, T or M; T209 replaced by A, G, I, L, S, M or V; L210 replaced by A, G, I, S, T, M or V; F211 replaced by W, or Y; R212 replaced by H, or K; 1214 replaced by A, G, L, S, T, M or V; Q215 replaced by N; N216 replaced by Q; M217 replaced by A, G, I, L, S, T or V; E219 replaced by D; T220 replaced by A, G, I, L, S, M or V; L221 replaced by A, G, I, S, T, M or V; N223 replaced by Q; N224 replaced by Q; S225 replaced by A, G, I, L, T, M or V; Y227 replaced by F, or W; S228 replaced by A, G, I, L, T, M or V; A229 replaced by G, I, L, S, T, M or V; G230 replaced by A, I, L, S, T, M or V; 1231 replaced by A, G, L, S, T, M or V; A232 replaced by G, I, L, S, T, M or V; K233 replaced by H, or R; L234 replaced by A, G, I, S, T, M or V; E235 replaced by D; E236 replaced by D; G237 replaced by A, I, L, S, T, M or V; D238 replaced by E; E239 replaced by D; L240 replaced by A, G, I, S, T, M or V; Q241 replaced by N; L242 replaced by A, G, I, S, T, M or V; A243 replaced by G, I, L, S, T, M or V; 1244 replaced by A, G, L, S, T, M or V; R246 replaced by H, or K; E247 replaced by D, N248 replaced by Q; A249 replaced by G, I, L, S, T, M or V; Q250 replaced by N; 1251 replaced by A, G, L, S, T, M or V; S252 replaced by A, G, I, .L, T, M or V; L253 replaced by A, G, I, S, T, M or V; D254 replaced by E; G255 replaced by A, I, L, S, T, M or V; D256 replaced by E; V257 replaced by A, G, I, L, S, T or M; T258 replaced by A, G, I, L, S, M or V; F259 replaced by W, or Y; F260 replaced by W, or Y; G261 replaced by A, I, L, S, T, M or V; A262 replaced by G, I, L, S, T, M or V; L263 replaced by A, G, I, S, T, M or V; K264 replaced by H, or R; L265 replaced by A, G, I, S, T, M or V; and / or L266 replaced by A, G, I, S, T, M or V. The polynucleotides encoding these polypeptides are also encompassed by the present invention. The resulting neutrokine-alpha proteins of the present invention can be routinely selected with respect to their functional activity and / or physical properties of neutrocine-alpha and / or neutrocine-alphaSV (such as, for example, greater or lesser stability and / or solubility). Preferably, the resulting proteins of the present invention have a higher and / or lower functional activity of neutrocine-alpha and / or neutrocine-alphaSV. Preferably, the neutrokine-alpha and / or neutrocine-alphaSV proteins resulting from the present invention have more than one functional activity and / or physical property of neutrokine-alpha and / or neutrocine-alphaSV increased and / or decreased. In another embodiment, the site-directed changes at the amino acid level of neutrocin-alpha can be made by replacing a particular amino acid with a conservative substitution. Preferably, mutations by conservative substitution of the amino acid sequence of neutrocin-alpha provided in SEQ ID NO: 23, include: R1 replaced by H, or K; V2 replaced by A, G, I, L, S, T or M; V3 replaced by A, G, I, L, S, T or M; D4 replaced by E; 15 replaced by A, G, I, S, T, M or V; S6 replaced by A, G, I, L, T, M or V; A7 replaced by G, I, L, S, T, M or V; AlO replaced by G, I, L, S, T, M or V; L13 replaced by A, G, I, S, T, M or V; G15 replaced by A, I, L, S, T, M or V; R17 replaced by H, or K; H18 replaced by K, or R; SI9 replaced by A, G, I, L, T, M or V; Q20 replaced by N; H21 replaced by K, or R; D22 replaced by E; D23 replaced by E; N24 replaced by Q; G25 replaced by A, I, L, S, T, M or V; M26 replaced by A, G, I, L, S, T or V; N27 replaced by Q; L28 replaced by A, G, I, S, T, M or V; R2"9 replaced by H, or K; N30 replaced by Q; R31 replaced by H, or K; T32 replaced by A, G, I, L, S, M or V; Y33 replaced by F, or W; T34 replaced by A, G, I, L, S, M or V; F35 replaced by W, or Y; V36 replaced by A, G, I, L, S, T or M; W38 replaced by F, or Y; L39 replaced by A, G, I, S, T, M or V; L40 replaced by A, G, I, S, T, M or V; S41 replaced by A, G, I, L, T, M or V; F42 replaced by W, or Y; K43 replaced by H, or R; R44 replaced by H, or K; G45 replaced by A, I, L, S, T, M or V; N46 replaced by Q; A47 replaced by G, I, L, S, T, M or V; L48 replaced by A, G, I, S, T, M or V; E49 replaced by D; E50 replaced by D; K51 replaced by H; or R; E52 replaced by D; N53 replaced by Q; K54 replaced by H, or R; 155 replaced by A, G, L, S, T, M or V; V56 replaced by A, G, I, L, S, T or M; V57 replaced by A, G, I, L, S, T or M; R58 replaced by H, or K; Q59 replaced by N; T60 replaced by A, G, I, L, S, M or V; G61 replaced by A, I, L, S, T, M or V; Y63 replaced by F, or W; F63 replaced by W; or Y; F64 replaced by W, or Y; 165 replaced by A, G, L, S, T, M or V; Y66 replaced by F; or W; S67 replaced by A, G, I, L, T, M or V; Q68 replaced by N; V69 replaced by A, G, I, L, S, T or M; L70 replaced by A, G, I, S, T, M or V; Y71 replaced by F, or W; T72 replaced by A, G, I, L, S, M or V; D73 replaced by E; 175 replaced by A, G, L, S, T, M or V; F76 replaced by W; or Y; A77 replaced by G, I, L, S, T, M or V; M78 replaced by A, G, I, L, S, T or V; G79 replaced by A, I, L, S, T, M or V; H80 replaced by K, or R; V81 replaced by A, G, I, L, S, T or M; 182 replaced by A, G, L, S, T, M or V; Q83 replaced by N; R84 replaced by H, or K; K85 replaced by H, or R; K86 replaced by H, or R; V87 replaced by A, G, I, L, S, T or M; H88 replaced by K, or R; V89 replaced by A, G, I, L, S, T or M; F90 replaced by W, or Y; G91 replaced by A, I, L, S, T, M or V; D92 replaced by E; E93 replaced by D; L94 replaced by A, G, I, S, T, M or V; S95 replaced by A, G, I, L, T, M or V; L96 replaced by A, G, I, S, T, M or V; V97 replaced by A, G, I, L, S, T or M; T98 replaced by A, G, I, L, S, M or V; L99 replaced by A, G, I, S, T, M or V; F100 replaced by W, or Y; R101 replaced by H, or K; 1103 replaced by A, G, L, S, T, M or V; Q104 replaced by N; N105 replaced by Q; M106 replaced by A, G, I, L, S, T or V; K108 replaced by H, or R; T109 replaced by A, G, I, L, S, M or V; L110 replaced by A, G, I, S, T, M or V; N112 replaced by Q; N113 replaced by Q; S114 replaced by A, G, I, L, T, M or V; Y116 replaced by F, or W; S117 replaced by A, G, I, L, T, M or V; A118 replaced by G, I, L, S, T, M or V; G119 replaced by A, I, L, S, T, M or V; 1120 replaced by A, G, L, S, T, M or V; A121 replaced by G, I, L, S, T, M or V; R122 replaced by H, or K; L123 replaced by A, G, I, S, T, M or V; E124 replaced by D; E125 replaced by D; G126 replaced by A, I, L, S, T, M or V; D127 replaced by E; E128 replaced by D; 1129 replaced by A, G, L, S, T, M or V; Q130 replaced by N; L131 replaced by A, G, I, S, T, M or V; A132 replaced by G, I, L, S, T, M or V; 1133 replaced by A, G, L, S, T, M or V; R135 replaced by H, or K; E136 replaced by D; N137 replaced by Q; A138 replaced by G, I, L, S, T, M or V; Q139 replaced by N; 1140 replaced by A, G, L, S, T, M or V; S141 replaced by A, G, I, L, T, M or V; R142 replaced by H, or K; N143 replaced by Q; G144 replaced by A, I, L, S, T, M or V; D145 replaced by E; D146 replaced by E; T147 replaced by A, G, I, L, S, M or V; F148 replaced by W; or Y; F149 replaced by W, or Y; G150 replaced by A, I, L, S, T, M or V; A151 replaced by G, I, L, S, T, M or V; L152 replaced by A, G, I, S, T, M or V; K153 replaced by H, or R; L154 replaced by A, G, I, S, T, M or V; and / or L155 replaced by A, G, I, S, T, M or V. The polynucleotides encoding these polypeptides are also encompassed by the present invention. The resulting neutrokine-alpha proteins of the present invention, they can be routinely selected with respect to their functional activity and / or physical properties of neutrokine-alpha and / or neutrocin-alphaSV (such as, for example, greater or lesser stability and / or solubility). Preferably, the resulting proteins of the present invention have a higher and / or lower functional activity of neutrocine-alpha and / or neutrocine-alphaSV. Preferably, the neutrokine-alpha and / or neutrocine-alphaSV proteins resulting from the present invention have more than one functional activity and / or physical property of neutrokine-alpha and / or neutrocine-alphaSV increased and / or decreased. In another embodiment, the site-directed changes at the amino acid level of neutrocin-alpha can be made by replacing a particular amino acid with a conservative substitution. Preferably, mutations by conservative substitution of the neutrokine-alpha amino acid sequence provided in SEQ ID NO: 38, include: Ml replaced by A, G, I, L, S, T or V; D2 replaced by E; E3 replaced by D; S4 replaced by A, G, I, L, T, M or V; A5 replaced by G, I, L, S, T, M or V; K6 replaced by H, or R; T7 replaced by A, G, I, L, S, M or V; L8 replaced by A, G, I, S, T, M or V; L13 replaced by A, G, I, S, T, M or V; F15 replaced by W, or Y; S17 replaced by A, G, I, L, T, M or V; E18 replaced by D; K19 replaced by H, or R; G20 replaced by A, I, L, S, T, M or V; E21 replaced by D; D22 replaced by E; M23 replaced by A, G, I, L, S, T or V; K24 replaced by H, or R; V25 replaced by A, G, I, L, S, T or M; G26 replaced by A, I, L, S, T, M or V; Y27 replaced by F, or W; D28 replaced by E; 130 replaced by A, G, L, S, T, M or V; T31 replaced by A, G, I, L, S, M or V; Q33 replaced by N; K34 replaced by H, or R; E35 replaced by D; E36 replaced by D; G37 replaced by A, I, L, S, T, M or V; A38 replaced by G, I, L, S, T, M or V; W39 replaced by F, or Y; F40 replaced by W, or Y; G41 replaced by A, I, L, S, T, M or V; 142 replaced by A, G, L, S, T, M or V; R44 replaced by H, or K; D45 replaced by E; G46 replaced by A, I, L, S, T, M or V; R47 replaced by H, or K; L48 replaced by A, G, I, S, T, M or V; L49 replaced by A, G, I, S, T, M or V; A50 replaced by G, I, L, S, T, M or V; A51 replaced by G, I, L, S, T, M or V; T52 replaced by A, G, I, L, S, M or V; L53 replaced by A, G, I, S, T, M or V; L54 replaced by A, G, I, S, T, M or V; L55 replaced by A, G, I, S, T, M or V; A56 replaced by G, I, L, S, T, M or V; L57 replaced by A, G, I, S, T, M or V; L58 replaced by A, G, I, S, T, M or V; S59 replaced by A, G, I, L, T, M or V; S60 replaced by A, G, I, L, T, M or V; S61 replaced by A, G, I, L, T, M or V; F62 replaced by W, or Y; T63 replaced by A, G, I, L, S, M or V; A64 replaced by G, I, L, S, T, M or V; M64 replaced by A, G, I, L, S, T or V; S66 replaced by A, G, I, L, T, M or V; L67 replaced by A, G, I, S, T, M or V; Y68 replaced by F, or W; Q69 replaced by N, L70 replaced by A, G, I, S, T, M or V; A71 replaced by G, I, L, S, T, M or V; A72 replaced by G, I, L, S, T, M or V; L73 replaced by A, G, I, S, T, M or V; Q74 replaced by N; A75 replaced by G, I, L, S, T, M or V; D76 replaced by E; L77 replaced by A, G, I, S, T, M or V; M78 replaced by A, G, I, L, S, T or V; N79 replaced by Q; L80 replaced by A, G, I, S, T, M or V; R81 replaced by H, or K; M82 replaced by A, G, I, L, S, T or V; E83 replaced by D; L84 replaced by A, G, I, S, T, M or V; Q85 replaced by N; S86 replaced by A, G, I, L, T, M or V; Y87 replaced by F, or W; R88 replaced by H, or K; G89 replaced by A, I, L, S, T, M or V; S90 replaced by A, G, I, L, T, M or V; A91 replaced by G, I, L, S, T, M or V; T92 replaced by A, G, I, L, S, M or V; A94 replaced by G, I, L, S, T, M or V; A95 replaced by G, I, L, S, T, M or V; A96 replaced by G, I, L, S, T, M or V; G97 replaced by A, I, L, S, T, M or V; A98 replaced by G, I, L, S, T, M or V; E100 replaced by D; L101 replaced by A, G, I, S, T, "M or V; T102 replaced by A, G, I, L, S, M or V; A103 replaced by G, I, L, S, T, M or V; G104 replaced by A, I, L, S, T, M or V; V105 replaced by A, G, I, L, S, T or M; K106 replaced by H, or R; L107 replaced by A, G , I, S, T, M or V, L108 replaced by A, G, I, S, T, M or V, T109 replaced by A, G, I, L, S, M or V, there replaced by G, I, L, S, T, M or V, A112 replaced by G, I, L, S, T, M or V, R114 replaced by H, or K, Hll6 replaced by K, or R, NI17 replaced by Q; SI18 replaced by A, G, I, L, T, M or V; S119 replaced by A, G, I, L, T, M or V; R120 replaced by H, or K; G121 replaced by A, I, L , S, T, M or V; H122 replaced by K, or R; R123 replaced by H; or K; N124 replaced by Q; R125 replaced by H, or K; R126 replaced by H, or K; A127 replaced by G , I, L, S, T, M or V; F128 replaced by W, or Y; Q129 replaced by N; G130 replaced by A, I, L, S, T, M or V; E132 replaced by D; E133 replaced by D; T134 replaced by A, G, I, L, S, M or V; E135 replaced by D; Q136 replaced by N; D137 replaced by E; V138 replaced by A, G, I, L, S, T or M; D139 replaced by E; L140 replaced by A, G, I, S, T, M or V; S141 replaced by A, G, I, L, T, M or V; A142 replaced by G, I, L, S, T, M or V; A145 replaced by G, I, L, S, T, M or V; L148 replaced by A, G, I, S, T, M or V; G150 replaced by A, I, L, S, T, M or V; R152 replaced by H, or K; H153 replaced by K, or R; S154 replaced by A, G, I, L, T, M or V; Q155 replaced by N; H156 replaced by K, or R; D157 replaced by E; DI58 replaced by E; N159 replaced by Q; G160 replaced by A, I, L, S, T, M or V; M161 replaced by A, G, I, L, S, T or V; NI62 replaced by Q; L163 replaced by A, G, I, S, T, M or V; R164 replaced by H, or K; NI65 replaced by Q; 1166 replaced by A, G, L, S, T, M or V; 1167 replaced by A, G, L, S, T, M or V; Q168 replaced by N; D169 replaced by E; L171 replaced by A, G, I, S, T, M or V; Q172 replaced by N; L173 replaced by A, G, I, S, T, M or V; 1174 replaced by A, G, L, S, T, M or V; A175 replaced by G, I, L, S, T, M or V; D176 replaced by E; S177 replaced by A, G, I, L, T, M or V; D178 replaced by E; TI79 replaced by A, G, I, L, S, M or V; Al81 replaced by G, I, L, S, T, M or V; L182 replaced by A, G, I, S, T, M or V; E183 replaced by D; E184 replaced by D; K185 replaced by H, or R; E186 replaced by D; NI87 replaced by Q; K188 replaced by H; or R; 1189 replaced by A, G, L, S, T, M or V; V190 replaced by A, G, I, L, S, T or M; VI91 replaced by A, G, I, L, S, T or M; R192 replaced by H, or K; Q193 replaced by N; T194 replaced by A, G, I, L, S, M or - - V; G195 replaced by A, I, L, S, T, M or V; Y196 replaced by F, or W; F197 replaced by W, or Y; F198 replaced by W; or Y; 1199 replaced by A, G, L, S, T, M or V; Y200 replaced by F, or W; S201 replaced by A, G, I, L, T, M or V; Q202 replaced by N; V203 replaced by A, G, I, L, S, T or M; L204 replaced by A, G, I, S, T, M or V; Y205 replaced by F, or W; T206 replaced by A, G, I, L, S, M or V; D207 replaced by E; 1209 replaced by A, G, L, S, T, M or V; F210 replaced by W, or Y; A211 replaced by G, I, L, S, T, M or V; M212 replaced by A, G, I, L, S, T or V; G213 replaced by A, I, L, S, T, M or V; H214 replaced by K, or R; V215 replaced by A, G, I, L, S, T or M; 1216 replaced by A, G, L, S, T, M or V; Q217 replaced by N; R218 replaced by H, or K; K219 replaced by H, or R; K220 replaced by H, or R; V221 replaced by A, G, I, L, S, T or M; H222 replaced by K, or R; V223 replaced by A, G, I, L, S, T or M; F224 replaced by W, or Y; G225 replaced by A, I, L, S, T, M or V; D226 replaced by E; E227 replaced by D; L228 replaced by A, G, I, S, T, M or V; S229 replaced by A, G, I, L, T, M or V; L230 replaced by A, G, I, S, T, M or V; V231 replaced by A, G, I, L, S, T or M; T232 replaced by A, G, I, L, S, M or V; L233 replaced by A, G, I, S, T, M or V; F234 replaced by W, or Y; R235 replaced by H, or K; 1237 replaced by A, G, L, S, T, M or V; Q238 replaced by N; N239 replaced by Q; M240 replaced by A, G, I, L, S, T or V; K242 replaced by H, or R; T243 replaced by A, G, I, L, S, M or V; L244 replaced by A, G, I, S, T, M or V; N246 replaced by Q; N247 replaced by Q; S248 replaced by A, G, I, L, T, M or V; Y250 replaced by F, or W; S251 replaced by A, G, I, L, T, M or V; A252 replaced by G, I, L, S, T, M or V; G253 replaced by A, I, L, S, T, M or V; 1254 replaced by A, G, L, S, T, M or V; A255 replaced by G, I, L, S, T, M or V; R256 replaced by H, or K; L257 replaced by A, G, I, S, T, M or V; E258 replaced by D; E259 replaced by D; G260 replaced by A, I, L, S, T, M or V; D261 replaced by E; E262 replaced by D; 1263 replaced by A, G, L, S, T, M or V; Q264 replaced by N, L265 replaced by A, G, I, S, T, M or V; A266 replaced by G, I, L, S, T, M or V; 1267 replaced by A, G, L, S, T, M or V; R269 replaced by H, or K; E270 replaced by D; N271 replaced by Q; A272 replaced by G, I, L, S, T, M or V; Q273 replaced by N; 1274 replaced by A, G, L, S, T, M or V; S275 replaced by A, G, I, L, T, M or V; R276 replaced by H, or K; N277 replaced by Q; G278 replaced by A, I, L, S, T, M or V; D279 replaced by E; D280 replaced by E; T281 replaced by A, G, I, L, S, M or V; F282 replaced by W, or Y; F283 replaced by - - W, or Y; G284 replaced by A, I, L, S, T, M or V; A285 replaced by G, I, L, S, T, M or V; L286 replaced by A, G, I, S, T, M or V; K287 replaced by H, or R; L288 replaced by A, G, I, S, T, M or V; and / or L289 replaced by A, G, I, S, T > M or V. The polynucleotides encoding these polypeptides are also encompassed by the present invention. The resulting neutrokine-alpha proteins of the present invention can be routinely selected with respect to their functional activity and / or physical properties of neutrocine-alpha and / or neutrocine-alphaSV (such as, for example, greater or lesser stability and / or solubility). Preferably, the resulting proteins of the present invention have a higher and / or lower functional activity of neutrocine-alpha and / or neutrocine-alphaSV. Preferably, the neutrokine-alpha and / or neutrocine-alphaSV proteins resulting from the present invention have more than one functional activity and / or physical property of neutrokine-alpha and / or neutrocine-alphaSV increased and / or decreased. The amino acids of the neutrokine-alpha and / or neutrocine-alphaSV polypeptides of the present invention that are essential for their function can be identified by methods known in the art, such as site-directed mutagenesis or alanine scanning mutagenesis (Cunningham and Wells, Science 244: 1081-1085 (1989)).

This last procedure introduces mutations of a single alanine in all the residues of the molecule. The resulting mutant molecules are subsequently tested for their functional activity, such as ligand binding and the ability to stimulate lymphocytes (e.g. B cells), for example proliferation, differentiation and / or activation. Of particular interest are substitutions of amino acids charged by other charged or neutral amino acids, which can produce proteins with highly desirable improved characteristics, such as less aggregation. Aggregation can not only reduce activity, but can also be problematic when preparing pharmaceutical formulations, because the aggregates can be immunogenic (Pinckard et al., Clin.Exp.Immunol.2: 331-340 (1967); Robbins et al., Diabetes 36: 838-845 (1987); Cleland et al., Crit. Rev. Therapeutic Drug Carrier Systems 10: 307-377 (1993) In another embodiment, the present invention provides polypeptides having amino acids that contain non-conservative substitutions of the amino acid sequence provided in SEQ ID NO: 2. For example, non-conservative substitutions of the neutrokine-alpha protein sequence provided in SEQ ID NO: 2, include: Ml replaced by D, E, H, K, R, N, Q, F,, Y, P d C, D2 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; D3 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; S4 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T5 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E6 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; R7 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E8 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; Q9 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; S10 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Rll replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L12 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T13 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S14 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; C15 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; L16 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K17 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K18 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; R19 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E20 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E21 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; M22 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K23 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L24 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K25 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E26 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; C27 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; V28 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S29 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 130 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L31 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P32 replaced by D, E; H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; R33 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K34 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, And, P or C; E35 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; S36 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P37 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; S38 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V39 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R40 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; S41 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S42 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K43 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; D44 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G45 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K46 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L47 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L48 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A49 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A50 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T51 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L52 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L53 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L54 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A55 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L56 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L57 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S58 replaced by D, E H, K, R, N, Q, F, W, Y, P or C; C59 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; C60 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; L61 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T62 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V63 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V64 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S65 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F66 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; Y67 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; Q68 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; V69 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A70 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A71 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L72 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q73 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; G74 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D75 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L76 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A77 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S78 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L79 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R80 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; A81 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E82 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L83 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q84 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; G85 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; H86 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; H87 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; A88 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E89 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K90 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L91 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P92 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; A93 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G94 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A95 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G96 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A97 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P98 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; K99 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; A100 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G101 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L102 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E103 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E104 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; A105 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P106 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C Al07 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C VI08 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C T109 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C A110 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C Glll replaced by D, E, H, K, R, N, Q, F, W, Y, P or C L112 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K113 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; 1114 replaced by D, E, H, K, K, N, Q, F, W, Y, P or C; F115 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; El16 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; P117 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; P118 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; A119 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P120 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; G121 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E122 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G123 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; N124 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; S125 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S126 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q127 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; N128 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; S129 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R130 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N131 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; K132 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; R133 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; A134 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V135 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q136 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, - F, W, Y, P or C; G137 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P138 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; E139 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, C; E140 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T141 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V142 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T143 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q144 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; D145 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; C146 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; L147 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q148 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; L149 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 1150 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A151 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D152 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; S153 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E154 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T155 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P156 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; T157 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 1158 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q159 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; K160 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G161 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; SI62 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y163 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; T164 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F165 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; VI66 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P167 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; W168 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; L169 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L170 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S171 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F172 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; K173 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; R174 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G175 replaced by D, E, H, K, R, N, Q, F, W, And, P or C; S176 replaced by D, E, H, K, R, N, Q, F, W, And, P or C; A177 replaced by D, E, H, K, R, N, Q, F, W, And, P or C; L178 replaced by D, E, H, K, R, N, Q, F, W, And, P or C; E179 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E180 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K181 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E182 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N183 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; K184 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; 1185 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L186 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V187 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K188 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E189 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T190 replaced by D, E, H, K, R, N, Q, F; W, Y, P or C; G191 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y192 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; F193 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; F194 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; 1195 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y196 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; G197 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q198 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; V199 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L200 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y201 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; T202 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D203 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K204 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T205 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y206 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; A207 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; M208 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G209 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; H210 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L211 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 1212 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q213 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; R214 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K215 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K216 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; V217 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; H218 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; V219 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F220 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; G221 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D222 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E223 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L224 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S225 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L226 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V227 replaced by D, E, H, K, R, N, Q, F, • W, Y, P or C; T228 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L229 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F230 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; R231 replaced by D, E, A, G, I, L, S, 1, M, V, N, Q, F, W, Y, P or C; C232 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; 1233 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q234 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; N235 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; M236 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P237 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; E238 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T239 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L240 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P241 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; N242 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; N243 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; S244 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; C245 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; Y2 6 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; S247 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A248 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G249 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 1250 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A251 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K252 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L253 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E254 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E255 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G256 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D257 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E258 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L259 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q260 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; L261 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A262 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 1263 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P264 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; R265 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E266 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N267 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; A268 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q269 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; 1270 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S271 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L272 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D272 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G274 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D275 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; V276 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T277 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F278 replaced by 'D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; F279 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; G280 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A281 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L282 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K283 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L284 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; and / or L285 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C. The polynucleotides encoding these polypeptides are also encompassed by the present invention. The resulting neutrokine-alpha proteins of the present invention can be routinely selected with respect to their functional activity and / or physical properties of neutrocine-alpha and / or neutrocine-alphaSV (such as, for example, greater or lesser stability and / or solubility), in the manner described in the present disclosure and known in the art. Preferably, the resulting proteins of the present invention have a higher and / or lower functional activity of neutrocine-alpha and / or neutrocine-alphaSV. More preferably, the neutrokine-alpha and / or neutrocine-alphaSV proteins resulting from the present invention have more than one functional activity and / or physical property of neutrokine-alpha and / or neutrocine-alphaSV increased and / or decreased. In a further embodiment, the neutrokine-alpha polypeptides of the present invention comprise, or alternatively consist of more than one amino acid (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 and 50) amino acids replaced by the substituted amino acids in the manner previously described (either conservatively or non-conservatively). In another embodiment of the present invention, non-conservative substitutions of the neutrocin-alphaSV protein sequence provided in SEQ ID NO: 19, include: Ml replaced by D, E, H, K, R, N, Q, F , W, Y, P or C; D2 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; D3 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; S4 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T5 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E6 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; R7 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E8 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; Q9 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; SIO replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Rll replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L12 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T13 replaced by D, £, H, K > R, N, Q, F, W, Y, P or C; S14 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; C15 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; L16 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K17 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K18 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; R19 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E20 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E21 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; M22 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K23 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L24 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K25 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E26 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; C27 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; V28 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S29 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 130 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L31 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P32 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; R33 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K34 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, And, P or C; E35 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; S36 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P37 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; S38 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V39 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R40 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; S41 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S42 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K43 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; D44 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G45 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K46 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L47 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L48 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A49 replaced by D, E, H, K, R / N, Q, F, W, Y, P or C; A50 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T51 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L52 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L53 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L54 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A55 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L56 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L57 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S58 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; C59 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; C60 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; L61 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T62 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V63 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V64 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S65 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F66 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; Y67 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; Q68 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; V69 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A70 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A71 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L72 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q73 replaced by D, E, H, K, R, A, G, I, L, S, 1, M, V, F, W, Y, P or C; G74 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D75 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L76 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A77 replaced by D, E, H, K, R N, Q, F, W, Y, P or C; S78 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L79 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R80 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; A81 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E82 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L83 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q84 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; G85 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; H86 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; H87 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; A88 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E89 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K90 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L91 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P92 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; A93 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G94 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A95 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G96 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A97 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P98 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; K99 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; A100 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G101 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L102 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E103 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E104 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; A105 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P106 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C Al07 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C VI08 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C T109 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C A110 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C Glll replaced by D, E, H, K, R, N, Q, F, W, Y, P or C L112 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K113 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; 1114 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F115 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; E116 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; P117 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; P118 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; A119 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P120 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; G121 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E122 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G123 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; N124 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; S125 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S126 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q127 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; N128 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; S129 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R130 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N131 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; K132 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; R133 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; A134 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V135 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q136 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; G137 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P138 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; E139 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, C; E140 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T141 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G142 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S143 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y144 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; T145 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F146 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; V147 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P148 replaced by D, E, H, K, R, A, G, 1 / L, S, T, M, V, N, Q, F, W, Y or C; W149 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; L150 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L151 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S152 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F153 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; K154 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; R155 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G156 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S157 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A158 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L159 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E160 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; El61 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K162 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; El63 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; NI64 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; K165 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; 1166 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L167 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; VI68 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K169 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E170 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T171 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G172 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y173 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; F174 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; F175 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; 1176 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y177 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; G178 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q179 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; V180 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L181 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y182 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; T183 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D184 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K185 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T186 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y187 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; A188 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; M189 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G190 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; H191 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L192 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 1193 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q194 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; R195 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K196 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K197 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; V198 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; H199 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; V200 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F201 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; G202 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D203 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E204 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L205 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S206 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L207 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V208 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T209 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L210 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F211 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; R212 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; C213 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; 1214 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q215 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; N216 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; M217 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P218 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; E219 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T220 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L221 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P222 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; N223 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; N224 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; S225 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; C226 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; Y227 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; S228 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A229 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G230 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 1231 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A232 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K233 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L234 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E235 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E236 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G237 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D238 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E239 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L240 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q241 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; L242 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A243 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 1244 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P245 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; R246 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E247 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N248 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; A249 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q250 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; 1251 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S252 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L253 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D254 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G255 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D256 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; V257 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T258 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F259 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; F260 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; G261 replaced by D, E, H, K, R N, Q, F, W, Y, P or C; A262 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L263 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K264 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L265 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; and / or 1266 replaced by D, E, H, K, R, N, Q, F, W, i, P or C. The polynucleotides encoding these polypeptides are also encompassed by the present invention. The resulting neutrokine-alpha proteins of the present invention can be routinely selected with respect to their functional activity and / or physical properties of neutrocine-alpha and / or neutrocine-alphaSV (such as, for example, greater or lesser stability and / or solubility) in the manner described in the present disclosure and known in the art. Preferably, the resulting proteins of the present invention have a higher and / or lower functional activity of neutrocine-alpha and / or neutrocine-alphaSV. More preferably, the neutrokine-alpha and / or neutrocine-alphaSV proteins resulting from the present invention have more than one functional activity and / or physical property of neutrokine-alpha and / or neutrocine-alphaSV increased and / or decreased. In a further embodiment, the neutrokine-alpha polypeptides of the present invention comprise, or alternatively consist of more than one amino acid (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 and 50) amino acids replaced by the substituted amino acids in the manner previously described (either conservatively or non-conservatively). For example, preferred non-conservative substitutions of the neutrocin-alpha protein sequence provided in SEQ ID NO: 23 include: Rl replaced by D, E, A, G, I, L, S, T, M, V , N, Q, F, W, Y, P or C; V2 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V3 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D4 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L5 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S6 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A7 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P8 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; P9 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; AlO replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Pll replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; C12 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; L13 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P14 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; G15 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; C16 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; R17 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; H18 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; S19 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q20 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; H21 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; D22 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; D23 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N24 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; G25 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; M26 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; N27 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; L28 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R29 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N30 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; R31 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T32 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y33 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; T34 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F35 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; V36 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P37 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; W38 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; L39 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L40 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S41 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F42 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; K43 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; R44 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G45 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; N46 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; A47 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L48 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E49 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E50 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, C; K51 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E52 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N53 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; K54 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; 155 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V56 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V57 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R58 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; Q59 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; T60 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G61 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y62 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; F63 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; F64 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; 165 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y66 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; S67 replaced by D # E, H, K, R, N, Q, F, W, Y, P or C; Q68 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; V69 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L70 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y71 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; T72 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D73 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; P74 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; 175 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F76 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; A77 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; M78 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G79 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; H80 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; V81 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 182 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q83 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; R84 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K85 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K86 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; V87 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; H88 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; V89 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F90 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; G91 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D92 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E93 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L94 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S95 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L96 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V97 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T98 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L99 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F100 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; R101 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; C102 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; 1103 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q104 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; N105 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; M106 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P107 replaced by D, E, H, K, R, A, G, I, L,?, T, M, V, N, Q, F, W, Y or C; K108 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T109 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L110 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Pili replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; N112 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; N113 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; S114 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; C115 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; Y116 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; S117 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A118 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G119 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 1120 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A121 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R122 replaced by D, E, A, G / I, L, S, T, M, V, N, Q, F, W, Y, P or C; L123 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E124 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E125 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G126 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D127 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E128 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; 1129 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q130 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; L131 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A132 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 1133 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P134 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; R135 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E136 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N137 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; A138 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q139 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; 1140 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S141 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R142 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N143 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; G144 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D145 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; D146 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T147 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F148 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; F149 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; G150 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A151 replaced by D, E, H, K, R N, Q, F, W, Y, P or C; L152 replaced by D, E, H, K, R N, Q, F, W, Y, P or C; K153 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L154 replaced - 3 - by D, E, H, K, R, N, Q, F, W, Y, P or C; and / or L55 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C. The polynucleotides encoding these polypeptides are also encompassed by the present invention. The resulting neutrokine-alpha proteins of the present invention can be routinely selected with respect to their functional activity and / or physical properties of neutrocine-alpha and / or neutrocine-alphaSV (such as, for example, greater or lesser stability and / or solubility) in the manner described throughout the present description and known in the art. Preferably, the resulting proteins of the present invention have a higher and / or lower functional activity of neutrocine-alpha and / or neutrocine-alphaSV. More preferably, the neutrokine-alpha and / or neutrocine-alphaSV proteins resulting from the present invention have more than one functional activity and / or physical property of neutrokine-alpha and / or neutrocine-alphaSV increased and / or decreased. In a further embodiment, the neutrokine-alpha polypeptides of the present invention comprise, or alternatively consist of more than one amino acid (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 and 50) amino acids replaced by the substituted amino acids in the manner previously described (already nea conservatively or non-conservatively).

For example, preferred non-conservative substitutions of the neutrocin-alpha protein sequence provided in SEQ ID NO: 38, include: Ml replaced by D, E, H, K, R, N, Q, F, W, Y , P or C; D2 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E3 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; S4 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A5 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K6 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T7 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L8 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P9 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; PL replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; Pll replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; C12 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; L13 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; C14 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; F15 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; C16 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; S17 replaced by D, E, H, K, R / N, Q, F, W, Y, P or C; E18 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K19 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G20 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E21 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; D22 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; M23 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K24 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; V25 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G26 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y27 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; D28 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; P29 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; 130 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T31 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P32 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; Q33 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; K34 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E35 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E36 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G37 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A38 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; W39 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; F40 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; G41 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 142 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; C43 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; R44 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; D45 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, C; G46 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R47 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L48 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L49 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A50 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A51 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T52 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L53 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L54 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L55 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A56 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L57 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L58 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S59 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S60 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S61 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F62 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; T63 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A64 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; M65 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S66 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L67 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y68 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; Q69 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; L70 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A71 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A72 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L73 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q74 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; A75 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D76 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L77 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; M78 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; N79 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; L80 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R81 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; M82 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E83 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L84 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q85 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; S86 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y87 replaced by D, E, H, K, R,, Q, A, G, I, L, S, T, M, V, P or C; R88 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G89 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S90 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A91 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T92 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P93 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; A94 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A95 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A96 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G97 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A98 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P99 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; E100 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L101 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T102 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A103 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G104 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V105 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K106 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L107 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L108 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T109 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; PllO replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; There replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A112 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P113 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; R114 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; P115 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; H116 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N117 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; S118 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S119 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R120 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G121 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; H122 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; R123 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N124 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; R125 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; R126 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; A127 replaced by D, E, H, • K, R, N, Q, F, W, Y, P or C; F128 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; Q129 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; G130 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P131 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; E132 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E133 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T134 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E135 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; Q136 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; D137 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; V138 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D139 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L140 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S141 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A142 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P143 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; P144 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; A145 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P146 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; C147 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; L148 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P149 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; G150 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; C151 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; R152 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; H153 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; S154 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q155 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; H156 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; D157 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; D158 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N159 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; G160 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; M161 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; N162 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; L163 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R164 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N165 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; 1166 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 1167 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q168 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; D169 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; C170 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; L171 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q172 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; L173 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 1174 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A175 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D176 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; S177 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D178 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T179 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P180 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; A181 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L182 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E183 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E184 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K185 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E186 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N187 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; K188 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; 1189 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V190 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V191 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R192 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; Q193 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; T194 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G195 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y196 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; F197 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; F198 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; 1199 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y200 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; S201 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q202 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; V203 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L204 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Y205 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; T206 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D207 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; P208 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; 1209 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F210 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; A211 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; M212 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G213 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; H214 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; V215 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 1216 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q217 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; R218 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K219 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; K220 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; V221 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; H222 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; V223 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F224 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; G225 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D226 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E227 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L228 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S229 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L230 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; V231 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; T232 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L233 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F234 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; R235 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; C236 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; 1237 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q238 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; N239 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; M240 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P241 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; K242 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T243 replaced by D, E; H, K, R, N, Q, F, W, Y, P or C; L244 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P245 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; N246 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; N247 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; S248 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; C249 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or P; Y250 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; S251 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A252 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; G253 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 1254 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A255 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R256 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L257 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; E258 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E259 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; G260 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D261 replaced by H, K, R K ,. A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E261 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; 1263 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q264 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; L265 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A266 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; 1267 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; P268 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y or C; R269 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; E270 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N271 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; A272 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; Q273 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; 1274 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; S275 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; R276 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; N277 replaced by D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P or C; G278 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; D279 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; D280 replaced by H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; T281 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; F282 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; F283 replaced by D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P or C; G284 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; A285 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; L286 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; K287 replaced by D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P or C; L288 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C; and / or L289 replaced by D, E, H, K, R, N, Q, F, W, Y, P or C. The polynucleotides encoding these polypeptides are also encompassed by the present invention. The resulting neutrokine-alpha proteins of the present invention can be routinely selected with respect to their functional activity and / or physical properties of neutrocine-alpha and / or neutrocine-alphaSV (such as, for example, greater or lesser stability and / or solubility) in the manner described throughout the present description and known in the art. Preferably, the resulting proteins of the present invention have a higher and / or lower functional activity of neutrocine-alpha and / or neutrocine-alphaSV. More preferably, the neutrokine-alpha and / or neutrocine-alphaSV proteins resulting from the present invention have more than one functional activity and / or physical property of neutrokine-alpha and / or neutrocine-alphaSV increased and / or decreased.

In a further embodiment, the neutrokine-alpha polypeptides of the present invention comprise, or alternatively consist of one or more amino acids (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 and 50) amino acids replaced by the substituted amino acids in the manner previously described (either conservatively or non-conservatively). The replacement of amino acids can change the selectivity of the binding of a ligand to cell surface receptors. For example, Ostade et al. , Nature 361: 266-268 (1993) describe certain mutations that result in the selective binding of TNF-alpha to only one of the two known types of TNF receptors. Since neutrokine-alpha and neutrokine-alphaSV are members of the TNF family of polypeptides, mutations similar to those in TNF-alpha may have similar effects in neutrokine-alpha and / or neutrocine-alphaSV. Sites that are critical for ligand-receptor binding can also be determined by structural analysis, such as crystallization, nuclear magnetic resonance or photoaffinity-labeled (Smith et al., J. Mol. Biol. 224: 899-904 (1992 ) and de Vos et al., Science 255: 306-312 (1992) .As neutrocin-alpha is a member of the family of proteins related to TNF, to modulate rather than completely eliminate functional activities (eg biological activities) of neutrocin-alpha, mutations can be made in sequences encoding amino acids in the conserved TNF domain, ie, at positions Gly-191 to Leu-284 of Figures 1A and IB (SEQ ID NO: 2), preferably in residues within this region that are not conserved in all, most or several members of the TNF family (eg, TNF-alpha, TNF-beta, LT-beta and Fas ligand) (see eg, Figures 2A-D). By making a specific mutation in the neutrocin-alpha in the position where t Typically such a conservative amino acid is found in the related TNFs, the mutein neutrocin-alpha will act as an antagonist, which thus possesses activity, for example, which inhibits lymphocyte proliferation (eg, B cells), differentiation and / or activation . Accordingly, the polypeptides of the present invention include neutrokine-alpha mutants. Such neutral-alpha mutants comprise, or alternatively consist of, full-length fragments, variants or derivatives or preferably of the extracellular domain of the neutrokine-alpha amino acid sequence shown in Figures IA and IB (SEQ ID NO: 2) ). The polynucleotides encoding the above neutral-alpha mutants are also encompassed by the present invention. Since neutrokine-alphaSV is a member of the family of proteins related to TNF, to modulate rather than completely eliminate functional activities (eg, biological activities) of neutrocine-alphaSV, mutations can be made in the sequences they encode for amino acids in the conservative TNF domain, ie at positions Gly-172 to Leu-265 of Figures 5A and 5B (SEQ ID NO: 19), preferably residues within this region that are not conserved in all, most or several members of the TNF family (eg , TNF-alpha, TNF-beta, LT-beta and Fas ligand) (see eg, Figures 2A-D). By making a specific mutation in neutrokine-alphaSV at the position where such a conserved amino acid is typically found in related TNFs, the neutrokine-alphaSV mutein will act as an antagonist, thereby having activity for example, which inhibits lymphocyte proliferation. (eg, B cells), differentiation and / or activation. Accordingly, the polypeptides of the present invention include neutrokine-alphaSV mutants. Such neutrokine-alphaSV mutants comprise, or alternatively consist of, full-length fragments, variants or derivatives or preferably the extracellular domain of the amino acid sequence of neutrokine-alphaSV shown in Figures 5A and 5B) SEQ ID NO: 19). The polynucleotides that code for the above neutrokine-alphaSV mutants, they are also encompassed by the present invention. In addition, a person skilled in the art will recognize which mutations directed toward regions of a neutrocyan-alpha polypeptide of the present invention spanning the insertion of ten and nine amino acid residues not found in the neutrocyl-alphaSV polypeptide sequence (ie, residues). of amino acid from Val-142 to Lys-160 of the sequence presented in Figures IA and IB and SEQ ID NO: 2), could affect the observed functional activity (eg biological activity) of the neutrocine-alpha polypeptide. More specifically, a partial, non-limiting and non-exclusive list of such residues of the neutrocin-alpha polypeptide sequence that can be mutated, includes the following amino acid residues of the neutrocin-alpha polypeptide sequence as shown in SEQ ID. NO: 2: V-142; T-143; Q-144; D-145; C-146; L-147; Q-148; L-149; 1-150; A-1551; D-152; S-153; E-154; T-155; P-156; T-157; 1-158; Q-159 and K-160. Recombinant DNA technology known to those skilled in the art (see for example, DNA Shuffling, supra) can be used to create new mutant proteins or muteins that include substitutions of single or multiple amino acids, deletions, additions or fusion proteins . Such modified polypeptides can demonstrate e.g., increased activity or increased stability. In addition, they can be purified in high yields and demonstrate a better solubility than the corresponding natural polypeptide, at least under certain purification and storage conditions. Thus, the present invention also encompasses neutrokine-alpha and / or neutrocin-alphaSV derivatives and analogs having one or more amino acid residues deleted, aggregated or substituted, to generate neutral-alpha and / or neutrocine-alphaSV polypeptide which are better suitable for expression, for scaling, etc., in the selected host cells. For example, the cysteine residues can be eliminated or replaced by other amino acid residues in order to eliminate the disulfide bridges; the N-linked glycosylation sites can be altered or eliminated to achieve, for example, the expression of a homogeneous product that is easier to recover and purify from yeast hosts known to hyperglycosylate the N-linked sites. For this purpose, a variety of amino acid substitutions in one or both of the first or third amino acid position in any one or more of the glycosylation recognition sequences in the neutrokine-alpha and / or neutrocine-alphaSV polypeptides of the present invention , and / or an amino acid deletion in the second position of any one or more such recognition sequences, will prevent glycosylation of neutrocine-alpha and / or neutrocine-alphaSV in the modified tripeptide sequence (see, eg, Miyajimo et al. , EMBO J 5 (6): 1193-1197). Additionally, one or more amino acid residues of the polypeptides of the present invention (e.g., arginine and lysine residues) can be removed or substituted by another residue, to eliminate undesirable processing by proteases, such as, for example, furins or quexins. One possible result of such a mutation is that the neutrocin-alpha polypeptide of the present invention is not degraded or detached from the cell surface. In a specific embodiment, the amino acids Lys-132 and / or Arg-133 of the neutrokine-alpha sequence shown in SEQ ID NO: 2, are mutated by another amino acid residue, or are removed together, to prevent or diminish the liberation of the soluble form of neutrocine-alpha by the cells expressing it. In a more specific embodiment, the Lys-132 residue of the neutrokine-alpha sequence shown in SEQ ID NO: 2 is mutated to Ala-132. In another non-exclusive specific embodiment, the Arg-133 residue of the neutrocin-alpha sequence shown in SEQ ID NO: 2 is mutated to Ala-133. These mutated proteins and / or polynucleotides that code for these proteins have uses such as for example ex vivo therapy or gene therapy, to engineer cells expressing a neutrocine-alpha polypeptide that is retained on the surface of the proteins. cells subjected to engineering manipulation. In a specific embodiment the Cys-1 6 residue of the neutrokine-alpha sequence shown in SEQ ID NO: 2, is mutated to another amino acid residue or deleted, for example, to help prevent or decrease oligomerization of the neutrocyte polypeptide -alpha mutant when expressed in an expression system (essentially in the manner described in Example 1). In a specific embodiment, the Cys-146 residue is replaced by a serine amino acid residue. The polypeptides that code for these polypeptides are also encompassed by the present invention. In another specific modality, the Cys-232 residue of the neutrokine-alpha sequence shown in SEQ ID NO: 2, is mutated to another amino acid residue or is removed, for example, to help prevent or decrease the oligomerization of the neutrocine-alpha polypeptide mutant when expressed in an expression system (essentially in the manner described in Example 1). In a specific embodiment, the Cys-232 residue is replaced by a serine amino acid residue. The polypeptides encoding these polypeptides are also encompassed by the present invention. In yet another specific modality, the waste Cys-245 of the neutrokine-alpha sequence shown in SEQ ID NO: 2, is mutated to another amino acid residue or is removed, for example, to help prevent or decrease the oligomerization of the mutant neutrocytic-alpha polypeptide when it is expressed in a system of expression (essentially in the manner described in Example 1). In a specific embodiment, the Cys-245 residue is replaced by a serine amino acid residue. The polypeptides encoding these polypeptides are also encompassed by the present invention. The polypeptides of the present invention are preferably provided in isolated form and preferably are substantially purified. A recombinantly produced version of the neutrokine-alpha and / or neutrocin-alphaSV polypeptides can be substantially purified by a one-step method described in Smith and Johnson, Gene 67: 31-40 (1988). The polypeptides of the present invention include the entire polypeptide encoded by the deposited cDNA (ATCC deposit No. 97768) including the intracellular, transmembrane and extracellular domains of the polypeptide encoded by the deposited cDNA, the mature soluble polypeptide encoded by the deposited cDNA, the domain extracellular minus the intracellular and transmembrane domains of the protein, the complete polypeptide of Figures IA and IB (amino acid residues 1 to 285 of SEQ ID NO: 2), the mature soluble polypeptide of Figures IA and IB (residues of amino acid from 134 to 285 of SEQ ID NO: 2), the extracellular domain of Figures IA and IB (amino acid residues 73 to 285 of SEQ ID NO: 2) minus the intracellular and transmembrane domains, as well as polypeptides that they have at least 80, 85, 90% similarity, preferably at least 95% similarity and still more preferably at least 96, 97, 98 or 99% similarity to aq those previously described. The polynucleotides encoding these polypeptides are also encompassed by the present invention. These polypeptides of the present invention also include the entire polypeptide encoded by the deposited cDNA, including the intracellular, transmembrane and extracellular domains of the polypeptide encoded by the deposited cDNA (ATCC deposit No. 203518), the mature soluble polypeptide encoded by the deposited cDNA, the extracellular domain minus the intracellular and transmembrane domains of the protein, the complete polypeptide of Figures 5A and 5B (amino acid residues 1 to 266 of SEQ ID NO: 19), the extracellular domain of Figures 5A and 5B (residues amino acid from 73 to 266 of SEQ ID NO: 19) minus the intracellular and transmembrane domains, as well as polypeptides having at least 80, 85, 90% similarity, preferably at least 95% similarity and still more preferably at least 96, 97, 98 or 99% similarity to those previously described. The polynucleotides encoding these polypeptides are also encompassed by the present invention. In addition, the polypeptides of the present invention include polypeptides having at least 80% or at least 85% identity, preferably at least 90 or 95% identity, still more preferably at least 96, 97, 98 or 99% identity to polypeptides encoded by the deposited cDNA (ATCC deposit No. 97768) or to the polypeptide of FIGURES IA or IB (SEQ ID NO: 2) and also include portions of such polypeptides having at least 30 amino acids and preferably at least 50 amino acids. The polynucleotides encoding these polypeptides are also encompassed by the present invention. Additional polypeptides of the present invention include polypeptides having at least 80% or at least 85% identity, preferably at least 90 or 95% identity, still more preferably at least 96, 97, 98 or 99% identity. the polypeptides encoded by the deposited cDNA (ATCC deposit No. 203518) or the polypeptide of FIGS. 5A or 5B (SEQ ID NO: 19) and also include portions of such polypeptides having at least 30 amino acids and preferably at least 50 amino acids. The polynucleotides that encode for these polypeptides are also encompassed by the present invention. The term "% similarity" for two polypeptides refers to a similarity score produced when comparing the amino acid sequences of the two polypeptides using the Bestfit program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, 575 Science Drive, Madison, Wl 53711) and the default conditions for determining similarity. The Bestfit program uses the local homology algorithm of Smith and Waterman (Advances in Applied Mathematics 2: 482-489, 1981) to find the best segment of similarity between two sequences. With the phrase a polypeptide having a amino acid sequence at least, for example, with 95% ____________! _____________! "Identity" to a reference amino acid sequence of a neutrocine-alpha and / or neutrocine-alphaSV polypeptide, is meant to mean that the amino acid sequence of the polypeptide is identical to the reference sequence, except that the polypeptide sequence may include up to 5 amino acid alterations per 100 amino acids of the reference amino acid sequence of the neutrocine-alpha and / or neutrocine-alphaSV polypeptide. In other words, to obtain a polypeptide having an amino acid sequence with an identity of at least 95% with respect to the reference amino acid sequence, up to 5% of the amino acid residues of the reference sequence may have been deleted or they can be substituted by other amino acids, or a number of amino acids of up to 5% of the total number of amino acid residues in the reference sequence, can be inserted into the reference sequence. These alterations of the reference sequence may occur in the amino-terminal or carboxyl-terminal positions of the reference amino acid sequence or in any other part between said terminal positions, interspersed either individually between residues of the reference sequence, or in one or more contiguous groups within the reference sequence. As a practical matter, if any particular polypeptide has at least 80, 85, 90, 95, 96, 97, 98 or 99% identity to, for example, the amino acid sequence shown in Figures IA and IB (SEQ ID NO: 2), the amino acid sequence encoded by the deposited cDNA clone HNEDU15 (Accession No. ATCC 97768), or fragments thereof, or, for example, to the amino acid sequence shown in Figures 5A and 5B (SEQ ID. NO: 19), the amino acid sequence encoded by the deposited cDNA clone HDPMC52 (Accession No. ATCC 203518), or fragments thereof, can be determined conventionally using computer programs such as the Bestfit program (Wisconsin Sequence Analysis Package). , Version 8 for Unix, Genetics Computer Group, University Research Park, 575 Science Drive, Madison, Wl 53711). When the Bestfit program or any other sequence alignment program is used to determine whether a particular sequence has an identity, eg, 95% with respect to a reference sequence in accordance with the present invention, the parameters are set, of course, such that the percent identity is calculated over the entire length of the reference amino acid sequence and that homology gaps of up to 5% of the total number of amino acid residues in the reference sequence are allowed. In a specific embodiment, the identity between a reference sequence (pattern) (a sequence of the present invention) and a subject sequence, also referred to as a global alignment sequence, is determined using the FASTDB computer program based on the Brutlag algorithm. et ai. (Composition, App. Biosci, 6: 237-245 (1990)). The preferred parameters used in an alignment of FASTDB amino acids are: Matrix = PAM 0, k-tupie = 2, Mismatch Penalty = 1, Joining Penalty = 20, Randomization Group Length = 0, Cutoff Score = 1, Window Size = sequence length, Gap Penalty = 5, Gap Size Penalty = 0.05, Window Size = 500 or the length of the subject amino acid sequence, whichever is shorter. In accordance with this modality, if the subject sequence is shorter than the standard sequence due to N-terminal or C-terminal deletions, not due to internal deletions, a manual correction is made to the results to take into consideration the fact that the FASTDB program does not account for N-terminal and C-terminal truncations of the subject sequence when calculating the percentage of global identity. For subject sequences truncated at the N-terminal and C-terminal ends, relative to the standard sequence, the percentage of identity is corrected by calculating the number of residues of the standard sequence that are N-terminal and C-terminal of the subject sequence , which are not paired / aligned with a corresponding subject residue, as a percentage of the total bases of the master sequence. A determination of whether a residue is paired / aligned is determined by the results of the FASTDB sequence alignment. Then, this percentage is subtracted from the identity percentage calculated by the previous FASTDB program, using the specified parameters, to arrive at a final identity percentage score. This final identification percentage grade is what is used for the purposes of this modality. Only the residues towards the N-terminal and C-terminal end of the subject sequence, which are not paired / aligned with the standard sequence, are considered for the purposes of manually adjusting the percent identity rating. That is, only the positions of pattern residues outside the N-terminal and C-terminal residues furthest from the subject sequence. For example, a subject sequence of 90 amino acid residues is aligned with a standard sequence of 100 residues to determine percent identity. The deletion occurs at the N-terminal end of the subject sequence and, therefore, the FASTDB alignment program does not show a pairing / alignment of the first 10 residues at the N-terminus. The 10 unpaired residues represent 10% of the sequence (number of residues at the N-terminal and C-terminal non-- paired / total number of residues in the standard sequence), so that 10% of the identity percentage score calculated by the FASTDB program. If the remaining 90 residues matched correctly, the final identity percentage would be 90%. In another example, a subject sequence of 90 residues is compared to a standard sequence of 100 residues. This time, the deletions are such that they were not residues at the N-terminal or C-terminal ends of the subject sequence, which are not paired / aligned with the pattern. In this case, the identity percentage calculated by the FASTDB program is not manually corrected. Again, only the residue positions outside the N-terminus and C-terminus of the subject sequence, as displayed FASTDB alignment, which are not paired / aligned with the pattern sequence, are manually corrected. No other manual correction is made for the purposes of this modality. The polypeptides of the present invention have uses that include, but are not limited to, molecular weight markers on SDS-PAGE gels or gel filtration columns with molecular sieves, using methods known to those skilled in the art. Additionally, as will be described in detail below, the polypeptides of the present invention have uses including, but not limited to, inducing polyclonal and monoclonal antibodies, which are useful in assays for the detection of Neutrocin-alpha polypeptide expression and / or Neutrocin-alfaSV, in the manner described below, or as agonists and antagonists capable of enhancing or inhibiting the function of Neutrokine-alpha and / or Neutrocin-alphaSV. The polypeptides of the present invention also have therapeutic uses, as described herein. In addition, such polypeptides can be used in the yeast two-hybrid system to "capture" Neutrocin-alpha and / or Neutrocin-alphaSV binding proteins, which are also agonist and antagonist candidates in accordance with the present invention. The two-hybrid system in yeast is described in Fields and Song, Nature 340: 245-246 (1989). Transgenic and "knock-outs" The polypeptides of the present invention can also be expressed in transgenic animals. Animals of any species, including but not limited to mice, rats, rabbits, hamsters, guinea pigs, pigs, dwarf pigs, goats, sheep, cows and non-human primates, e. g. , baboons, monkeys and chimpanzees, can be used to generate transgenic animals. In a specific embodiment, the techniques described herein or in other documents known in the art, are used to express the polypeptides of the present invention in humans, as part of a gene therapy protocol. Any technique known in the art can be used to introduce the transgene (i.e., polynucleotides of the present invention) into animals, to produce founder lines of transgenic animals. Such techniques include, but are not limited to, pronuclear microinjection (Paterson, et al., Appl. Microbiol. Biotechnol. 40: 691-698 (1994).; Carver et al., Biotechnology (NY) 11: 1263-1270 (1993); Wright et al., Biotechnology (NY) 9: 830-934 (1991); and Hoppe et al. , U.S. Patent No. 4,873.19"1 (1989)); gene transfer mediated by retroviruses in germ lines (Van der Putten et al., Proc. Nati, Acad. Sci., USA 82: 6148-6152 (1985)), blastocysts or embryos; white genes in embryonic undifferentiated stem cells (Thompson et al., Cell 56: 313-321 (1989)); electroporation of cells or embryos (Lo, 1983, Mol Cell, Biol. 3: 1803-1814 (1983)); introduction of the polynucleotides of the present invention using a gene gun (see, e.g., Ulmer et al., Science 259: 1745 (1993)); introduction of nucleic acid construction in embryonic pluripotent stem cells and transfer of the stem cells back to the blastocyst; and sperm-mediated gene transfer (Lavitrano et al., Cell 57: 717-723 (1989), etc. For more complete review of such techniques, see Gordon, "Transgenic Animáis," Intl. Rev. Cytol. 115: 171 -229 (1989), which is incorporated herein by reference in its entirety, See also US Pat. No. 5,464,764 (Capecchi et al., Positive-Negative Selection Methods and Vectors), US Patent No. 5,631,153 (Capecchi et al. , Cells and Non-Human Organisms Containing Predetermined Genomic Modifications and Positive Negative Selection Methods and Vectors for Making Same), US Patent 4,736,866 (Leder et al., Transgenic Non-Human Animáis), and US Patent 4,873,191 (US Pat. Wagner et al., Genetic Transformation of Zygotes), each of which is hereby incorporated in its entirety as a reference, any technique known in the art can be used to produce transgenic clones containing the p olinucleotides of the present invention, for example nuclear transfer in enucleated oocysts of nuclei from embryonic, fetal or cultured adult cells induced at the latency state (Campell et al., Nature 380: 64-66 (1996); Wilmut et al., Nature 385: 810-813 (1997)). The present invention provides transgenic animals that are carriers of the transgene in all its cells, as well as animals that are carriers of the transgene only in some, but not all of its cells, i. and. , mosaic or chimerical animals. The transgene can be integrated as a single transgene or as multiple copies, for example with catomers, e. g. , tandems with head with head or tandems with head and tail. The transgene can also be selectively introduced and activated in a particular cell type, following for example the teachings of Lasko et al. , (Lasko et al., Proc. Nati, Acad. Sci. USA 89: 6232-6236 (1992)). The regulatory sequences required for such cell-type specific activation, will depend on the particular cell type of interest will be apparent to those skilled in the art. When it is desired that the transgenic polynucleotide be integrated into the chromosomal site of the endogenous gene, it is preferred to target a target gene. Briefly, when such a technique is used, vectors containing some nucleotide sequences homologous to the endogenous gene are designated for the purpose of integrating, through homologous recombination with chromosomal sequences, and disrupting the function of the nucleotide sequence of the endogenous gene. The transgene can also be selectively introduced into a particular cell type, thereby inactivating the endogenous gene only in that cell type, following for example the teachings of Gu et al. , (Gu et al., Science 165: 103-106 (1994)). The regulatory sequences required for such cell-type specific inactivation will depend on the particular cell type of interest and will be apparent to those skilled in the art. In addition, to express the polypeptide of the present invention in a ubiquitous or tissue-specific manner, in transgenic animals, it would also be routine for a person skilled in the art to generate constructs that regulate the expression of the polypeptide by a variety of other mechanisms (e.g., expression regulated by development or chemically). Once transgenic animals have been generated, the expression of the recombinant gene can be analyzed using standard techniques. The initial analysis can be carried out by Southern blot analysis or by PCR techniques, to analyze animal tissues to verify that the integration of the transgene has been carried out. The level of mRNA expression of the transgene in the tissues of the transgenic animals can also be assessed using techniques including, but not limited to, Northern blot analysis of tissue samples obtained from animals, analysis of In situ hybridization, Reverse transcriptase PCR (RCP-TI); and RCP TaqMan. Tissue samples expressing the transgenic gene can also be evaluated by immunocytochemistry or immunohistochemistry, using specific antibodies against the transgenic product. Once the founding animals are produced, they can be bred, bred inbreeding, raised exogamically or crossed to produce colonies of the particular animal. Examples of such breeding strategies include, but are not limited to: exogamic breeding of founder animals with more than one integration site in order to establish separate lines; inbreeding of separate lines in order to produce transgenic compounds that express the transgene at higher concentrations due to the effects of the additive expression of each transgene; crossing of heterozygous transgenic animals to produce animals homozygous for a given integration site, in order to increase expression and eliminate the need to select animals by DNA analysis; crosses from separate homozygous lines to produce lines of heterozygous or homozygous compounds; breeding to place the transgene in a different background that is appropriate for an experimental model of interest; and crosses of transgenic animals with other animals carrying a different transgene or a knock-out mutation. The transgenic and "knock-out" animals of the present invention have uses that include, but are not limited to, animal model systems useful for studying the biological function of Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides, to study disorders and / or diseases associated with the aberrant expression of Neutrocin-alpha and / or Neutrocin-alphaSV and select effective compounds to ameliorate such disorders and / or diseases. In further embodiments of the present invention, cells that are engineered to express the polypeptides of the present invention, or alternatively that are engineered to not express the polypeptides of the present invention (eg, knockouts), are administered to a patient alive. Such cells can be obtained from the patient (i.e., animal, including humans) or a compatible MHC donor and can include, but not be limited to fibroblasts, bone marrow cells, blood cells (e.g., lymphocytes), adipocytes, muscle cells, endothelial cells, etc. The cells are engineered by in vitro using the recombinant DNA technique to introduce the coding sequence of the polypeptides of the present invention, or alternatively, to alter the coding sequence and / or the endogenous regulatory sequence associated with the polypeptides of the invention. present invention, eg , by transduction (using viral vectors and preferably vectors that integrate the transgene into the genome of cells) or transfection procedures, including but not limited to, the use of plasmids, cosmids, YACs, naked DNA, electroporation, liposomes, etc. . The coding sequence of the polypeptides of the present invention can be placed under the control of a strong constitutive or inducible promoter or a promoter / enhancer, to achieve the expression and preferably the secretion of the polypeptides of the present invention. Genetically engineered cells that express and preferably secrete the polypeptides of the present invention can be introduced into the patient systemically, e. g. , in the blood circulation or intraperitoneally. Alternatively, the cells can be incorporated into a matrix and implanted in the body, e. g. , fibroblasts manipulated by genetic engineering, can be implanted as part of a skin graft; Endothelial cells manipulated by genetic engineering can be implanted as part of a lymphatic or vascular graft (see for example, Anderson et al., American Patent US 5,399,349; and Mulligan and Wilson, US Pat. No. 5,460,959, each of which is incorporated herein by reference in its entirety). When the cells to be administered are not autologous or are not MHC compatible, they can be administered using known techniques that prevent the development of a host immune response against the introduced cells. For example, cells can be introduced in encapsulated form which, while allowing an exchange of components with the immediate extracellular environment, does not allow the introduced cells to be recognized by the immune system. Antibodies In addition, the polypeptides of the present invention refer to antibodies and T cell antigen (TCR) receptors that immunospecifically bind to a polypeptide, polypeptide fragment or variant of SEQ ID No. 2 and / or SEQ ID No. 19, and / or an epitope of the present invention (determined by immunoassays known in the art to evaluate the specific binding of antibody-antigen). The antibodies of the present invention, include but are not limited to, polyclonal, monoclonal, multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F (ab ') fragments. fragments produced by a Fab expression library, anti-idiotypic (anti-ld) antibodies (including e.g., anti-ld antibodies against antibodies of the present invention) and epitope-binding fragments of any of the foregoing. The term "antibody" as used herein, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i. and. , molecules that contain an antigen binding site, that bind immunospecifically to an antigen. The immunoglobulin molecules of the present invention can be of any type (eg, IgG, IgE, IgM, IgD, IgA and IgY), of any kind (eg, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), or any subclass of immunoglobulin molecule. Immunoglobulins can have a heavy chain and a light chain. An array of heavy chains of IgG, IgE, IgM, IgD, IgA and IgY can be paired with a light chain of the kappa or lambda forms. Preferably, the antibodies are antigen-binding human antibody fragments of the present invention and include, but are not limited to, Fab ', Fab' and F (ab ') 2, Fd, Fvs single-stranded (scFv) fragments. , single chain antibodies, Fvs linked to disulfide (sdFv) and fragments comprising a domain VI or VH. Antigen-binding antibody fragments, including single-chain antibodies, may comprise the variable region or regions alone or in combination with all or a portion of the following: the hinge region, the CH1, CH2, and CH3 domains. Also included in the present invention are antigen binding fragments that also comprise any combination of variable regions with a hinge region, a CH1, CH2, and CH3 domain. The antibodies of the present invention can come from any animal origin, including birds and mammals. Preferably, the antibodies are human, murine (e.g., mouse and rat), donkey, rabbit, goat, guinea pig, camel, horse or chicken. As used herein, "human" antibodies include antibodies that have the amino acid sequence of a human immunoglobulin and include antibodies isolated from any human immunoglobulin library or from animals transgenic for one or more human immunoglobulins and that do not express endogenous immunoglobulins , as described below and, for example, as described in U.S. Patent No. 5,939,598 to Kucherlapati et al. The antibodies of the present invention may be monospecific, bispecific, trispecific or polyspecific. The polyspecific antibodies may be specific for different epitopes of a polypeptide of the present invention or may be specific for both a polypeptide of the present invention and a heterologous epitope, such as a heterologous polypeptide or a solid support material. See e. g. , PCT International Publications WO 93/17715; WO 92/08802; WO 91/00360 WO 92/05793; Tutt et al., J. Immunol. 147: 60-69 (1991) U.S. Patent Nos. 4,474,893; 4,714,681 4,925,648; 5,573,920 and 5,601,819; Kostelny et al., J. Immunol. 148: 1547-1553 (1992). The antibodies of the present invention can be described or specified in terms of epitopes or portions of a polypeptide of the present invention that specifically recognize or bind. The epitope or polypeptide portions can be specified as described herein, e. g. , by N-terminal and C-terminal positions, by size in contiguous amino acid residues, or listed in the Tables and Figures. Antibodies that bind specifically to any epitope or polypeptide of the present invention can also be excluded. Therefore, the present invention includes antibodies that specifically bind to polypeptides of the present invention and allow the exclusion thereof. In specific embodiments, the antibodies of the present invention bind to polypeptides that comprise residues Phe-115 to Leu-147, Ile-150 to Tyr-163, Ser-171 to Phe-194, Glu-223 to Tyr-246 and Ser-271 to Phe-278 of the amino acid sequence of SEQ ID No. 2. In another specific embodiment, the antibodies of the present invention bind to polypeptides consisting of residues Phe-115 to Leu-147, Ile 150 to Tyr-163, Ser-171 to Phe-194, Glu-223 to Tyr-246 and Ser-271 to Phe-278 of the amino acid sequence of SEQ ID No. 2. In a preferred embodiment, the The present invention binds to a polypeptide comprising the residues of Glu-223 to Tyr-246 of SEQ ID No. 2. In another preferred embodiment, the antibodies of the present invention bind to a polypeptide consisting of the residues of Glu-223 to Tyr-246 of SEQ ID No. 2. In a more preferred embodiment, the antibodies of the present invention bind to a polypeptide consisting of the residues s of Phe-230 to Asn-242 of SEQ ID No. 2. In additional and non-exclusive preferred embodiments, the antibodies of the present invention inhibit one or more biological activities of the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides of the present invention, by means of a specific union. In more preferred modes, the antibodies of the present invention inhibit the proliferation of B cells mediated by Neutrocin-alpha and / or Neutrocin-alphaSV. The antibodies of the present invention can also be described or specified in terms of their cross-reactivity. Antibodies that do not bind to any other analog, ortholog, or homologue of a polypeptide of the present invention are included. Antibodies that bind to polypeptides that have at least 95, at least 90, at least 85, at least 80, at least 75, at least 70, at least 65, at least 60, at least 55, and at least 50% identity (calculated using methods known in the art and described herein) to a polypeptide of the present invention, are also included in the present invention. In specific embodiments, the antibodies of the present invention cross-react with murine, rat and / or rabbit homologs, human proteins and corresponding epitopes thereof. Antibodies that do not bind polypeptides with less than 95, less than 90, less than 85, less than 80, less than 75, less than 70, less than 65, less than 60, less than 55, and less than 50% identity, (calculated using methods known in the art and described herein) to a polypeptide of the present invention, are also included in the present invention. In a specific embodiment, the cross-reactivity described above is with respect to any specific antigenic or immunogenic polypeptide, or combination of 2, 3, 4, 5 or more antigenic, or specific immunogenic polypeptides described herein. Also included in the present invention are antibodies that bind polypeptides encoded by polynucleotides that hybridize with a polynucleotide of the present invention, under hybridization conditions (as described herein). The antibodies of the present invention can also be described or specified in terms of their binding affinity to a polypeptide of the present invention. Preferred binding affinities include those with a dissociation constant or Kd less than 5 X 10 ~ 5 M, 10"5 M, 5 X 10" 6 M, 10"6 M, 5 X 10" 7 M, 10 ~ 7 M, 5 X 10"8 M, 10" 8 M, 5 X 10 ~ 9 M, 10 ~ 9 M, 5 X 10"10 M, 10" 10 M, 5 X 10"11 M, 10" 11 M, 5 X 10"12 M, 10"?; M, 5 X 10-13 M, 10-13 M, 5 X 10 ~ 14 M, 10"14 M, 5 X 10" 15 M, 10"15 M. The present invention also provides antibodies that competitively inhibit the binding of an antibody to an epitope of the present invention, which is determined by any method known in the art to determine competitive binding, eg, the immunoassays described herein In preferred embodiments, the antibody competitively inhibits epitope binding at minus 95, at least 90, at least 85, at least 80, at least 75, at least 70, at least 60 or when 50% Antibodies of the present invention may act as agonists or antagonists of the polypeptides of the present invention For example, the present invention includes antibodies that interrupt receptor / ligand interactions with the polypeptides of the present invention, either partially or completely, Preferably, the antibodies of the present invention binds n to an antigenic epitope described herein, or to a portion thereof. The present invention describes receptor-specific antibodies and ligand-specific antibodies. The present invention also discloses receptor-specific antibodies that do not prevent binding of the ligand but that prevent activation of the receptor. The activation of the receptor (i.e., signaling) can be determined by the techniques described herein or other techniques known in the art. For example, receptor activation can be determined by detecting the phosphorylation (eg, tyrosine or serine / threonine) of the receptor or its substrate, by immunoprecipitation, followed by a Western blot analysis (eg, as described above). In specific embodiments, antibodies are provided which inhibit ligand activity or receptor activity in at least 95, at least 90, at least 85, at least 80, at least 75, at least 70, at least SO, at least 50 % activity in the absence of the antibody.

The present invention also discloses receptor-specific antibodies that prevent ligand binding and receptor activation, as well as antibodies that recognize the receptor-ligand complex and, preferably, do not specifically recognize the unbound receptor or the unbound ligand. Similarly, neutralizing antibodies that bind to the ligand and prevent binding of the ligand to the receptor are included in the present invention, as well as antibodies that bind to the ligand, thus preventing the activation of the receptor, but do not prevent the ligand binds to the receptor. In addition, antibodies that activate the receptor are included in the invention. These antibodies can act as receptor agonists, i. and. , enhancing or activating all or a subset of biological activities of receptor activation mediated by the ligand, for example, by inducing receptor dimerization. The antibodies may be specific as agonists, antagonists or inverse agonists for the biological activities comprising the specific biological activities of the peptides of the invention described herein. The above antibody agonists can be prepared using methods known in the art. See e. g. , PCT International Publication WO 96/40281; U.S. Patent No. 5,811,097; Deng et al. , Blood 92 (6): 1981-1988 (1998); Chen et al., Cancer Res. 58 (16): 3668-3678 (1998); Harrop et al. , J. Immunol, 161 (4): 1786-1794 (1998); Zhu et al., Cancer Res. 58 (15): 3209-3214 (1998); Yoon et al. , J. Immunol. 160 (7): 3170-3179 (1998); Prat et al., J. Cell. Sci. 111 (pt2): 237-247 (1998); Pitard et al., J. Immunol. Methods 205 (2): 177-190 (1997); Liautard et al., Cytokine 9 (4): 233-241 (1997); Carlson et al. , J. Biol. Chem. 272 (17): 11295-11301 (1997); Taryman et al. , Neuron 14 (4): 755-762 (1995); Muller et al., Structure 6 (9): 1153-1167 (1998); Bartunek et al., Cytokine 8 (l): 14-20 (1996) (which are hereby incorporated by reference in their entirety). The antibodies of the present invention can be used, for example, but without limitation, to purify, detect and target the peptides of the present invention, including methods of diagnoand treatment in vivo and in vi tro. For example, antibodies have use in immunoassays to measure • qualitatively and quantitatively the concentration of the peptides of the present invention in biological samples.

See e. g. , Harlow et al. , Antibodies: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 2nd edition, 1988) (which is hereby incorporated by reference in its entirety.) As described in detail below, the antibodies of the present invention may be used alone or in combination with Other compositions The antibodies can additionally be fused recombinantly with a heterologous polypeptide at the N-terminal or C-terminal end, or they can be chemically conjugated (including covalent and non-covalent conjugations) with polypeptides or other compositions. antibodies of the present invention can be recombinantly fused or conjugated with molecules useful as markers for detection assays and effector molecules such as heterologous polypeptides, drugs, radionuclides or toxins, see, eg, PCT International Publications WO 92/08495; WO 91 / 14438; WO 89/12624; US Patent 5,314,995; and European Patent EP 396,387; The antibodies of the present invention include derivatives that are modified, i. and. , by covalent binding of any type of molecule to the antibody, in such a way that the covalent binding does not prevent the antibody from generating an anti-idiotypic response. For example, but not by way of limitation, antibody derivatives include antibodies that have been modified, e.g., by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivation by known protecting / blocking groups, proteolytic cleavage, binding to a cellular ligand or other protein, etc. Any of numerous chemical modifications known in the art can be carried out, including, but not limited to specific chemical breakdown, acetylation, formylation, metabolic synthesis of tunicamycin, etc. Additionally, the derivative may contain one or more non-classical amino acids. The antibodies of the present invention can be generated by any suitable method known in the art. Polyclonal antibodies against an antigen of interest can be produced by various methods known in the art. For example, a polypeptide of the present invention can be administered to several host animals, including but not limited to rabbits, mice, rats, etc., to induce the production of sera containing polyclonal antibodies specific for the antigen. It is possible to employ various adjuvants to increase the immune response, depending on the host species, and including but not limited to Freund's adjuvant (complete and incomplete), mineral gels such as aluminum hydroxide, surface-active substances such as lysolecithin, pluronic polyols , polyanions, peptides, emulsions in oil, limpet hemocyanin, dinitrophenol and potentially useful human adjuvants such as BCG (Bacillus Calmette-Guerin) and Corynebacterium parvum. Such adjuvants are also known in the art. Monoclonal antibodies can be prepared using a variety of techniques known in the art, including the use of hybridomas, recombinant and phage display technologies, or a combination thereof. For example, monoclonal antibodies can be produced using hybridoma techniques including those known in the art and taught, for example, in Harlow et al. , Antibodies: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 2nd edition, 1988); Hammerling, et al. , in: Monoclonal Antibodies and T-Cell Hybridomas, 563-681 (Elsevier, N.Y., 1981) (such references are incorporated herein, in their entirety, as references). The term "monoclonal antibody", as used herein, is not limited to antibodies produced by hybridoma technology. The term "monoclonal antibody" refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic or phage clone, and not the method by which it is produced. A "monoclonal antibody" may comprise or alternatively consist of, two proteins, i.e., a heavy chain and a light chain. Methods for producing and selecting specific antibodies using hybridoma technology are routine and known in the art and are described in detail in the Examples (e.g., Example 9). In a non-limiting example, mice can be immunized with a polypeptide of the present invention or a cell that expresses such a polypeptide. Once an immune response is detected, e.g., specific antibodies are detected against the antigen in the mouse serum, the spleen of the mouse is removed and the splenocytes are isolated. Then, the splenocytes are fused by known techniques, with any suitable myeloma cell, for example cells of the SP20 line available from the ATCC (North American Collection of Type Crops). Hybridomas are selected and cloned by limited dilution. Hybridoma clones are subsequently evaluated by methods known in the art for cells that secrete antibodies capable of binding to a polypeptide of the present invention. Ascitic fluid, which generally contains high concentrations of antibodies, can be generated by immunizing mice with positive hybridoma clones. In accordance with the foregoing, the present invention provides methods for generating monoclonal antibodies as well as antibodies produced by the method comprising culturing a hybridoma cell secreting an antibody of the present invention wherein, preferably, the hybridoma is generated by fusing isolated splenocytes of a mouse immunized with an antigen of the present invention, with myeloma cells and then selecting the hybridomas resulting from the fusion of the hybridoma clones that secrete an antibody capable of binding to a polypeptide of the present invention. Antibody fragments that recognize specific epitopes can be generated by known techniques. For example, the Fab and F (ab ') 2 fragments of the present invention can be produced by proteolytic cleavage of immunoglobulin molecules, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F (ab) fragments. ')2). The fragments of F (ab ') 2 contain the variable region, the constant region of the light chain and the CH1 domain of the heavy chain. For example, the antibodies of the present invention can also be generated using various phage display methods known in the art. In phage display methods, functional antibody domains are displayed on the surface of the phages that carry the polynucleotide sequences encoding them. In a particular embodiment, these phages can be used to display antigen-binding domains expressed in a repertoire or in a library of combination antibodies (e.g., human or murine). Phages that express an antigen-binding domain that binds to the antigen of interest can be selected or identified with the antigen, e.g., by using a labeled antigen or an antigen bound or captured on a solid surface or on an account. The phages used in these methods are typically filamentous phages that include the fd and M13 binding domains expressed on the phage with the Fab, Fv or Fv antibody domains stabilized with disulfide bridges fused recombinantly to any protein of gene III or VIII gene of the phage. Examples of phage display methods can be used to prepare the antibodies of the present invention, including those described in Brinkman et al., J. Immunol. Methods 182: 41-50 (1995); Ames et al. , J. Immunol. Methods 184: 177-186 (1995); Kettleborough et al. , Eur. J. Immunol. 24: 952-958 (1994); Persic et al., Gene 187 9-18 (1997); Burton et al., Advances in Immunology 57: 191-280 (1994); PCT Application No. PCT / GB91 / 01134; PCT International Publications WO 90/02809; WO 91/10737; WO 92/01047; WO 92/18619; WO 93/11236; WO 95/15982; WO 95/20401; and U.S. Patent Nos. 5,698,426; 5,223,409; 5,403,484; 5,580,717; 5,427,908; 5,750,753; 5,821,047; 5,571,698; ,427,908; 5,516,637; 5,780,225; 5,658,727; 5,733,743 and 5,969,108; each of which is incorporated herein, in its entirety, as a reference. As described in the above references, after selecting the phage, the coding regions of the antibody from the phage can be isolated and used to generate complete antibodies, including human antibodies or any other desired antigen-binding fragment, and can be expressed in any desired host, including mammalian cells, insect cells, plant cells, yeast and bacteria, eg, as described in detail below. For example, techniques for recombinantly producing Fab, Fab 'and F (ab') 2 fragments can also be employed using methods known in the art, such as those described in PCT International Publication WO 92/22324; Mullinax et al., BioTechniques 12 (6): 864-869 (1992); and Sawai et al., AJRI 34: 26-34 (1995); and Better et al., Science 240: 1041-1043 (1988) (such references are incorporated herein by reference in their entirety). Examples of techniques that can be used to produce single chain Fvs and antibodies, include those described in US Patents 4,946,778 and 5,258,498; Huston et al., Methods in Enzymology 203: 46-88 (1991); Shu et al., PNAS 90: 7995-7999 (1993) and Skerra et al., Science 240: 1038-1040 (1988). For some uses, including the in vivo use of antibodies in humans and in vitro detection assays, it may be preferable to use chimeric, humanized or human antibodies. A chimeric antibody is a molecule in which different portions of the antibody are derived from different animal species, such as antibodies having a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region. Methods for producing chimeric antibodies are known in the art. See e.g., Morrison, Science 229: 1202 (1985); Oi et al., BioTechinques 4: 214 (1986); Gillies et ai. (1989) J. Immunol. Methods 125: 191-202; U.S. Patent Nos. 5,807,715; 4,816,567 and 4,816,397; which are incorporated herein, in their entirety, as a reference. Humanized antibodies are antibody molecules from a non-human species, which bind to the desired antigen having one or more complementary determining regions (CDRs) from a non-human species and a framework region from a human immunoglobulin molecule. . Often, framework residues in the human framework regions will be replaced by the corresponding residues of the donor CDR antibody to alter, preferably, enhance antigen binding. These frame substitutions are identified by methods known in the art, eg, by modeling interactions of the CDR and frame residues, to identify framework residues important for antigen binding, and sequence comparison to identify unusual framework residues in particular positions (see, eg, Queen et al., US Pat. No. 5,585,089, Riechmann et al., Nature 332: 323 (1988), which are incorporated herein in their entirety, by way of reference.) Antibodies can be humanized using a variety of techniques known in the art, including, for example, CDR grafts (European Patent EP 239,400; PCT International Publication WO 91/09967; US Patents 5,225,539; 5,530,101 and 5,585,089), surface coating or resurfacing ( European Patents EP 592,106; 519,596; Padlan, Molecular Immunology 28 (4/5): 489-498 (1991); Studnicka et al., Protein Engineering 7 (6): 805-814 (1994); ska et al., PNAS 91: 969-973 (1994)) and chain drag (US Patent 5,565,332). Fully human antibodies are particularly desirable for the treatment of human patients. Human antibodies can be prepared by a variety of methods known in the art, including the phage display methods described above, using libraries of antibodies derived from human immunoglobulin sequences. See also U.S. Patent Nos. 4,444,887 and 4,716.11 and PCT International Publications WO 98/46645, WO 98/50433, WO 98/24893, WO 98/16654, WO 96/34096, WO 96/33735 and WO 91/10741.; each of which are incorporated herein, in their entirety, as a reference. Human antibodies can also be produced using transgenic mice that are unable to express functional endogenous immunoglobulins, but which can express human immunoglobulin genes. For example, the human immunoglobulin heavy and light chain gene complexes can be introduced randomly or by homologous recombination into murine embryonic stem cells. Alternatively, the human variable region, the constant region and the diversity region can be introduced into murine embryonic stem cells, in addition to the human heavy and light chain genes. The heavy and light chain genes of mouse immunoglobulins can become non-functional separately or simultaneously with the introduction of human immunoglobulin loci by homologous recombination. In particular, the homozygous deletion of the JH region prevents the endogenous production of antibodies. Modified embryonic stem cells expand and are microinjected into blastocysts to produce chimeric mice. The chimeric mice are subsequently bred to produce homozygous offspring that express human antibodies. Transgenic mice are immunized in the normal manner with a selected antigen, e.g., all or a portion of a polypeptide of the present invention. Monoclonal antibodies directed against the antigen can be obtained from immunized transgenic mice, using conventional hybridoma technology. The human immunoglobulin transgenes carried by the transgenic mice rearrange during the differentiation of B cells and subsequently undergo a class change and somatic mutation. Thus, using such a technique, it is possible to produce therapeutically useful IgG, IgA, IgM and IgE antibodies. For a more extensive review of this technology, for the production of human antibodies, see Lonberg and Huszar, Int. Rev. Immunol. 13: 65-93 (1995). For a detailed description of this technology for producing human antibodies and human monoclonal antibodies, and protocols for producing such antibodies, see e.g., PCT International Publications WO 9J / 24893; WO 92/01047; WO 96/34096; WO 96/33735; European Patent EP 0,598,877; US Patents US - 3 - ,413,923; 5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318; 5,885,793; 5,916,771 and 5,939,598, which are incorporated herein by reference in their entirety. In addition, companies such as Abgenix, Inc. (Freemont, CA) and Genpharm (San Jose, CA) can be used to produce human antibodies directed against a selected antigen, employing technologies similar to those described above. Fully human antibodies that recognize a selected epitope can be generated using a technique called "guided selection". In this approach, a selected non-human monoclonal antibody, eg, a murine antibody, is used to guide the selection of a fully human antibody that recognizes the same epitope (Jespers et al., Bio / technology 12: 899-903 (1988)). ). In addition, other antibodies against the polypeptides of the present invention can be used to generate anti-idiotypic antibodies that "mimic" the polypeptides of the present invention, employing techniques known to those skilled in the art (see, eg, Greenspan and Bona, FASEB J. 7 (5): 437-444 (1989), and Nissinoff, J. Immunol. 147 (8): 2429-2438 (1991)). For example, antibodies that bind to and competitively inhibit multimerization and / or binding of a polypeptide of the present invention to a ligand, can be used to generate anti-idiotypic antibodies that "mimic" the multimerization and / or binding domain of the polypeptide and , as a consequence, they bind to, and neutralize the polypeptide and / or its ligand. Such neutralizing anti-idiotypic antibodies or Fab fragments of such anti-idiotypic antibodies can be used in therapeutic regimens to neutralize the polypeptide ligand. For example, such anti-idiotypic antibodies can be used to bind to a polypeptide of the present invention and / or bind to its ligands / receptors and, thus, block its biological activity. Polynucleotides Encoding Antibodies The present invention further provides polynucleotides comprising a nucleotide sequence encoding an antibody of the present invention and fragments thereof. The present invention also encompasses polynucleotides that hybridize under stringent or less stringent conditions, eg, as defined supra, with polynucleotides that encode an antibody, preferably that binds specifically to a polypeptide of the present invention, preferably an antibody that it binds to a polypeptide having the amino acid sequence of SEQ ID No. 2. In another preferred embodiment, the antibody specifically binds to a polypeptide having the amino acid sequence of SEQ ID No. 19. In another preferred embodiment , the antibody binds specifically to a polypeptide having the amino acid sequence of SEQ ID No. 23. In another preferred embodiment, the antibody specifically binds to a polypeptide having the amino acid sequence of SEQ ID No. 28. In another preferred embodiment, the antibody specifically binds to a polypeptide having the amino acid sequence of SEQ ID No. 30. containing polynucleotides and the nucleotide sequence of determined polynucleotides, by any method known in the art. For example, if the nucleotide sequence of the antibody is known, a polynucleotide encoding the antibody can be assembled from chemically synthesized oligonucleotides (eg, in the manner described in Jutmeier et al., BioTechniques 17: 242 (1994)). , which, briefly, includes the synthesis of overlapping oligonucleotides containing portions of the antibody coding sequence, these oligonucleotides are paired and ligated and then an amplification of the ligated oligonucleotides is performed, by PCR. Alternatively, a polynucleotide encoding an antibody can be generated from a nucleic acid from a suitable source. Yes - - a clone containing a nucleic acid encoding a particular antibody is not available, but the sequence of the antibody molecule is known, a nucleic acid encoding the immunoglobulin can be chemically synthesized or can be obtained from a suitable source (eg, an antibody cDNA library or a cDNA library generated at from them or from nucleic acids, preferably poly A + RNA, from any isolated cell or tissue expressing the antibody, such as hybridoma cells selected to express an antibody of the present invention) by PCR amplification, using primers synthetics that hybridize to the 3 'and 5' ends of the sequence, or by cloning using an oligonucleotide probe specific for the particular gene sequence to be identified, eg, a cDNA clone from a cDNA library encoding the antibody . The amplified nucleic acids generated by PCR, thereafter, can be cloned into replicable cloning vectors, using any method known in the art. Once the nucleotide sequence and the corresponding amino acid sequence of the antibody are determined, the nucleotide sequence of the antibody can be manipulated using methods known in the art for the manipulation of nucleotide sequences, eg, recombinant DNA techniques. , site-directed mutagenesis, RCP, etc. (see, for example, the techniques described in Sambrook et al., Molecular Cloning: A Laboratory Manual 2nd edition, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY and Ausubel et al., eds 1998, Current Protocols in Molecular Biology, John Wiley &; Sons, NY, which are incorporated herein in their entirety, as a reference), to generate antibodies having a different amino acid sequence, for example to create substitutions, deletions and / or amino acid insertions. In a specific embodiment, the amino acid sequence of the variable domains of the heavy chain and / or of the light chain can be inspected to identify the sequences of the complementarity determining regions (CDRs), by methods that are known in the art. , eg, by a comparison with known amino acid sequences from other heavy and light chain variable regions, to determine regions of sequence hypervariability. Using routine recombinant DNA techniques, one or more CDRs can be inserted into the framework regions, e.g., in human framework regions to humanize a non-human antibody, in the manner described above. Frame regions - may be of natural origin or may be consensual framework regions and preferably human frame regions (See e.g., Chothia et al., J. Mol. Biol. 278: 457-479. (1988) to obtain a list of human frame regions). Preferably, the polynucleotide generated by the combination of the framework regions and the CDRs codes for an antibody that specifically binds to a polypeptide of the present invention. Preferably, as described supra, one or more amino acid substitutions can be made in the framework regions and, preferably, the amino acid substitutions improve the binding of the antibody with its antigen. Additionally, such methods can be used to make substitutions or deletions of amino acids from one or more cysteine residues of the variable region that participate in intrachain disulfide bonds, to generate antibody molecules lacking one or more intrachain chain disulfide bridges. Other alterations to the polynucleotides are encompassed by the present invention and are within the skill of those skilled in the art. In addition, the techniques developed for the production of "chimeric antibodies" can be used (Morrison et al., Proc. Nati, Acad. Sci. 81-855 (1984); Neuberger et al. , Nature 312_604-608 (1984); Takeda et al. , Nature 314: 452-454 (1985)) by splicing genes - from a murine antibody molecule with an appropriate antigen specificity, together with genes from a human antibody molecule with an appropriate biological activity. As described supra, a chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region, e.g., humanized antibodies. Alternatively, the techniques described for the production of single chain antibodies (Patent North American US 4,946,778; Bird, Science 242: 423-42 (1988); and Ward et al., Nature 334: 544-54 (1989)) can be adapted to produce single chain antibodies. The single chain antibodies are formed by binding the heavy and light chain fragments of the Fv region through an amino acid bridge, resulting in a single chain polypeptide. Techniques for the assembly of functional Fv fragments in E. coli can also be used (Skerra et al., Science 242: 1038-1041 (1988)). Methods for Producing Antibodies The antibodies of the present invention can be produced by any method known in the art, in particular by chemical synthesis or preferably by recombinant expression techniques. The recombinant expression of an antibody of the present invention, or fragment, derivative or analogue thereof (eg, a heavy or light chain of an antibody of the present invention or a single chain antibody of the present invention), requires the construction of an expression vector that contains a polynucleotide that codes for the antibody. Once a polynucleotide encoding an antibody molecule or a heavy or light chain of an antibody or a portion thereof (preferably containing the variable domain of the heavy or light chains) of the present invention has been obtained, the vector can be produced for the production of the antibody molecule by recombinant DNA technology, using techniques known in the art. Thus, methods for preparing a protein by expression of a polynucleotide containing a nucleotide sequence encoding an antibody are described herein. Methods that are known to those skilled in the art can be used to construct expression vectors containing appropriate antibody coding sequences and transcription and translation control signals. These methods include, for example, recombinant DNA techniques, synthetic techniques and genetic recombination in vivo. The present invention, therefore, provides replicable vectors comprising a nucleotide sequence encoding an antibody molecule of the present invention or a heavy or light chain thereof, or a heavy or light chain variable domain, operably linked to a promoter . Such vectors can include the nucleotide sequence coding for constant region of the antibody molecule (see e.g., PCT International Publication WO 86/05807; PCT International Publication WO 89/01036 and US Patent 5,122,464) and the variable domain of the antibody can be cloned into such vectors, for the expression of the complete heavy or light chain. The expression vector is transferred to a host cell by conventional techniques and the transfected cells are subsequently cultured by conventional techniques, to produce an antibody of the present invention. Thus, the present invention includes host cells that contain a polynucleotide encoding an antibody of the present invention or a heavy or light chain thereof or a single chain antibody of the present invention, operably linked to a heterologous promoter. In preferred embodiments for the expression of double-chain antibodies, the vectors encoding the heavy and light chains can be coexpressed in the host cell for the expression of the complete immunoglobulin molecule, as described below. A variety of host expression vector systems can be used to express the antibody molecules of the present invention. Such host expression systems represent vehicles by which the coding sequences of interest can be produced and subsequently purified, but also represent cells that when transformed or transfected with the appropriate nucleotide coding sequences, express an antibody molecule of the present invention. in if you These include, but are not limited to, microorganisms such as bacteria (e.g., E. coli, B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA, or cosmid DNA expression vectors containing antibody coding sequences; yeasts (e.g., Saccharomyces, Pichia) transformed with expression vectors in recombinant yeast containing antibody coding sequences; insect cell systems infected with recombinant viral expression vectors (e.g., baculoviruses) containing the antibody coding sequences; plant cell systems infected with recombinant viral expression vectors (eg, cauliflower mosaic virus, CaMV, tobacco mosaic virus, TMV) or transformed with plasmid expression vectors (eg, Ti plasmid) containing coding sequences of the antibody; or mammalian cell systems (eg, COS, CHO, BHK, 293, 3T3) carrying recombinant expression constructs containing promoters derived from the mammalian cell genome (e.g., the metallothionein promoter) or from human mammals (eg, the late adenovirus promoter, the vaccinia virus 7.5K promoter). Preferably, bacterial cells such as Escherichia coli are used and more preferably eukaryotic cells, especially for the expression of the complete recombinant antibody molecule, for the expression of a recombinant antibody molecule. For example, mammalian cells such as Chinese Hamster Ovary (CHO) cells, in conjunction with a vector such as the promoter element of the early major intermediate gene of human cytomegalovirus, is an effective expression system for antibodies (Foecking et al. ., Gene 45: 101 (1986); Cockett et al., BioTechnology 8: 2 (1990)). In bacterial systems, a number of expression vectors can advantageously be selected, depending on the intended use of the antibody molecule being expressed. For example, when a large amount of such a protein is to be produced, for the generation of pharmaceutical compositions of an antibody molecule, vectors that direct the expression of high levels of fusion protein products that are easily purified may be desirable. Such vectors include, but are not limited to, the E. coli expression vector pUR278 (Ruther et al., EMBO J. 2: 1791 (1983)), in which the antibody coding sequence can be ligated individually into the vector, in the frame with the lac Z coding region, to produce a fusion protein; pIN vectors (Inouye &Inouye, Nucleic Acids Res. 13: 3101-3109 (1985); Van Heeke &Schuster, J. Biol. Chem. 24: 5501-5509 (1989)); and similar. PGEX can also be used to express foreign polypeptides in the form of fusion proteins with glutathione S-transferase (GST). In general, such fusion proteins are soluble and can be easily purified from the lysed cells, by absorption and binding to an array of glutathione-agarose beads, followed by an elution in the presence of free glutathione. The pGEX vectors are designed to include thrombin or factor Xa protease cleavage sites, such that the cloned white gene product can be released from the GST portion. In an insect system, the virus is used - Autographa californica nuclear polyhedrosis (AcNPV) as a vector to express foreign genes. The virus grows in Spodoptera frugiperda cells. The antibody coding sequence can be cloned individually into non-essential regions (eg, the polyhedrin gene) of the virus and can be placed under the control of the AcNPV promoter (eg, the polyhedrin promoter). In mammalian host cells, a number of virus-based expression systems can be employed. In cases where an adenovirus is used as an expression vector. The coding sequence of the antibody of interest can be ligated to a transcription / translation control complex, e.g., the late promoter and the tripartite leader sequence. This chimeric gene can subsequently be inserted into the adenovirus genome by in vitro or in vivo recombination. Insertion into a non-essential region of the viral genome (eg, the El region or E3) will result in a recombinant virus that is viable and capable of expressing the antibody molecule in infected hosts (eg, see Logan and Shenk, Proc. Nati, Acad Sci. USA 81: 355-359 (1984) ) . Specific initiation signals may also be required for the efficient translation of the inserted antibody coding sequences. These signals - - include the ATG start codon and adjacent sequences. In addition, the initiation codon must be in phase with the reading frame of the desired coding sequence, to ensure translation of the complete insert. These exogenous signals of translation control and initiation codons can be from a variety of origins, both natural and synthetic. The efficiency of expression can be increased by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (See Bittner et al., Methods in Enzymol, 153: 51-544 (1987)). In addition, a host cell strain can be selected that modulates the expression of the inserted sequences or modifies and processes the gene product in the specific manner desired. Such modifications (e.g., glycosylation) and processing (e.g., disruption) of protein products may be important for the production of the protein. Different host cells have specific characteristics and mechanisms for processing and post-translational modification of proteins and gene products. Appropriate cell lines or host systems can be selected to ensure correct modification and processing of the expressed foreign protein. For this purpose, eukaryotic host cells possessing the cellular machinery can be used for the appropriate processing of the primary transcript, glycosylation and phosphorylation of the gene product. Such mammalian host cells include, but are not limited to, CHO, VERY, BHK, HeLa, COS, MDCK, 293, 3T3, WI38 and in particular, breast cancer cell lines such as BT483, Hs578T, HTB2, BT20 and T47D and a line of normal mammary gland cells such as for example CRL7030 and Hs578Bst. For the long-term high yield production of recombinant proteins, stable expression is preferred. For example, cell lines that stably express the antibody molecule can be engineered. Rather than using expression vectors containing viral origins of replication, host cells can be transformed with DNA controlled by appropriate expression control elements (eg, promoters, enhancers, sequences, transcription terminators, polyadenylation sites, etc.) and a selectable marker After the introduction of the foreign DNA, the manipulated cells can be grown for 1 or 2 days in an enriched medium and then can be changed to a selective medium. The selectable marker in the recombinant plasmid confers resistance to the selection and allows the cells to stably integrate the plasmid into its chromosome and - - grow to form foci which, in turn, can be cloned and expanded into cell lines . This method can advantageously be used to genetically engineer cell lines that express the antibody molecule. Such manipulated cell lines can be particularly useful for the selection and evaluation of compounds that interact directly or indirectly with the antibody molecule. A selection system number can be used, including but not limited to the herpes simplex virus thymidine kinase genes (Wigler et al., Cell 11: 223 (1977), hypoxanthine-guanine phosphoribosyl transferase (Szybalska and Szybalski, Proc. Nati, Acad. Sci. USA 48: 202 (1992)) and adenine phosphoribosyltransferase (Lowy et al., Cell 22: 817 (1980)) in tk-, hgprt- or aprt- cells, respectively. use antimetabolite resistance as a basis for selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler et al., Nati Acad Sci USA 77: 357 (1980); O'Hare et al., Proc. Nati, Acad. Sci. USA 78: 1527 (1981)); gpt, which confers resistance to mycophenolic acid (Mulligan and Berg, Proc. Nati, Acad. Sci. USA 78: 2072 (1981)); neo, which confers resistance to the aminoglycoside G-418 (Clinical Pharmacy 12: 488-505; Wu and Wu, Biotherapy 3: 87-95 (1991); Tolstoshev, Ann. Rev.

- - Pharmacol. Toxicol 32: 573-596 (1993); Mulligan, Science 260: 926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem. 62: 191-217 (1993); May 1993, TIB TECH 11 (5): 155-215); and hygro, which confers resistance to hygromycin (Santerre et al., Gene 30: 147 (1984)). Methods commonly known in recombinant 7DNA technology can be routinely applied to select the desired recombinant clone and such methods are described, for example, in Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993); Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990); and in Chapters 12 and 13, Dracopoli et al. (eds.) Current Protocols in Human Genetics, John Wiley & Sons, NY (1994); Colberre-Garapin et al., J. Mol. Biol. 150: 1 (1981), which are incorporated, in their entirety, as a reference. The expression levels of an antibody molecule can be increased by amplification with vectors (for a review, see Bebbington and Hentschel, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, Vol. 3 (Academic Press, New York, 1987)). When a marker in the vector system expressing an antibody is amplifiable, an increase in the level of the inhibitor present in the culture of the host cell will increase the copy number of the marker gene. Since the amplified region is associated with the antibody gene, the production of the antibody will also increase (Crouse et al., Mol.Cell. Biol. 3: 257 (1983)). The host cell can be cotransfected with two expression vectors of the present invention, wherein the first vector encodes a heavy chain derived from the polypeptide and the second vector encodes a light chain derived from the polypeptide. The two vectors may contain identical selectable markers that make possible an equal expression of the heavy chain and light chain polypeptides. Alternatively, a single vector encoding and capable of expressing both heavy and light chain polypeptides can be used. In such situations, the light chain can be placed before the heavy chain to avoid an excess of toxic free heavy chain (Proudfoot, Nature 322: 52 (1986); Kohier, Proc. Nati. Acad. Sci. USA 77: 2197 ( 1980)). The coding sequences of the heavy and light chains can comprise cDNA or genomic DNA. Once an antibody molecule of the present invention has been produced by an animal, has been chemically synthesized or recombinantly expressed, it can be purified by any method known in the art 1 for the purification of immunoglobulin molecules, for example by chromatography (eg, ion exchange, affinity chromatography, particularly by affinity for the specific antigen after Protein A, and column chromatography by size), centrifugation, differential solubility or by any other standard technique for protein purification. In addition, the antibodies of the present invention or fragments thereof can be fused with heterologous polypeptide sequences described herein or others known in the art, to facilitate purification. The present invention encompasses recombinantly fused or chemically conjugated antibodies (including covalent and non-covalent conjugates) to a polypeptide (or portion thereof, preferably at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 amino acids of the polypeptide) of the present invention, to generate fusion proteins. The merger does not necessarily have to be direct, but it can happen through linker sequences. The antibodies may be specific for antigens other than the polypeptides of the present invention (or portions thereof, preferably at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 amino acids of the polypeptide) of the present invention. For example, antibodies can be used to target the polypeptides of the present invention toward particular cell types, either in vi tro or in vi ve, by fusing or conjugating the polypeptides of the present invention with specific antibodies against surface receptors. cellular phones. Antibodies fused or conjugated to the polypeptides of the present invention can also be used in in vitro immunoassays and purification methods, employing methods known in the art. See e.g., Harbor et al., Supra and PCT International Publication WO 93/212232.; European Patent EP 439,095; Naramura et al. , Immunol. Lett. 39: 91-99 (1994); U.S. Patent No. 5,474,981; Gillies et al. , PNAS 89: 1428-1432 (1992); Fell et al., J. Immunol. 146: 2446-2452 (1991), which are incorporated herein by reference in their entirety. The present invention further includes compositions comprising the polypeptides of the present invention fused or conjugated with antibody domains other than the variable regions. For example, the polypeptides of the present invention can be fused or conjugated to an antibody Fc region or a portion thereof. The antibody portion fused to a polypeptide of the present invention may comprise the constant region, the hinge region, the CH1 domain, the CH2 domain and the CH3 domain, or any combination of whole domains or portions thereof. The polypeptides can also be fused or conjugated with the above antibody portions to form multimers. For example, Fc portions fused to the polypeptides of the present invention can form dimers through disulfide bridges between the Fc portions. Higher multimerics can be prepared by fusing the polypeptides with portions of IgA and IgM. Methods for fusion or conjugation of the polypeptides of the present invention with portions of antibodies are known in the art. See, e.g., U.S. Patent Nos. 5,336,603; 5,622,929; 5,359,046; 5,349,053; 5,447,851 and 5,112,946; European Patents EP 307,434 and 367,166; PCT International Publications WO 96/04388 and WO 91/06570; Ashkenazi et al., Proc. Nati Acad. Sci. USA 88: 10535-10539 (1991); Zheng et al. , J. Immunol. 154: 5590-5600 (1995); and Vil et al. , Proc. Nati Acad. Sci. USA 89: 11337-11341 (1992) (these references are incorporated herein by reference in their entirety). As described supra, polypeptides corresponding to a polypeptide, polypeptide fragment or variant of SEQ ID No. 2, can be fused or conjugated with the aforementioned antibody portions, to increase the in vivo half-life of the polypeptides - - or for use in immunoassays by methods known in the art. In addition, the polypeptides corresponding to SEQ ID No. 2 can be fused or conjugated with the aforementioned antibody portions, to facilitate purification. Also as described supra, polypeptides corresponding to a polypeptide, polypeptide fragment or variant of SEQ ID No. 19, can be fused or conjugated with the aforementioned antibody portions, to increase the in vivo half-life of the polypeptides or for use in immunoassays by methods known in the art. In addition, the polypeptides corresponding to SEQ ID No. 19 can be fused or conjugated with the aforementioned antibody portions, to facilitate purification. One reported example describes chimeric proteins consisting of the first two domains of the human CD4 polypeptide and several domains of the constant regions of the heavy or light chains of mammalian immunoglobulins (European Patent EP 394,827; Traunecker et al., Nature 331: 84- 86 (1988)). Polypeptides of the present invention fused or conjugated with an antibody having dimeric structures linked by disulfide bridges (due to IgG), may also be more efficient to bind and neutralize other molecules, as compared to secreted 1-monomeric protein or a single protein fragment (Fountoulakis et al., J. Biochem 270: 3958-3964 (1995)). in many cases, the Fc part in a fusion protein is beneficial and in therapy and diagnosis and, therefore, may result, for example, better pharmacokinetic properties (European Patent EP A 232,262). Alternatively, deletion of the Fc part after the fusion protein has been expressed, detected and purified would be desirable. For example, the Fc portion can prevent therapy and diagnosis if the fusion protein is used as an antigen for immunizations. In drug discovery, for example, human proteins such as hIL-5 have been fused with Fc portions for the purpose of high throughput screening assays to identify hIL-5 antagonists (see Bennett et al., J. Molecular Recognition 8: 52-58 (1995); Johanson et al. , J. Biol. Chem. 270: 9459-9471 (1995). In addition, the antibodies or fragments thereof of the present invention can be fused with marker sequences such as a peptide to facilitate purification. In preferred mode, the amino acid sequence of the tag is a hexahistidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, CA, 91311), among others, many of which are available on trade. As described in Gentz et al. , Proc. Nati Acad. Sci. USA 86: 821-824 (1989), for example, hexahistidine provides convenient purification of the fusion protein. Other useful peptide tags for purification include, but are not limited to, the "HA" tag which corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., Cell 37: 767 (1984)) and the mark "flag" The present invention also includes antibodies or fragments thereof conjugated with a diagnostic or therapeutic agent. Antibodies can be used diagnostically, for example, to monitor the development or progress of a tumor as part of a clinical testing procedure, for example to determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling the antibody with a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radioactive materials, positron emitting materials that utilize various positron emission tomographies and non-radioactive paramagnetic metal ions. The detectable substance can be coupled or conjugated, either directly to the antibody (or fragment thereof), or else indirectly through an intermediary (such as, for example, a linker known in the art), employing the techniques known in this art. countryside. See, for example, US Pat. No. 4,741,900 for information on metal ions that can be conjugated for use as diagnostic reagents in accordance with the present invention. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin / biotin and avidin / biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinyl amine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin and aequorin; and examples of suitable radioactive materials include 125 I, 131 I, ll x In or 99 Tc. In addition, an antibody or fragment thereof can be conjugated to a therapeutic moiety such as a cytotoxin, e.g., a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha emitters such as 213Bi. A cytotoxin or cytotoxic agent includes any agent that is harmful to the cells. Some examples include paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracenedione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine , tetracaine, lidocaine, propranolol and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites (eg, methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil-decarbazine), alkylating agents (eg, mechlorethamine, chlorambucilothioepa, melphalan, carmustine (BSNU) and lomustine ( CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C and cis-dichlorodiamine platinum (II) (DDP), cis-platinum), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin and anthramycin (AMC)), and antimitosis agents (e.g., vincristine and vinblastine). The conjugates of the present invention can be used to modify a given biological response, wherein the therapeutic agent or drug portion should not be considered as limited to the classical chemical therapeutic agents. For example, the drug portion can be a protein or polypeptide having a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin or diphtheria toxin.; a protein such as tumor necrosis factor, alpha-interferon, beta-interferon, neural growth factor, platelet-derived growth factor, tissue plasminogen activator, an apoptotic agent, eg, TNF-alpha, TNF-beta, AIM I (see International Publication WO 97/33899), AIM II (see International Publication WO 97/34911), Ligand Fas (Takahashi et al., Jn. Immunol., 6: 1567-1574 (1994)), VEGI ( see International Publication WO 99/23105), Ligand CD40, a thrombotic agent or an angiogenic agent, eg, angiostatin or endostatin; or biological response modifiers such as for example lymphokines, interleukin-1 ("IL-1"), interleukin-2 ("IL-2"), interleukin-6 ("IL-6"), granulocyte colony stimulating factor macrophages ("FEC-GM"), granulocyte colony-stimulating factor ("FEC-G"), or other growth factors. The antibodies can also be attached to solid supports, which are particularly useful for immunoassays or purification of the target antigen. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene. Techniques for conjugating such therapeutic moieties with antibodies are well known, see e.g., Arnon et al. "Monoclonal Antibodies for Immunotargeting of Drugs in Cancer Therapy", in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al. , "Antibodies for Drug Delivery", in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review", in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et ai. (eds.), pp. 475-506 (1985); Analysis Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody in Cancer Therapy ", in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., "The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates", Immunol. Rev. 62: 119-58 (1982). Alternatively, an antibody can be conjugated to a second antibody to form a heteroconjugate antibody, in the manner described by Segal in U.S. Patent No. 4,676,980, which is incorporated herein by reference in its entirety.

- - An antibody, with or without a therapeutic portion conjugated thereto, administered alone or in combination with cytotoxic factors and / or cytokines, can be used as a therapeutic agent. Immunophenotyping The antibodies of the present invention can be used for the immunophenotyping of cell lines and biological samples. The translation product of the gene of the present invention may be useful as a specific marker of cells or more specifically, as a cellular marker that is differentially expressed in several stages of differentiation and / or maturation of particular types of cells. Monoclonal antibodies directed against a specific epitope, or against a combination of epitopes, will allow the selection of cell populations that express the marker. Various techniques can be employed using monoclonal antibodies to select cell populations expressing the marker (s), and include magnetic separation using magnetic beads coated with the antibody, "immersion" with the antibody bound to a solid matrix (ie, a plate) and cytometry of flow (see eg, U.S. Patent No. 5,985,660 and Morrison et al., Cell, 96: 131-49 (1999)). These techniques allow the selection of particular populations of cells, which could be found in malignant haematological diseases (ie minimal residual disease (MRE) in patients with acute leukemia) and "non-self" cells in transplants, to prevent graft disease. versus-guest (EIVH). Alternatively, these techniques allow the selection of the hematopoietic branch and progenitor cells capable of undergoing proliferation and / or differentiation, as could be found in the blood of the human umbilical cord. Antibody Binding Assays The antibodies of the present invention can be tested for immunospecific binding, by any method known in the art. Immunoassays that may be used include, but are not limited to, competitive and non-competitive assay systems employing techniques such as Western blot, radioimmunoassays, ELISA (enzyme-linked immunosorbent assay), sandwich immunoassays, immunoprecipitation assays, precipitin reactions, precipitin reactions by gel diffusion, immunodiffusion assays, agglutination assays, complement fixation assays, immunoradiometric assays, fluorescent immunoassays, immunoassays with protein A, or to name a few. Such assays are routine and known in the art (see, eg, Ausubel et al., Eds. 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley &Sons, Inc., New York, which is incorporated in the present in its entirety as a reference Some exemplary immunoassays are briefly described below (but are not intended to be limiting). Immunoprecipitation protocols generally comprise lysing a population of cells in a lysis buffer, such as RIPA regulatory solution (NP-). 40 to 1% or Triton X-100, 1% sodium deoxycholate, 0.1% SDS, 0.15M NaCl, 0.01M sodium phosphate at pH 7.2, 1% Trasylol) supplemented with protein phosphatase and / or protease inhibitors (eg, AEDT, PMSF, aprotinin, sodium vanadate), adding the antibody of interest to the cell lysate, incubating for a period of time (eg, 1-4 hours) at 4 ° C, adding protein A and / or sepharose beads with G protein to the cell lysate, incubating for approximately one hour or more at 4 ° C, washing the beads with the lysis buffer and resuspending accounts in a regulatory solution with SDS / sample. The ability of the antibody of interest to immunoprecipitate a particular antigen can be assessed, for example, by western blot analysis. A person skilled in the art would know the parameters that can be modified to increase the binding of the antibody to an antigen and decrease background phenomena (e.g., previously clarify the cell lysate with sepharose beads). For further description regarding the immunoprecipitation protocols, see e.g., Ausubel et al., Eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & amp;; Sons, Inc. New York on 10.16.1. Western blot analysis generally involves preparing the protein sample, electrophoresing the protein sample on a polyacrylamide gel (eg, 8-20% SDS-SDA, depending on the molecular weight of the antigen), transferring the protein sample of the polyacrylamide gel to a membrane such as a nitrocellulose membrane, PVDF or nylon, block the membrane with blocking solution (eg, PBS with 3% ASB (Bovine Serum Albumin) in skimmed milk), wash the membrane with washing buffer (eg, PBS-Tween 20), block the membrane with a primary antibody (the antibody of interest) diluted with blocking buffer, wash the membrane with wash buffer, block the membrane with a secondary antibody ( which recognizes the primary antibody, eg, an anti-human antibody) conjugated to an enzyme substrate (eg, horseradish peroxidase or alkaline phosphatase) or a Lécula - - Radioactive (e.g. 32P or 125I) diluted with blocking buffer, wash the membrane with wash buffer and detect the presence of the antigen. A person skilled in the art would know which parameters can be modified to detect the detected signal and reduce the background noise. For further description with respect to Western blot protocols, see e.g., Ausubel et al., Eds. 1994. Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York on 10.8.1. ELISA tests comprise preparing the antigen, coating the wells of a 96-well microplate with the antigen, adding the antibody of interest conjugated to a detectable compound such as an enzyme substrate (eg, horseradish peroxidase or alkaline phosphatase) to the well. and incubate for a period of time, and detect the presence of the antigen. In the ELISA assay, the antibody of interest does not have to be conjugated to a detectable compound; instead, a second antibody (recognizing the antibody of interest) conjugated to a detectable compound can be added to the well. In addition, instead of coating the well with the antigen, the antibody can be coated in the well. In this case, a second antibody conjugated with a detectable compound can be added after the addition of the antigen of interest to the coated well. A person skilled in the art would know which parameters can be modified to increase the detected signal, as well as other known variations of the ELISA assay. For an additional description with respect to the ELISA assays, see, e.g., Ausubel et al. , eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York in 11.2.1. The binding affinity of an antibody with an antigen and the rate of antibody-antigen interaction can be determined by competitive binding assays. An example of a competitive binding assay is a radioimmunoassay comprising the incubation of the labeled antigen (e.g., 3H or 125I) with the antibody of interest in the presence of increasing amounts of the unlabeled antigen and detection of the antibody bound to the labeled antigen. The affinity of the antibody of interest for a particular antigen and the binding rates can be determined from the data by analyzing a scatter plot. Competition with a second antibody can also be determined using radioimmunoassays. In this case, the antigen is incubated with the antibody of interest conjugated with a labeled compound (e.g. 3H or 1I) in the presence of increasing amounts of a second unlabeled antibody. Therapeutic Uses The present invention further relates to antibody-based therapies that include the administration of the antibodies of the present invention to an animal, preferably a mammal, and more preferably a human, for the treatment of one or more diseases, disorders, or conditions described. The therapeutic compounds of the present invention include, but are not limited to, antibodies of the present invention (including fragments, analogs and derivatives thereof, as described herein) and nucleic acids encoding the antibodies of the present invention. invention (including fragments, analogs and derivatives thereof and anti-idiotypic antibodies, as described herein). The antibodies of the present invention can be used for the treatment, inhibition or prevention of diseases, disorders or conditions associated with the aberrant expression and / or activity of a polypeptide of the present invention, including but not limited to, any one or more of the diseases, disorders or conditions described herein (eg, diseases, disorders or autoimmune conditions associated with such diseases or disorders, including but not limited to, autoimmune hemolytic anemia, autoimmune neonatal thrombocytopenia, idiopathic thrombocytopenic purpura, autoimmunocytopenia, hemolytic anemia , antiphospholipid syndrome, dermatitis, allergic encephalomyelitis, myocarditis, recurrent polychondritis, rheumatic heart disease, glomerulonephritis (eg, IgA nephropathy), multiple sclerosis, neuritis, uveitis, ophthalmia, polyendocrinopathies, purpura (eg, Henloch-Scoenlein purpura), disease of R eiter, Stiff-nucleic acid molecule, autoimmune lung inflammation, Guillain-Barre syndrome, insulin-dependent diabetes mellitus and autoimmune inflammatory eye disease, autoimmune thyroiditis, hypothyroidism (ie, Hashimoto's thyroiditis), systemic lupus erythematosus, Goodpasture syndrome, pemphigus, recipient autoimmunities such as for example (a) Graves' disease, (b) myasthenia gravis and (c) insulin resistance, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, rheumatoid arthritis, scleroderma with anti-collagen antibodies, mixed connective tissue disease , polymyositis / dermatomyositis, pernicious anemia, idiopathic Addison's disease, infertility, glomerulonephritis such as primary glomerulonephritis and IgA nephropathy, pemphigus bullosa, Sjogren's syndrome, diabetes mellitus and resistance to adrenergic drugs (including resistance to adrenergic drugs with asthma or cystic fibrosis) ), I've chronic active patitis, primary biliary cirrhosis, other insufficiencies of glands - endocrine, vitiligo, vasculitis, post-MI, cardiotomy syndrome, urticaria, atopic dermatitis, asthma, inflammatory myopathies and other inflammatory, granulomatous, degenerative and atrophic diseases). In a specific embodiment, the antibodies of the present invention can be used for the treatment, to inhibit, predict, diagnose or prevent rheumatoid arthritis. In another specific embodiment, the antibodies of the present invention are used to treat, inhibit, predict, diagnose or prevent systemic lupus erythematosus. For the treatment and / or prevention of diseases, disorders or conditions associated with the expression and / or aberrant activity of a polypeptide of the present invention, includes but is not limited to alleviating the symptoms associated with said diseases, disorders or conditions. The antibodies of the present invention can also be used to target and kill cells that express neutrocin-alpha on their surface and / or cells that have neutrocin-alpha attached to their surface. The antibodies of the present invention can be provided in pharmaceutically acceptable compositions, as is known in the art, or as described herein.

A summary of the different ways in which the antibodies of the present invention can be used therapeutically, includes the binding of polynucleotides or polypeptides of the present invention locally or systemically in the body or by direct cytotoxicity of the antibody, eg, mediated by the complement. (CDC) or effector cells (ADCC). Some of these approaches are described in detail later. Armed with the teachings provided herein, a person skilled in the art will know how to use the antibodies of the present invention for diagnostic purposes., supervision or therapy, without undue experimentation. The antibodies of the present invention can advantageously be used in combination with other monoclonal or chimeric antibodies, or with lymphokines or hematopoietic growth factors (such as eg IL-2, IL-3 and IL-7, for example, which serve to increase the number or activity of effector cells that interact with the antibodies The antibodies of the present invention can be administered alone or in combination with other types of treatments (eg, radiation therapy, chemotherapy, hormone therapy, immunotherapy, antitumor agents , antibiotics and immunoglobulins.) It is generally preferred to administer products from one species or react with a species (in the case of antibodies) that is the same species as the patient's. Thus, in a preferred embodiment, antibodies are administered. , derivative fragments, analogs or human nucleic acids, to a human patient for therapy purposes It is preferred to use antibodies of high affinity and / or potency in vivo, inhibitory and / or neutralizing antibodies against polypeptides or polynucleotides of the present invention, fragments or regions thereof, for targeted immunoassays and for the therapy of disorders related to polynucleotides or polypeptides, including fragments thereof, of the present invention. Such antibodies, fragments or regions will preferably have an affinity for the polynucleotide or polypeptide of the present invention, including fragments thereof. Preferred binding affinities include those with a dissociation constant or Kd less than 5 X 10_5M, 10_5M, 5 X 10"% 10"% 5 X 10"% 10"% 5 X 10"% 10"% 5 x 10" 10"% 5 X 10": 0M, 10"10M, 5 x 10-1M, 10_11M, 5 X 10" 12M, 10"12M, 5 X 10" 13M, 10"13M, 5 X 10" 14M, 10" 1M, 5 X 10"15M and 10" 15M. Gene Therapy In a specific embodiment, nucleic acids comprising antibody coding sequences or functional derivatives thereof, are administered to treat, inhibit or prevent a disease or disorder associated with the expression and / or aberrant activity of a polypeptide of the present invention, in the form of gene therapy. Gene therapy refers to a therapy performed by administering to a subject an expressed or expressible nucleic acid. In this embodiment of the present invention, the nucleic acids produce their encoded protein that regulates a therapeutic effect. Any of the gene therapy methods available in the art can be used in accordance with the present invention. Some examples of methods are described below. For a general review of gene therapy methods, see Goldspiel et al., Clinical Pharmacy 12: 488-505 (1993); Wu and Wu, Biotherapy 3: 87-95 (1991); Tolstoshev, Ann. Rev. Pharmacol. Toxicol 32: 573-596 (1993); Mulligan, Science 260: 926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem. 62: 191-217 (1993); May TIBTECH 11 (5): 155-215 (1993). The methods commonly known in the art of recombinant DNA technology that can be used are described in Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, NT (1993); and Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press. NY (1990).

- - In a preferred embodiment, the compound comprises nucleic acid sequences encoding an antibody, wherein said nucleic acid sequences are parts of expression vectors expressing the antibody or fragments thereof or chimeric proteins or heavy or light chains thereof, in an appropriate guest. In particular, such nucleic acid sequences have promoters operably linked to the coding region of the antibody, wherein the promoters are inducible or constitutive and, optionally, tissue-specific. In another particular embodiment, nucleic acid molecules are used in which the antibody coding sequences and any other desired sequence are flanked by regions that promote homologous recombination at a desired site in the genome, thereby providing an intrachromosomal expression of the nucleic acids encoding the antibody (Koller and Smithies, Proc. Nat'l Acad. Sci. USA, 86: 8932-8935 (1989); Zijlstra et al., Nature 342: 435-438 (1989). The expressed antibody molecule is a single chain antibody, alternatively, the nucleic acid sequences include sequences encoding both heavy chains and light chains or fragments thereof, of the antibody.

- - The administration of nucleic acids in a patient can be direct, in which case the patient is directly exposed to the nucleic acid or nucleic acid carrier vectors, or indirectly, in which case the cells are first transformed with the nucleic acid in vi tro and then they are transplanted to the patient. These two approaches are known, respectively, as gene therapy in vivo or ex vivo. In a specific embodiment, the nucleic acid sequences are administered directly in vi, where they are expressed to produce the encoded product. This can be achieved by any of numerous methods known in the art, e.g. constructing them as part of an appropriate nucleic acid expression vector and administering them in such a way that they become intracellular, eg, by infection using defective or attenuated retroviruses or other viral vectors (see US Patent No. 4,980,286) or by direct injection of Naked DNA or by the use of microparticle bombardment (eg, a gene gun; Biolistic, DuPont) or by coating with lipids or cell surface receptors or transfecting agents, encapsulating in liposomes, microparticles or microcapsules, or administering them linked to a peptide that is known to enter the nucleus, administering them bound to a - - ligand that is subject to receptor-mediated endocytosis (See e.g., Wu and Wu, "Biol. Chem., 262: 4429-443 (1987); (which can be used to target cell types that express receptors specifically), and so on. In another embodiment, nucleic acid-ligand complexes can be formed in which the ligand comprises a fusogenic viral peptide to break down endosomes, thereby allowing the nucleic acid to prevent lysosomal degradation. In yet another embodiment, the nucleic acid can be targeted in vivo to specific cells for incorporation and expression, by targeting a specific receptor (see, e.g., PCT International Publications WO 92/06180; WO 92/22635; WO 92/20316; WO 93/14188, WO 93/20221). Alternatively, the nucleic acid can be introduced intracellularly and incorporated into the DNA of a host cell for expression, by homologous recombination (Koller and Smithies, Proc. Nat'l Acad. Sci. USA 86: 8932-8935 (1989); Zijlstra et al., Nature 342: 435-438 (1989)). In a specific embodiment, viral vectors containing nucleic acid sequences encoding an antibody of the present invention are used. For example, it is possible to use a retroviral vector (see Miller et al., Meth. Enzymol, 217: 581-599 (1993)). These retroviral vectors contain the necessary components - - for the correct packaging of the viral genome and the integration into the DNA of the host cell. The nucleic acid sequences encoding the antibody to be used in gene therapy are cloned into one or more vectors, which facilitates the distribution of the gene in a patient. More details about retroviral vectors can be found in Boesen et al., Biotherapy 6: 291-302 (1994), where the use of a retroviral vector to distribute the mdrl gene in hematopoietic stem cells is described in order to make Stem cells are more resistant to chemotherapy. Other references that illustrate the use of retroviral vectors in gene therapy are: Clowes et al. , J. Clin. Invest. 93: 644-6551 (1994); Kiem et al., Blood 83: 1467-1473 (1994); Salmons and Gunzberg, Human Gene Therapy 4: 129-141 (1993) and Grossman and Wilson, Curr. Opin. in Genetics and Devel, 3: 110-114 (1993). Adenoviruses are other viral vectors that can be used in gene therapy. Adenoviruses are especially attractive vehicles for distributing genes to the respiratory epithelium. Adenoviruses naturally infect the respiratory epithelium, where they cause mild disease. Other targets for adenovirus-based distribution systems are the liver, central nervous system, endothelial cells and muscle.

- - Adenoviruses have the advantage of being able to infect non-dividing cells. Kozarsky and Wilson, Current Opinion in Genetics and Development 3: 499-503 (1993) present a review of adenovirus-based gene therapy. Bout et ai., Human Gene Therapy 5: 3-10 (1994) demonstrated the use of adenoviral vectors to transfer genes to the respiratory epithelium of rhesus monkeys. Other cases of adenovirus use in gene therapy can be found in Rosenfeld et al. , Science 252: 431-434 (1991); Rosenfeld et al. , Cell 68: 143-155 (1992); Mastrangeli et al., J. Clin. Invest. 91: 225-234 (1993); PCT Publication WO 94/12649; and Wang et al., Gene Therapy 2: 775-783 (1995). In a preferred embodiment, adenoviral vectors are used. Adeno-associated viruses (AAV) have also been proposed for use in gene therapy (Walsh et al., Proc. Soc. Exp. Biol. Med. 204: 289-300 (1993), US Patent No. 5,436,146). Another approach of gene therapy includes the transfer of a gene to cells that are in tissue culture, by methods such as electroporation, lipofection, calcium phosphate mediated transfection or viral infection. Typically, the transfer method includes the transfer of a selectable marker to the cells. Then, the cells are placed under selection-conditions to isolate those cells that have incorporated and express the transferred gene. Then these cells are administered to a patient. In this embodiment, the nucleic acid is introduced into a cell prior to in vivo administration of the resulting recombinant cell. Such introduction can be carried out by any method known in the art, including but not limited to, transfection, electroporation, microinjection, infection with a viral or bacteriophage vector containing the nucleic acid sequences, cell fusion, gene transfer mediated by the chromosome, gene transfer mediated by microcells, fusion of spheroplasts, and so on. Numerous techniques are known for the introduction of foreign genes into cells (see, eg, Loeffler and Behr, Meth, Enzymol, 217: 599-618 (1993), Cohen et al., Meth. Enzymol, 217: 618-644 (1993). Clin Clin Pharmac Ther 29: 69-92, (1985) and may be used in accordance with the present invention, as long as the necessary physiological and developmental functions of the recipient cells are not interrupted. a stable transfer of the nucleic acid into the cell, so that the nucleic acid is expressible by the cell and preferably heritable and expressible in the progeny of said cell.The resulting recombinant cells can be administered to a patient by various methods known in the art. Preferably recombinant blood cells are administered intravenously (eg, hematopoietic stem cells or progenitor cells) The amount of cells to be used depends on the desired effect, the state of the patient, etc., and this can be determined by a technician in the field. Cells into which a nucleic acid can be introduced for gene therapy purposes include any type of desired cell available, and include, but are not limited to, epithelial cells, endothelial cells, keratinocytes, fibroblasts, muscle cells, hepatocytes; blood cells such as T lymphocytes, B lymphocytes, monocytes, macrophages, neutrophils, eosinophils, megakaryocytes, granulocytes; various stem or progenitor cells, in particular hematopoietic stem or progenitor cells, e.g., those obtained from the bone marrow, umbilical cord blood of peripheral blood, fetal liver, and so on. In a preferred embodiment, the cell used for gene therapy is autologous to the patient. In an embodiment in which recombinant cells are used in gene therapy, the nucleic acid sequences encoding the antibody are introduced into the cells, in such a way that they are expressed by the cells or by their progeny, and the recombinant cells are subsequently administered in vivo to obtain a therapeutic effect. In a specific embodiment, stem cells or progenitor cells are used. Potentially any parent and / or progenitor cell that can be isolated and maintained in vi tro, according to this embodiment of the present invention (see e.g., PCT International Publication WO 94/08598) can be used.; Stemple and Anderson, Cell 71: 973-985 (1992); Rheinwald, Meth. Cell. Bio. 21A.-229 (1980) and Pittelkow and Scott, Mayo Clinic Proc. 61: 771 (1986)). In a specific embodiment, the nucleic acid to be introduced for gene therapy purposes comprises an inducible promoter operably linked to the coding region, such that the expression of the nucleic acid is controlled by controlling the presence or absence of the nucleic acid. appropriate transcription inducer. Demonstration of Therapeutic or Prophylactic Activity The compounds or pharmaceutical compositions of the present invention are preferably tested in vi tro and then in vivo for the desired therapeutic or prophylactic activity, before being used in humans. For example, in vitro tests to demonstrate the therapeutic or prophylactic utility of a compound or pharmaceutical composition include the effect of a compound on a cell line or tissue sample of a patient. The effect of the compound or composition on the cell line and / or tissue sample can be determined using techniques known to those skilled in the art, including but not limited to rosetting assays and cell lysis assays. In accordance with the present invention, in vi tro assays that can be used to determine whether the administration of a specific compound is indicated, include assays in cell cultures in vi tro in which a tissue sample from a patient is grown in culture and is exposed to a compound and the effect of such a compound on the tissue sample is observed. Therapeutic and / or Prophylactic Administration and Composition The present invention provides methods of treatment, inhibition and prophylaxis by administering to a subject an effective amount of a compound or pharmaceutical composition of the present invention, preferably an antibody of the present invention. In a preferred embodiment, the compound is substantially purified (e.g., substantially free of substances that limit its effect or produce undesirable side effects). The subject of preference is an animal, including but not limited to animals such as cows, pigs, horses, chickens, cats, dogs, etc. and - - preferably it is a mammal, more preferably a human being. The formulations and methods of administration that can be employed when the compound comprises a nucleic acid or an immunoglobulin, were described above; additional formulations and appropriate administration routes can be selected from those described below. Various administration systems are known and can be used to administer a compound of the present invention, e.g. encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the compound, receptor-mediated endocytosis (see, eg, Wu and Wu, J. Biol. Chem., 262: 4429-443 (1987), construction of a nucleic acid as part of a retroviral vector or other vector, etc. Introduction methods include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and other routes.Compounds and compositions can be administered by any convenient route, for example by infusion or bolus injection, by absorption through the epithelial or mucocutaneous lining (eg, oral mucosa, rectal and intestinal mucosa, etc.) and can be administered together with other biologically active agents.The administration can be systemic or local Furthermore, it may be desirable to introduce the compounds or pharmaceutical compositions of the present invention into the central nervous system. ral, by any suitable route, including intraventricular and intrathecal injection; Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a container, such as an Ommaya container. Pulmonary administration can also be employed, e.g., by the use of an inhaler or nebulizer, and the formulation with an aerosol agent. In a specific embodiment, it may be desirable to administer the compounds or pharmaceutical compositions of the present invention locally in the area in need of treatment.; this can be carried out, for example and not with limitations, by local infusion during surgery, topical application eg, in conjunction with a wound healing after surgery, by injection, by means of a catheter, by means of a suppository or by means of an implant, wherein said implant is of a porous, non-porous or gelatinous material, including membranes such as sialastic membranes, or fibers. Preferably, when administering a protein, including an antibody of the present invention, care must be taken in using materials in which the protein is not absorbed. In another embodiment, the compound or composition can be administered in a vesicle, in particular a liposome (see Langer, Science 249: 1527-1533 (1990); Treat et al., In Liposomes in the Therapy of Infectious Disease and Cancer). , Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989), Lopez-Berestein, ibid., Pp. 317-327, in general see ibid.). In yet another embodiment, the compound or composition can be administered in a controlled release system. In one embodiment, a pump can be used (see Langer, supra, Sefton, CRC Crit Ref Biomed Eng 14: 201 (1987), Buchwald et al., Surgery 88: 507 (1980), Saudek et al. , N. Engl. J. Med. 321: 574 (1989)). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Relay, Langer and Wise (eds.), CRC Press, Boca Raton, Florida (1974), Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball ( eds.), Wiley, New York (1984), Ranger and Peppas, J., Macromol, Sci. Rev. Macromol, Chem. 23:61 (1983), see also Levy et al., Science 228: 190 (1985); During et al., Ann Neurol., 25: 351 (1989), Howard et al., J. Neurosurg., 71: 105 (1989)). In yet another embodiment, a controlled release system can be placed in proximity to the therapeutic target, i.e. the brain, thus requiring only a fraction of the systemic dose (see e.g., Goodson, in Medical Applications of Controlled Relay, supra, vol.2, pp. 115-138 (1984)). Other controlled-release systems are described in Langer's review (Science 249: 1527-1533 (1990)). In a specific embodiment wherein a compound of the present invention is a nucleic acid encoding a protein, the nucleic acid can be administered in vivo to promote the expression of its encoded protein, constructing it as part of an appropriate nucleic acid expression vector and administering it in such a way that it becomes intracellular, eg, by the use of a retroviral vector (see U.S. Patent No. 4,980,286) or by direct injection or by the use of microparticle bombardment (eg, a gene gun; Biolistic, DuPont), or coating with lipids or cell surface receptors or with transfectant agents, or administering it bound to a peptide known to enter the nucleus (see, eg, Joliot et al., Proc. Nat'l Acad. Sci. USA 88: 1864-1868 (1991)), et cetera. Alternatively, a nucleic acid can be introduced intracellularly and incorporated into the DNA of the host cell for expression, by homologous recombination. The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of a compound and a pharmaceutically acceptable carrier. In a specific modality, the term "pharmaceutically acceptable" means approved by the regulatory institutions of the Federal Government or a state government, or that is listed in the United States Pharmacopoeia or in another pharmacopoeia generally recognized for use in animals, and more particularly in humans. The term "vehicle" as used herein, refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic component is administered. Such pharmaceutical vehicles can be sterile liquids such as water and oils, including those of petroleum, of animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred vehicle when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous solutions can be used in dextrose and glycerol as liquid carriers, particularly for injectable solutions. Suitable pharmaceutically suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dehydrated skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, may contain minor amounts of wetting agents or emulsifiers, or pH regulating agents. These compositions may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations and the like. The composition can be formulated as a suppository, using binders and traditional carriers such as triglycerides. An oral formulation may include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc., in pharmaceutical grade. Examples of pharmaceutically acceptable carriers are described in "Remington's Pharmaceutical Sciences" of E.W. Martin. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of the vehicle, to provide the appropriate administration form for the patient. The formulation must be adapted to the mode of administration. In a preferred embodiment, the composition is formulated in accordance with routine procedures in the form of a pharmaceutical composition adapted for intravenous administration to humans. Typically, compositions for intravenous administration are solutions in a sterile isotonic aqueous buffer.

When necessary, the composition may also include a solubilizing agent and a local anesthetic, such as lignocaine to decrease pain at the site of injection. Generally, the ingredients are supplied separately or mixed together in a dosage unit form, for example, in the form of a lyophilized powder or a dehydrated concentrate in a hermetically sealed container, such as an ampule or a pouch, indicating the amount of the active agent When the composition is to be administered by infusion, it can be dispensed into an infusion bottle containing water or sterile pharmaceutical grade saline. When the composition is administered by injection, a sterile water ampule for injection or saline is provided, so that the ingredients can be mixed before administration. The compounds of the present invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with anions such as derivatives of hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etcetera.

- - The amount of the compound of the present invention that will be effective in the treatment, inhibition and prevention of a disease or disorder associated with the expression and / or aberrant activity of a polypeptide of the present invention, can be determined by standard clinical techniques. In addition, in vi tro assays can optionally be used to help identify optimal dose ranges. The precise dose to be used in the formulation will also depend on the route of administration and the severity of the disease or disorder, and should be decided according to the judgment of the medical practitioner and the circumstances of each patient. Effective doses can be extrapolated from dose-response curves derived from test systems in in vitro models or in animal models. For antibodies, the dose administered to a patient is typically 0.1 to 100 mg / kg of the patient's body weight. Preferably, the dose administered to a patient is between 0.1 and 20 mg / kg of the patient's body weight, more preferably 1 to 10 mg / kg of the patient's body weight. In general, human antibodies have a longer half-life in the human body than antibodies from other species, due to the immune response against foreign polypeptides. Thus, it is often possible to obtain lower doses of human antibodies and less frequent administrations. Furthermore, the dose and frequency of administration of the antibodies of the present invention can be reduced by increasing the incorporation and tissue penetration (e.g., in the brain) of the antibodies, by modifications such as, for example, lipidation. The present invention also provides a pharmaceutical pack or equipment comprising one or more containers that are filled with one or more of the ingredients of the pharmaceutical compositions of the present invention. Optionally associated with such containers, there may be a notification in the form prescribed by a governmental institution that regulates the manufacture, use or sale of pharmaceutical or biological products, which reflects the approval for manufacturing, use or sale for administration in humans , by that institution. Diagnosis and Imaging The labeled antibodies and derivatives and analogs thereof, which specifically bind to a polypeptide of interest, may be used for diagnostic purposes to detect, diagnose or monitor diseases and / or disorders associated with expression and / or activity. aberrant of a polypeptide of the present invention. The present invention makes possible the detection of the aberrant expression of a polypeptide of interest, comprising (a) evaluating the expression of the polypeptide of interest in cells or body fluids of an individual, using one or more specific antibodies against the polypeptide of interest and (b) comparing the level of gene expression with a standard gene expression level, whereby, an increase or decrease in the level of gene expression of the polypeptide tested, compared to the level of standard expression, is indicative of an aberrant expression. The present invention provides a diagnostic assay for the diagnosis of a disorder, comprising (a) assaying the expression of the polypeptide of interest in cells or body fluids of an individual, employing one or more specific antibodies against the polypeptide of interest and (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the level of gene expression of the polypeptide tested, as compared to the level of standard expression, is indicative of a particular disorder. With respect to cancer, the presence of a relatively high amount of transcription in the tissue subjected to biopsy of an individual, may indicate a predisposition for the development of the disease, or - may provide a mechanism for detecting the disease prior to appearance of real clinical symptoms. A more definitive diagnosis of this type could allow health professionals to use preventive measures or aggressive early treatment, thus preventing the development or progress of cancer. The antibodies of the present invention can be used to test the concentration of proteins in a biological sample, using classical immunohistological methods known to those skilled in the art (eg, see Jalkanen, et al., J. Cell. Biol. 101: 976-985 (1985); Jalkanen, et al., J. Cell. Biol. 105: 3087-3096 (1987)). Other antibody-based methods useful for detecting gene expression of proteins include immunoassays such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIE). Suitable labels for antibody testing are known in the art and include enzymatic labels such as glucose oxidase; radioisotopes such as iodine (131I, 125I, 123I, 12iI), carbon (14C), sulfur (35S), tritium (3H), indium (115mIn, 113mIn, 112In,? In) and technetium (99Tc, 99mTc), thallium ( 201Ti), gallium (68Ga, 67Ga); palladium (103Pd), molybdenum (99Mo), xenon (133Xe), fluorine (18F), 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 186Re, 188Re, 142Pr, 105Rh, 97Ru; luminescent labels such as luminol; and fluorescent labels such as fluorescein and rhodamine, and biotin. The known techniques can be applied to label the antibodies of the present invention. Such techniques include, but are not limited to, the use of bifunctional conjugating agents (see, U.S. Patents 5,756,065, 5,714,631, 5,696,239, 5,652,361, 5,505,931, 5,489,425, 5,435,990, 5,428,139, 5,342,604, 5,274,119, 4,994,560, and 5,808,003; wherein the content of each one is incorporated in the present in its entirety as a reference). One embodiment of the present invention is the detection and diagnosis of a disease or disorder associated with an aberrant expression of a polypeptide of interest in an animal, preferably a mammal and more preferably a human. In one embodiment, the diagnosis comprises: (a) administering (eg, parenterally, subcutaneously or intraperitoneally) to a subject, an effective amount of a labeled molecule that specifically binds to the polypeptide of interest; (b) waiting for a time interval after administration, to allow the labeled molecule to be preferably concentrated at sites of the subject where the polypeptide is expressed (and so that the unbound labeled molecules are purified to the basal level); (c) - - determine the concentration or background level; and (d) detecting the labeled molecule in the subject, wherein such detection of the labeled molecule above the background level indicates that the subject has a particular disease or disorder associated with an aberrant expression of the polypeptide of interest. The concentration or background level can be determined by several methods, including comparing the amount of labeled molecule detected with a previously determined standard value for a particular system. As described herein, the specific embodiments of the present invention relate to the use of the antibodies of the invention to quantitate or label cell concentrations of the B cell line, or cells of the monocytic line. Also, as described herein, the antibodies of the present invention can be used for the treatment, diagnosis or prognosis of an individual suffering from an immunodeficiency. In a specific embodiment, antibodies of the present invention are used to treat, diagnose and / or prognose an individual having a common variable immunodeficiency disease (EIVC) or a variant of this disease. In another embodiment, the antibodies of the present invention are used to diagnose, predict, treat or prevent a disorder characterized by a deficient serum production of immunoglobulins, recurrent infections and / or dysfunction of the immune system. As described herein, the antibodies of the invention can be used to treat, diagnose or predict an individual having an autoimmune disease or disorder. In a specific embodiment, the antibodies of the present invention are used to treat, diagnose and / or predict an individual suffering from systemic lupus erythematosus or a variant of this disease. In another specific modality, the antibodies of the present invention are used to treat, diagnose and / or predict an individual suffering from rheumatoid arthritis or a variant of this disease. It should be understood in the art that the size of the subject and the imaging system used will determine the amount of image portion necessary to produce images of diagnostic value. In the case of a radioisotope portion, for a human being the amount of radioactivity injected will normally vary within the range of about 5 to 20 millicuries of 99mTc. The antibody or labeled antibody fragment, subsequently, preferably will accumulate in the location of the cells containing the specific protein. Images for tumors in vivo are described - in S. W. Burchiel et al. , "Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments". (Chapter 13 in Tumor Iaging: The Radiochemical Detection of Cancer, SW Burchiel and BA Rhodes, eds., Masson Publishing Inc. (1982).) Depending on several variables, including the type of brand used and the mode of administration, the range of time after administration to allow the labeled molecule to be preferably concentrated at the sites of the subject and for the unbound labeled molecule to be purified to baseline, is 6 to 48 hours or 6 to 24 hours or 6 hours at 12 o'clock In another modality, the time interval after administration is 5 to 20 days or 5 to 10 days In one modality, the supervision of the disease or disorder is carried out by repeating the diagnostic method of the disease, for example, one month after the initial diagnosis, six months after the initial diagnosis, one year after the initial diagnosis, etc. The presence of the labeled molecule can be detected in the patient using methods known in the art for in vivo scanning. These methods depend on the type of marking used. Those skilled in the art will be able to determine the appropriate method of detecting a particular brand. Methods and devices that can be used in the diagnostic methods of the present invention, include but are not limited to, computed tomography (CT), whole body scanning for example by positron emission tomography (PET), images by magnetic resonance imaging (MRI) and sonography. In a specific embodiment, the molecule is labeled with a radioisotope and detected in the patient using a surgical instrument that responds to radiation (Thurston et al., US Patent No. 5,441,050). In another embodiment, the molecule is labeled with a fluorescent compound and detected in the patient using a scanning instrument that responds to fluorescence. In another embodiment, the molecule is labeled with a positron emitting metal and is detected in the patient using positron emission tomography. In yet another embodiment, the molecule is labeled with a paramagnetic mark and detected in a patient using magnetic resonance imaging (MRI). Packages The present invention provides packages that can be used in the above methods. In one embodiment, a package comprises an antibody of the present invention, preferably a purified antibody, in one or more containers. In a specific embodiment, the packages of the present invention contain a substantially isolated polypeptide comprising an epitope that is specifically immunoreactive with an antibody included in the package. Preferably, the packages of the present invention further comprise a control antibody that does not react with the polypeptide of interest. In another specific embodiment, the packages of the present invention comprise two or more antibodies (monoclonal and / or polyclonal) that recognize the same and / or different sequences or regions of the polypeptide of the invention. In another specific embodiment, the packages of the present invention contain a means for detecting the binding of an antibody to a polypeptide of interest (e.g., the antibody can be conjugated to a detectable substrate, such as a fluorescent compound, an enzymatic substrate, a radioactive compound or a luminescent compound, or a second antibody that recognizes the first antibody can be conjugated to a detectable substrate). In another specific embodiment of the present invention, the package is a diagnostic package for use in the analysis of serum containing specific antibodies against the proliferative and / or cancerous polynucleotides and polypeptides. Such a package may include a control antibody that does not react with the polypeptide of interest. This package may include a substantially isolated polypeptide antigen comprising an epitope that is specifically immunoreactive with at least one antibody against the polypeptide. In addition, such a package includes elements for detecting the binding of the antibody to the antigen (e.g., the antibody can be conjugated to a fluorescent compound such as fluorescein or rhodamine, which can be detected by flow cytometry). In specific embodiments, the package may include a polypeptide antigen produced recombinantly or chemically synthesized. The polypeptide antigen in the package may also be attached to a solid support. In a more specific embodiment, the detection mechanism of the package described above includes a solid support to which the polypeptide antigen is bound. Such a package may also include a labeled anti-human antibody, unbound reporter. In this embodiment, the binding of the antibody to the polypeptide antigen can be detected by the binding of said reporter-labeled antibody. In a further embodiment, the present invention includes a diagnostic package for use in the analysis of sera containing antigens of the polypeptide of the present invention. The diagnostic package includes a substantially isolated antibody specifically immunoreactive with polypeptide or polynucleotide antigens and elements for detecting the binding of the polynucleotide or polypeptide antigen with the antibody. In one embodiment, the antibody is bound to a solid support. In a specific embodiment, the antibody can be a monoclonal antibody. The detection element of the package may include a second labeled monoclonal antibody. Alternatively or in addition, the detection means may include a labeled competitive antigen. In a diagnostic configuration, the test serum is reacted with a solid phase reagent having an antigen bound to a surface obtained by the methods of the present invention. After binding with the antibody antigen specific to the reagent and removal of unbound serum components by washing, the reagent is reacted with the reporter-labeled anti-human antibody, to bind the reporter to the reagent in proportion to the amount of antigen antibody bound on the solid support. The reagent is again washed to remove unbound labeled antibody and the amount of reporter associated with the reagent is measured. Typically, the reporter is an enzyme that is detected by incubating the solid phase in the presence of a suitable substrate - fluorometric, luminescent or colorimetric (Sigma, St. Louis, MO). The solid surface reagent in the above test is prepared by known techniques for attaching protein materials to a solid support material, such as polymer beads, dip-bonding, 96-well plates or filter material. These binding methods generally include non-specific adsorption of the protein to the support or covalent attachment of the protein, typically through a free amino group, to a chemically reactive group found on the solid support, such as a carboxyl group , hydroxyl or activated aldehyde. Alternatively, streptavidin coated plates can be used in conjunction with biotinylated antigens. So that, the present invention provides a test system or package for carrying out this diagnostic method. The package generally includes a support with recombinant antigens attached to its surface and a reporter-labeled anti-human antibody to detect antigenic antibody bound to the surface. The present invention also relates to antibodies that act as agonists or antagonists of the polypeptides of the present invention. For example, the present invention includes antibodies that interrupt the receptor / ligand interactions with the polypeptides of the present invention, either partially or completely. Specific receptor antibodies and ligand specific antibodies are included. Included are receptor-specific antibodies that do not prevent ligand binding, but that prevent receptor activation. The activation of the receptor (i.e., signaling) can be determined by the techniques described herein or otherwise known in the art. Also included are receptor-specific antibodies that prevent ligand binding and receptor activation. Similarly, neutralizing antibodies that bind to the ligand and prevent binding of the ligand to the receptor are included, as well as antibodies that bind to the ligand, thus preventing the activation of the receptor, but which do not prevent the ligand from one to the receiver. In addition, antibodies that activate the receptor are included. These antibodies can act as agonists for all or less of all the biological activities effected by receptor activation mediated by the ligand. The antibodies can be specified as agonists or antagonists of biological activities comprising specific activities described herein. Also included are antibodies that bind to neutrokine-alpha and / or neutrokine-alphaSV regardless of whether neutrokine-alpha or neutrokine-alphaSV is linked to a Neutrokine-alpha Receptor. These antibodies act as agonists of neutrokine-alpha and / or neutrocine-alphaSV, which is reflected in an increase in cell proliferation in response to the binding of neutrocine-alpha and / or neutrocine-alphaSV with a neutrocyte receptor- alpha, in the presence of these antibodies. The aforementioned antibody agonists can be prepared using methods known in the art. See e.g., International Publication WO 96/40281; U.S. Patent No. 5,811,097; Deng, B. et al., Blood 92 (6) .1981-1988 (1998); Chen, Z. et al., Cancer Res. 58 (16): 3668-3678 (1998); Harrop, J.A. et al. , J. Immunol. 161 (4) -1786-1794 (1998); Zhu, Z. et al., Cancer Res.58 (15): 3209-3214 (1998); Yoon, D.Y. et al. , J. Immunol. 160 (7): 3170-3179 (1998); Prat, M. et al., J. Cell. Sci. 111 (Pt2): 237-247 (1998); Pitard, V. et al. , J. Immunol. Methods 205 (2): 177-190 (1997); Liautard, J. et al., Cytokinde 9 (4): 233-241 (1997); Carlson, N.G. et al. , J. Biol. Chem. 272 (17): 11295-11301 (1997); Taryman, R.E. et al. , Neuron 14 (4): 755-762 (1995); Muller, Y.A. et al., Structure 6 (9): 1153-1167 (1998); Bartunek, P. et al. , Cytokine 8 (1): 14-20 (1996) (the references of which are incorporated herein by reference in their entirety).

At least 14 monoclonal antibodies against neutrocin-alpha have been generated. These monoclonal antibodies are designated as: 12D6, 2E5, 9B6, 1B8, 5F4, 9A5, 10G12, 11G12, 16B4, 3D4, 16C9, 13D5, 15C10 and 12C5. The preliminary analysis of these antibodies indicates that each one binds to the neutrocyan-alpha protein in a Western blot analysis and when the neutrocin-alpha protein is bound to an ELISA plate. However, further analysis of the 12D6, 2E5, 9B6, 1B8, 5F4, 9A5, 10G12, 11G12 and 16B4 antibodies indicates that only antibodies designated as 12D6, 9B6, 2E5, 10G12, 9A5 and 11G12 bind to a bound form to the membrane of neutrocine-alpha. Thus, a subset of the monoclonal antibodies generated against neutrocin-alpha has been determined to bind only to the neutrokine-alpha membrane-bound form (ie, this subpopulation or subset does not bind to the soluble form of neutrocin-alpha corresponding to amino acids 134 to 285 of SEQ ID NO: 2), which as described herein, is primarily limited to expression in monocytes and dendritic cells. The 9B6 antibody was found to bind specifically to the membrane-bound form of neutrocine-alpha, but not to the soluble form of neutrokine-alpha.

Epitope mapping of antibody 9B6 indicated that this antibody binds specifically to an amino acid sequence contained in the amino acid residues of about Ser-171 to about Phe-194 of SEQ ID NO: 2. More particularly, the mapping of epitopes indicated that antibody 9B6 binds specifically to a peptide comprising the amino acid residues of Lys-173 to Lys-188 of SEQ ID NO: 2. In contrast, antibodies 16C9 and 15C10 were found to bind to the form soluble of the neutrocin-alpha (amino acids 134 to 285 of SEQ ID NO: 2) and inhibit the proliferation of B cells mediated by neutrokine-alpha. See for example, Example 10. It has also been found that 15C10 antibody inhibits the binding of neutrocine-alpha to its receptor. Epitope mapping of antibody 15C10 indicated that this antibody binds specifically to an amino acid sequence contained in the amino acid residues of about Glu-223 to about Tyr-246 of SEQ ID NO: 2. More particularly, epitope mapping indicated that the 15C10 antibody binds specifically to a peptide comprised of the amino acid residues of Val-227 to Asn-242 of SEQ ID NO: 2. The 15C10 antibody also specifically binds to a peptide comprising the amino acid residues of Phe-230 to Cys-245 of SEQ ID NO: 2.

- - As described above, antineutrocin-alpha monoclonal antibodies have already been prepared. Hybridomas producing the antibodies designated 9B6 and 15C10 were deposited in the ATCC and assigned the accession numbers PTA-1158 and PTA-1159, respectively. In one embodiment, the antibodies of the present invention have one or more of the same biological characteristics as one or more of the antibodies secreted by the hybridoma cell lines deposited with accession numbers PTA-1158 or PTA-1159. The term "biological characteristics" as used herein means the activities in vi tro or in vivo or properties of the antibodies, such as for example the ability to bind to neutrocin-alpha (eg, the polypeptide of the SEQ ID NO: 2, the mature form of neutrocin-alpha, the membrane bound form of neutrocin-alpha, the soluble form of neutrocin-alpha (amino acids 134 through 285 of SEQ ID NO: 2) and a antigenic and / or epitopic region of neutrokine-alpha), the ability to substantially block neutrokine-alpha / neutrokine-alpha receptor binding or the ability to block neutrokine-alpha-mediated biological activity (eg, stimulation of the proliferation of B cells and the production of immunoglobulins). Optionally, the antibodies of the present invention will bind to the same epitope as at least one of the antibodies specifically referred to herein. Such binding to the epitope can be determined routinely using assays known in the art. Thus, in one embodiment, the present invention provides antibodies that specifically bind to the membrane-bound form of neutrokine-alpha and do not bind to the soluble form of neutrokine-alpha. These antibodies have uses that include, but are not limited to, uses as a diagnostic probe for the identification and / or isolation of monocyte lines expressing the membrane bound form of neutrokine-alpha. For example, the expression of the membrane-bound form of neutrokine-alpha is raised in activated monocytes and, accordingly, the antibodies encompassed by the present invention can be used to detect and / or quantitate activated monocyte levels. . Additionally, antibodies can be used that only bind to the membrane-bound form of neutrocin-alpha to direct toxins to neoplastic, preneoplastic, and / or other cells that express the membrane-bound form of neutrokine-alpha (eg. , monocytes and dendritic cells). In another embodiment, the antibodies of the present invention specifically bind only to the soluble form of neutrokine-alpha (amino acids 134 to 285 of SEQ.

ID NO: 2). These antibodies have uses that include, but are not limited to, uses as diagnostic probes to analyze soluble neutrocin-alpha in biological samples and as therapeutic agents to direct toxins to cells that express neutrokine-alpha receptors (eg, B cells). and / or to reduce or block, in vi tro or in vi ve, the biological activity mediated by neutrokine-alpha (eg, stimulation of B cell proliferation and / or production of immunoglobulins). The present invention also provides antibodies that specifically bind both the membrane-bound form and the soluble form of neutrokine-alpha. As described above, the present invention encompasses antibodies that inhibit or reduce the ability of neutrocin-alpha and / or neutrocin-alphaSV to bind to the neutrocyan-alpha receptor and / or the neutrocyn-alphaSV receptor, in vi tro and / or in vivo. In a specific embodiment, the antibodies of the present invention inhibit or reduce the ability of neutrokine-alpha and / or neutrocine-alphaSV to bind with the neutrocyan-alpha receptor and / or with the neutrocine-alphaSV receptor in vi tro. In another specific non-exclusive embodiment, the antibodies of the present invention inhibit or reduce the ability of neutrokine-alpha and / or neutrocine-alphaSV to bind with the neutrokine-alpha receptor and / or the neutrokine-alphaSV receptor in alive. Such inhibition can be evaluated using the techniques described herein or known in some other way in this field. The present invention also includes antibodies that bind specifically to neutrokine-alpha and / or neutrocine-alphaSV, but which do not inhibit the ability of neutrokine-alpha and / or neutrocine-alphaSV to bind with the neutrokine-alpha receptor and / or the neutrocine-alphaSV receptor, in vi tro and / or in vi vo. In a specific embodiment, the antibodies of the present invention do not inhibit or reduce the ability of neutrokine-alpha and / or neutrocine-alphaSV to bind with the neutrokine-alpha receptor and / or the neutrokine-alphaSV receptor, in vi tro . In another specific non-exclusive embodiment, the antibodies of the present invention do not inhibit or reduce the ability of neutrokine-alpha and / or neutrocine-alphaSV to bind with the neutrocine-alpha receptor and / or the neutrocine-alphaSV receptor, in alive. As described above, the present invention includes antibodies that inhibit or reduce a biological activity mediated by neutrocine-alpha and / or neutrocine-alphaSV, in vi tro and / or in vivo. In a specific embodiment, the antibodies of the present invention inhibit or reduce the proliferation of B-cells mediated by - neutrocin-alpha and / or neutrocin-alphaSV, in vi tro. Such inhibition can be assessed by routine modified B cell proliferation assays, described herein or otherwise known in the art. In another specific non-exclusive embodiment, the antibodies of the present invention inhibit or reduce the proliferation of B cells mediated by Neutrocin-alpha and / or Neutrocin-alphaSV. In a specific embodiment, the antibody of the present invention is 15C10 or a humanized form thereof. In another preferred specific embodiment, the antibody is 16C9 or a humanized form thereof. Thus, in specific embodiments of the invention, 16C9 and / or 15C10 antibodies or humanized forms thereof are used to bind Neutrokine-alpha and / or Neutrokine-soluble alphaSV and / or agonists and / or antagonists thereof and in this way inhibit (partially or completely) the proliferation of B cells. Alternatively, the present invention also encompasses antibodies that bind specifically to a Neutrocin-alpha and / or Neutrocin-alphaSV, but which do not inhibit or reduce biological activity Neutrokine-alpha and / or Neutrocin-alphaSV in vi tro and / or in vivo mediated (eg, stimulation of B cell proliferation). In a specific embodiment, the antibodies of the present invention do not inhibit or reduce the biological activity - mediated by Neutrocin-alpha and / or Neutrocin-alphaSV, in vi tro. In another non-exclusive embodiment, the antibodies of the present invention do not inhibit or reduce the biological activity mediated by Neutrocin-alpha and / or Neutrocin-alphaSV, in vivo. In a specific embodiment, the antibody of the present invention is 9B6 or a humanized form thereof. As described above, the present invention includes antibodies that specifically bind to the same epitope as at least one of the antibodies specifically referenced herein, in vi tro and / or in vivo. In a specific embodiment, the antibodies of the present invention specifically bind to an amino acid sequence contained in the amino acid residues of about Ser-171 to about Phe-194 of SEQ ID No. 2 in vi tro. In another non-exclusive specific embodiment, the antibodies of the present invention bind specifically to an amino acid sequence contained in the amino acid residues of about Ser-171 to about Phe-194 of SEQ ID No. 2, in vivo. In another specific embodiment, the antibodies of the present invention specifically bind to an amino acid sequence contained in the amino acid residues of Lys-173 to Lys-188 of the SEQ - - ID No. 2 in vi tro. In another specific non-exclusive embodiment, the antibodies of the present invention specifically bind to an amino acid sequence contained in the amino acid residues of Lys-173 to Lys-188 of SEQ ID No. 2, in vivo. In a further specific embodiment, the antibodies of the present invention bind specifically to an amino acid sequence contained in the amino acid residues of about Glu-223 to about Tyr-246 of SEQ ID No. 2 in vi tro. In another specific non-exclusive embodiment, the antibodies of the present invention bind specifically to an amino acid sequence contained in the amino acid residues of about Glu-223 to about Tyr-246 of SEQ ID No. 2, in vivo. In another specific non-exclusive embodiment, the antibodies of the present invention specifically bind to an amino acid sequence contained in the amino acid residues of Val-227 to Asn-242 of SEQ ID No. 2 in vi tro. In another specific non-exclusive embodiment, the antibodies of the present invention specifically bind to an amino acid sequence contained in the amino acid residues of Val-227 to Asn-242 of SEQ ID No. 2, in vivo. In another specific non-exclusive embodiment, the antibodies of the present invention specifically bind to an amino acid sequence contained in the amino acid residues of Phe-230 to Cys-245 of SEQ ID No. 2 in vi tro. In another specific non-exclusive embodiment, the antibodies of the present invention bind specifically to an amino acid sequence contained in the amino acid residues of Phe-230 to Cys-245 of SEQ ID No. 2, in vivo. The present invention also provides antibodies that competitively inhibit the binding of monoclonal antibody 9B6 produced by the hybridoma deposited as PTA-1159, to a polypeptide of the present invention, preferably the polypeptide of SEQ ID No. 2, more preferably to a polypeptide having the amino acid sequence of the residues of Ser-171 to Phe-194 of SEQ ID No. 2. The competitive inhibition can be determined by any method known in the art, for example using the competitive binding assays described in I presented. In preferred embodiments, the antibody competitively inhibits the binding of monoclonal antibody 9B6 to at least 95, at least 90, at least 85, at least 80, at least 75, at least 70, at least 60, at least 50% to polypeptide SEQ ID No. 2 or preferably a polypeptide having the amino acid sequence of the residues of Ser-171 to Phe-194 of SEQ ID No. 2. The present invention also provides - - antibodies that competitively inhibit binding of the 15C10 monoclonal antibody produced by the hybridoma deposited as PTA-1158, to a polypeptide of the present invention, preferably the polypeptide of SEQ ID No. 2, more preferably to a polypeptide having the amino acid sequence of the Glu residues -223 to Tyr-246 of SEQ ID No. 2. In preferred embodiments, the antibody competitively inhibits binding of 15C10 antibody by at least 95, at least 90, at least 85, at least 80, when or at least 75, at least 70, at least 60, at least 50% to the polypeptide of SEQ ID No. 2 or preferably to a polypeptide having the amino acid sequence of the residues of Glu-223 to Tyr-246 of the SEQ ID No. 2. Additional embodiments of the present invention relate to antibody 9B6 and to the hybridoma cell line expressing this antibody. A hybridoma cell line expressing antibody 9B6 was deposited with the ATCC on January 7, 2000 and assigned the ATCC Deposit number PTA-1159. In a preferred embodiment, the 9B6 antibody is humanized. Additional embodiments of the present invention relate to the 15C10 antibody and to the hybridoma cell line expressing this antibody. A hybridoma cell line expressing antibody 15C10 was deposited with the ATCC on January 7, 2000 and assigned the ATCC Deposit number PTA-1158. In a preferred embodiment, the 15C10 antibody is humanized. In a specific embodiment, the specific antibodies described above are humanized using the techniques described herein or otherwise known in the art and then used as therapeutic agents in the manner described herein. In another specific embodiment, any of the antibodies listed above is used in soluble form. In another specific embodiment, any of the antibodies listed above is conjugated with a toxin or a tag (as described below). Such conjugated antibodies are used to kill a particular population of cells or to quantify a particular population of cells. In a preferred embodiment, these conjugated antibodies are used to kill B cells expressing the Neutrocin-alpha receptor on their surface. In another preferred embodiment, such conjugated antibodies are used to quantitate B cells that express the Neutrocin-alpha receptor on their surface. In another specific embodiment, any of the antibodies listed above is conjugated with a - toxin or with a tag (as described below). Such conjugated antibodies are used to kill monocytic cells expressing the membrane bound form of Neutrocin-alpha. In another preferred embodiment, such conjugated antibodies are used to quantitate monocytic cells expressing the membrane-bound form of Neutrocin-alpha. The antibodies of the present invention also have uses as therapeutic and / or prophylactic agents that include, but are not limited to, activating monocytes or blocking the activation of monocytes and / or killing monocyte lines expressing the membrane-bound form of the Neutrokine-alpha on its cell surface (eg, for the treatment, prevention and / or diagnosis of myeloid leukemias, leukemias based on monocytes and lymphomas, monocytosis, monocytopenia, rheumatoid arthritis and other diseases or disorders associated with activated monocytes). In a specific embodiment, the antibodies of the present invention bind the complement. In other specific embodiments, as described herein, the antibodies of the invention (or fragments thereof) are associated with heterologous polypeptides or heterologous nucleic acids (eg, toxins, such as compounds that bind and activate endogenous cytotoxic effector systems). and radioisotopes; and cytotoxic prodrugs).

- - In another embodiment, one or more monoclonal antibodies are produced that recognize or bind Neutrocin-alpha and / or a mutein thereof, but do not recognize or bind Neutrocin-alphaSV and / or a mutein thereof. . In related mode, one or more monoclonal antibodies are produced which recognize or bind Neutrocin-alphaSV and / or a mutein thereof, but which do not recognize or bind Neutrocin-alpha and / or a mutein thereof. . As described above, the antibodies against Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides of the present invention, in turn, can be used to generate anti-idiotypic antibodies that "mimic" Neutrocin-alpha, employing known techniques for those skilled in the art (see, eg, Greenspan and Bona, FASEB J. 7 (5): 437-444 (1989) and Nissinoff, J. Immunol. 147 (8): 2429-2438 (1991)). For example, antibodies that bind to Neutrokine-alpha and / or Neutrokine-alphaSV and competitively inhibit the multimerization and / or ligand binding of Neutrocin-alpha and / or Neutrocin-alphaSV, can be used to generate anti-idiotypic antibodies that "mimic" the multimerization of the Neutrokine-alpha TNF and / or the binding domain and, as a result, bind and neutralize Neutrocin-alpha or Neutrocin-alphaSV and / or its ligand. Such neutralizing anti-idiotypic antibodies or Fab fragments of such anti-idiotypic agents can be used in therapeutic regimens to neutralize the Neutrokine-alpha ligand. For example, these anti-idiotypic antibodies can be used to bind to Neutrocin-alpha and / or Neutrocin-alphaSV or to bind to Neutrocin-alpha and / or Neutrocin-alphaSV receptors on the surface of B cells and, thus, block the activation, proliferation and / or differentiation of B cells mediated by Neutrocin-alpha and / or Neutrocin-alphaSV. Diagnosis of Disorders Related to the Immune System Neutrokine-alpha is expressed in kidney, lungs, peripheral leukocytes, bone marrow, T-cell lymphoma, B-cell lymphoma, activated T cells, stomach cancer, smooth muscle, macrophages, and tissue. umbilical cord blood, particularly cells of the monocytic line. In addition, Neutrocin-alphaSV is expressed mainly in dendritic cells. Additionally, Neutrocin-alpha is expressed on the cell surface of the following non-hematopoietic tumor cell lines. HCT 116 colon carcinoma (Accession No. ATCC CCL-247) and HT-29 (Accession No. ATCC HTB-38); colon adenocarcinomas Caco-2 (Accession No. ATCC HTB-37), COLÓ 201 (Accession No. ATCC CCL-224) and WiDr (Accession No. ATCC CCL-218); - - mammary adenocarcinoma MDA-MB-231 (Accession No. ATCC HTB-26); squamous cell carcinoma of the bladder SCABER (Accession No. ATCC HTB-3); Bladder carcinoma HT-1197 (Accession No. ATCC CRL-1473); Kidney carcinomas A-498 (Accession No. ATCC HTB-44), Caki-1 (Accession No. ATCC HTB-46) and Caki-2 (Accession No. ATCC HTG-17); Wilms renal tumor SK-NEP-1 (Accession No. ATCC HTB-48) and pancreatic carcinomas Hs 766T (Accession No. ATCC HTB-134), MIA PaCa-2 (Accession No. ATCC CRL-1420) and SU.86.86 (Accession No. ATCC CRL-1837). For a number of disorders related to the immune system, substantially altered (increased or decreased) levels of the expression of the Neutrokine-alpha and / or Neutrocin-alphaSV gene can be detected in the tissue of the immune system and other cells or body fluids ( eg, serum, plasma, urine, synovial fluid or spinal fluid) taken from individuals suffering from such disorder, in relation to the expression level of the Neutrokine-alpha gene and / or Neutrokine-alphaSV "standard"; that is, the level of expression of Neutrocin-alpha and / or Neutrocin-alphaSV in the tissues of the immune system or body fluids of an individual who does not suffer from any disorder of the immune system. Thus, the present invention provides a diagnostic method useful for the diagnosis of an immune system disorder, which includes measuring the level of expression - of the gene coding for the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide in the tissue of the immune system or other cells or body fluids of an individual and comparing the level of gene expression measured with a standard gene expression level of Neutrocin-alpha and / or Neutrocin-alphaSV, whereby an increase or decrease in the expression level of the gene, compared to a standard, is indicative of an immune or activation system disorder, proliferation, differentiation and / or normal death. In particular, certain tissues in mammals with cancer of cells or tissues of the immune system are thought to express significantly increased or decreased amounts of the Neutrokine-alpha and / or Neutrocin-alphaSV polypeptide and mRNA coding for the Neutrokine-alpha polypeptide and / or Neutrocin-alfaSV, compared to the corresponding "standard" level. In addition, it is thought that the increased or decreased levels of Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide can be detected in certain body fluids (eg, serum, plasma, urine and spinal fluid) or in cells or tissues from mammals that have such cancer, when compared with sera from mammals of the same species that do not suffer from said cancer. For example, as described herein, - Neutrokine-alpha is highly expressed in cells of the monocytic line. Accordingly, the polypeptides of the present invention (eg, polynucleotide sequences complementary to all or a portion of the .RNA of Neutrokine-alpha and / or Neutrokine-alphaSV mRNA) and antibodies (and antibody fragments) directed against the polypeptides of the present invention, can be used to quantify or qualify cell concentrations of the monocytic line (eg, monocytic leukemia cells) that express Neutrocin-alpha on its cell surface. These antibodies additionally have diagnostic applications for detecting abnormalities of the level of expression of the Neutrokine-alpha gene, or abnormalities in the structure and / or temporal, tissue, cellular or subcellular localization of Neutrokine-alpha and / or Neutrocin-alphaSV. These diagnostic assays can be performed in vivo or in vi tro, for example in blood samples, tissue biopsies or tissue autopsies. Additionally, as described herein, the Neutrokine-alpha receptor is expressed primarily in cells of the B cell line. Accordingly, the Neutrokine-alpha polypeptides of the present invention (including Neutrokine-alpha polypeptides) labeled and fusion proteins of - -Neutrokine-alpha) and Antineutrocin-alpha antibodies, (including fragments of Antineutrocin-alpha antibodies) against the polypeptides of the present invention, can be used to quantify or label cell concentrations of the B cell line (eg, cell-related leukemias). B or lympholas) that express the receptor Neutrocin-alpha on its cell surface. These Neutrokine-alpha polypeptides and antibodies, additionally, have diagnostic applications for detecting abnormalities of the gene expression level of the Neutrokine-alpha receptor or abnormalities in the structure and / or temporal, tissue, cellular or subcellular location of the Neutrokine receptor. alpha and / or activity diagnosis / defects in the signaling pathways associated with Neutrocin-alpha. These diagnostic assays can be performed in vivo or in vi tro, for example in blood samples or tissue biopsies, using techniques described herein or otherwise known in the art. In one embodiment, Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides or Neutrocin-alpha and / or Neutrocin-alphaSV agonists or antagonists (eg, Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies) of the present invention , are used for the treatment, prevention, diagnosis or prognosis of an individual suffering from an immunodeficiency. Immunodeficiencies that can be treated, prevented, diagnosed and / or predicted with Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides or Neutrocin-alpha and / or Neutrocin-alphaSV agonists or antagonists (eg, Antineutrocin-alpha antibodies) and / or Antineutrocin-alphaSV) of the present invention, include but are not limited to one or more of the immunodeficiencies that are selected from the group consisting of: severe combined immunodeficiency (IDCG) -related to sex, autosomal IDCG, deficiency of adenosine deaminase (ADA deficiency), sex-linked agammaglobulinemia (XLA), Bruton's disease, congenital agammaglobulinemia, infantile agammaglobulinemia linked to sex, acquired agammaglobulinemia, adult agamaglobulinemia, late-onset agammaglobulinemia, dysgamaglobulinemia, hypogammaglobulinemia, transient hypogammaglobulinemia of childhood , nonspecific hypogammaglobulinemia, amaglobulinemia, common variable immunodeficiency (EIVC) (ad quirida), Wiskott-Aldrich syndrome (SWA), sex-linked immunodeficiency with hyperglym, non-sex-linked immunodeficiency with hyperglym, selective IgA deficiency, IgG subclass deficiency (with or without IgA deficiency), - - deficiency of antibodies with normal or elevated Igs, immunodeficiency with thymoma, heavy chain Ig deletions, kappa chain deficiency, B-cell lymphoproliferative disorder (BLPD), selective IgM immunodeficiency, recessive agammaglobulinemia (Swiss type), reticular dysgenesis, neonatal neutropenia , severe congenital leukopenia, alinfoplasia-thymic aplasia or dysplasia with immunodeficiency, ataxia-telangiectasia, dwarfism of short limbs, sex-linked lymphoproliferative syndrome (XLP), Nezelof syndrome combined with immunodeficiency of Igs, deficiency of purine nucleoside phosphorylase (PNP), MHC Class II deficiency (Scarce Lymphocyte Syndrome) and severe combined immunodeficiency. In accordance with this embodiment, an individual suffering from an immunodeficiency expresses aberrantly low levels of Neutrokine-alpha and / or Neutrocin-alphaSV when compared to an individual who does not suffer from an immunodeficiency. Any means described herein or in some other manner known in the art can be applied to detect Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention (eg, SCAF analysis (Fluorescence Activated Cell Sorter) ) or detection by ELISA of the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides of the present invention and hybridization or PCR detection of the Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides of the present invention) and determining the expression profile of the Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides and / or polypeptides of the present invention, in a biological sample. A biological sample of a person affected by an immunodeficiency, is characterized by low levels of expression of Neutrocin-alpha and / or Neutrocin-alphaSV when compared with those observed in individuals who do not have an immunodeficiency. Thus, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides and / or polypeptides of the present invention and / or agonists or antagonists thereof, can be used in accordance with the methods of the present invention in diagnosis and / or prognosis of an immunodeficiency. For example, a sample obtained from a person suspected of having an immunodeficiency ("the subject") can be analyzed with respect to the relative expression levels of Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides and / or polypeptides. of the present invention. The expression levels of one or more of these molecules of the invention are subsequently compared to the expression levels of the same molecules of the present invention expressed in a person known not to have an immunodeficiency. A significant difference in the expression levels of the Neutrocin-alpha and / or Neutrocinu-alphaSV polynucleotides and / or polypeptides of the present invention, and / or agonists and / or antagonists thereof, between samples obtained from the subject and control, suggests that the subject is affected by an immunodeficiency. In another embodiment, Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides or Neutrocin-alpha and / or Neutrocin-alphaSV agonists or antagonists (eg, Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies) of the present invention , are used for the treatment, diagnosis and / or prognosis of an individual suffering from a common variable immunodeficiency disease ("EIVC"; also known as "acquired agammaglobulinemia" and "acquired hypogammaglobulinemia") or a variant of this disease. In accordance with this embodiment, an individual having EIVC or a subset of individuals having EIVC, expresses aberrant levels of Neutrokine-alpha and / or Neutrokine-alpha receptor in their B cells and / or monocytes, when compared to individuals. who do not have EIVC. Any means described herein or otherwise known in the art can be applied to detect the Neutrokine-alpha polynucleotides or polypeptides of the present invention and / or receptor polypeptides of - Neutrokine-alpha (eg, SCAF analysis or ELISA detection of Neutrokine-alpha and / or Neutrocin-alphaSV polypeptides of the present invention and PCR hybridization or detection of Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides of the present invention) and to differentially determine the expression profile of the Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention and / or Neutrocin-alpha receptor polypeptides in a sample containing at least monocyte cells or some components of the same (eg, RNA), compared to a sample that contains at least B cells or a component thereof (eg, AR?). In the case where a sample containing at least monocyte cells or some components thereof (eg, AR?) Is determined to reflect the expression of the polynucleotide or polypeptide? Eutrocin-alpha and / or? Eutrocin-alphaSV and a sample that contains at least B cells or a component thereof (eg, AR?) is determined to reflect less than the normal expression levels of? eutrocin-alpha polynucleotides or polypeptides, the samples can be correlated with the presence of EIVC (ie , "acquired agamaglobulinemia" or "acquired hypogammaglobulinemia"). A subset of people affected by EIVC is characterized by high levels of expression of both Neutrokine-a and Neutrokine-alpha receptor ("NAR") in peripheral blood cells or in circulating B cells, when compared to levels observed in individuals who do not have EIVC. In contrast, people who are not affected by EIVC are typically characterized by low levels of Neutrokine-alpha expression and high levels of NAR expression in peripheral blood cells or circulating B cells. Thus, the Neutrocin-alpha, Neutrocin-alphaSV and / or NAR polypeptides, polynucleotides and / or polypeptides of the present invention, and / or agonists or antagonists thereof, may be used in accordance with the methods of the invention in the differential diagnosis of this subpopulation of EIVC. For example, a sample of peripheral blood B cells obtained from a person suspected of having DVID ("the subject") can be analyzed with respect to the relative expression levels of Neutrocin-alpha, Neutrocin-alphaSV and / or polynucleotides NAR and / or polypeptides of the present invention. The expression levels of one or more of these molecules of the invention are subsequently compared to the expression levels of the same molecules of the invention expressed in a person known to be unaffected by EIVC ("the control") . A - - significant difference of the expression levels of Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention, and / or NAR polypeptides and / or agonists and / or antagonists thereof, between samples obtained of the subject and control, suggests that the subject is affected by this variant of EIVC. In a specific embodiment, Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides, or agonists or antagonists thereof (eg, Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies), are used for diagnosis, prognosis, treatment or prevention of a disorder characterized by a deficient production of serum immunoglobulins, recurrent infections and / or dysfunction of the immune system. In addition, Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides, or agonists or antagonists thereof (eg, Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies), can be used for diagnosis, prognosis, treatment or prevention of infections of the joints, bones, skin and / or parotid glands, blood infections (eg, sepsis, meningitis, septic arthritis and / or osteomyelitis), autoimmune diseases (eg, those described herein), inflammatory disorders and malignancies, and / or any - disease or disorder or condition associated with these infections, diseases, disorders and / or malignancies), including, but not limited to, EIVC, other primary immunodeficiencies, HIV disease, LLC, recurrent bronchitis, sinusitis , otitis media, conjunctivitis, pneumonia, hepatitis, meningitis, herpes zoster (eg, severe herpes zoster), and / or Pneumocystis carnii. In another embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides and / or polypeptides or Neutrocin-alpha and / or Neutrocin-alphaSV agonists or antagonists (eg, Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies) of the present invention, are used for the treatment, diagnosis or prognosis in an individual suffering from an autoimmune disease or disorder. Autoimmune diseases or disorders that can be treated, diagnosed or predicted using Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides or Neutrocin-alpha and / or Neutrocin-alphaSV agonists or antagonists (eg, Antineutrocin-alpha antibodies) and / or Antineutrocin-alphaSV) of the present invention, include but are not limited to, one or more of the following: autoimmune hemolytic anemia, autoimmune neonatal thrombocytopenia, idiopathic thrombocytopenic purpura, autoimmunocytopenia, hemolytic anemia, antiphospholipid syndrome, dermatitis, allergic encephalomyelitis, myocarditis, recurrent polychondritis, rheumatic heart disease, glomerulonephritis (eg, IgA nephropathy), multiple sclerosis, neuritis, uveitis, ophthalmia, polyendocrinopathies, purpura (eg, Henloch-Scoenlein purpura), Reiter's disease, Stiff-Man, autoimmune pulmonary inflammation, Guillain-Barre syndrome, diabetes insulin dependent testes and autoimmune ocular inflammation, autoimmune thyroiditis, hypothyroidism (ie, Hashimoto's thyroiditis, systemic lupus erythematosus, Goodpasture's syndrome, pemphigus, receptor autoimmunities such as for example (a) Graves' disease, (b) myasthenia gravis and (c) insulin resistance, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, rheumatoid arthritis, scleroderma with anti-collagen antibodies, mixed connective tissue disease, polymyositis / dermatomyositis, pernicious anemia, idiopathic Addison's disease, infertility, glomerulonephritis such as primary glomerulonephritis and IgA nephropathy, pemphigus bullosa, Sjogren's syndrome, diabetes mellitus and resistance to adrenergic drugs (including resistance to adrenergic drugs with asthma or cystic fibrosis), active chronic hepatitis, primary biliary cirrhosis, other insufficiencies of endocrine glands, vitiligo, vasculitis, post-MI, cardiotomy syndrome, urticaria, atopic dermatitis, asthma, inflammatory myopathies and other inflammatory, granulomatous, degenerative and atrophic diseases. According to this embodiment, an individual suffering from an autoimmune disease or an autoimmune disorder expresses aberrantly high levels of Neutrokine-alpha, Neutrokine-alphaSV and / or NAR, when compared to an individual who does not suffer from a disease or disorder autoimmune Any means described herein or otherwise known in the art can be applied to detect Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention and / or NAR polypeptides (eg, SCAF analysis or detection by ELISA of Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides of the present invention and PCR hybridization or detection of the Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides of the present invention) and to determine the expression profile of Neutrokine-alpha and / or Neutrocin-alphaSV, polynucleotides and / or polypeptides of the present invention and / or NAR polypeptides, in a biological sample. A biological sample of people affected by an autoimmune disease or disorder is characterized by high expression levels of Neutrokine-alpha, Neutrokine-alphaSV and / or NAR, when compared to the levels seen in individuals who do not have a disease or autoimmune disorder. Thus, the Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides and / or polypeptides of the present invention, and / or agonists or antagonists thereof, can be used in accordance with the methods of the invention in diagnosis and / or prognosis of an autoimmune disease or disorder. For example, a biological sample obtained from a person suspected of being affected by an autoimmune disease or disorder ("the subject") can be analyzed with respect to the relative levels of expression of the Neutrokine polynucleotides and / or polypeptides. alpha and / or Neutrocin-alphaSV of the present invention and / or NAR polypeptides. The levels of expression of one or more of these molecules of the invention, subsequently, are compared with the expression levels of the same molecules of the invention expressed in a person known to be unaffected by an autoimmune disease or disorder. A significant difference in the expression levels of Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides and / or polypeptides of the present invention, and / or agonists and / or antagonists thereof, and / or NAR polypeptides, between samples obtained - from subjects and controls, suggests that the subject is affected by an autoimmune disease or disorder. In another embodiment, the Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides, or Neutrocin-alpha and / or Neutrocin-alphaSV agonists or antagonists (eg, Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies) of the present invention, are used for treatment, diagnosis or prognosis in an individual suffering from systemic lupus erythematosus or a variety of this disease. According to this embodiment, an individual suffering from systemic lupus erythematosus or a variety of individuals suffering from systemic lupus erythematosus, express aberrantly high levels of Neutrokine-alpha and / or Neutrocin-alphaSV, when compared to individuals who do not suffer from Systemic lupus erythematosus or this variety of systemic lupus erythematosus. Any means described herein or otherwise known in the art can be applied to detect the Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention (e.g., SCAF analysis or ELISA detection of the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides of the present invention and PCR hybridization or detection of Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides of the present invention) and for determining the expression profile of the Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides and / or polypeptides of the present invention in a biological sample. A biological sample of people affected by systemic lupus erythematosus, is characterized by high levels of expression of Neutrocin-alpha and / or Neutrocin-alphaSV when compared with the levels observed in individuals who do not suffer from systemic lupus erythematosus. Thus, the Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides and / or polypeptides of the present invention, and / or agonists or antagonists thereof, can be used in accordance with the methods of the present invention in diagnosis and / or prognosis of systemic lupus erythematosus or a variant of systemic lupus erythematosus. For example, a biological sample obtained from a person suspected of being affected by systemic lupus erythematosus ("the subject") can be analyzed with respect to the relative expression levels of Neutrocin-alpha polynucleotides and / or polypeptides and / or Neutrocin-alphaSV of the present invention. The expression levels of one or more of these molecules of the invention are subsequently compared to the expression levels of the same molecules of the invention expressed in a person known to be unaffected by systemic lupus erythematosus ("the control") . A significant drence in the expression levels of Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides and / or polypeptides of the present invention, and / or agonists and / or antagonists thereof, between samples obtained from subjects and controls , suggests that the subject is affected by systemic lupus erythematosus, or a variety thereof. In addition, there is a direct correlation between the severity of systemic lupus erythematosus or a variety of this disease, and the concentration of polynucleotides (RNA) and / or Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides of the present invention. Thus, the Neutrokine-alpha and / or Neutrocin-alphaSV polypeptides (RNAs), polypeptides and / or agonists or antagonists of the invention can be used according to the methods of the invention in the prognosis of the severity of lupus erythematosus. systemic or a variety of systemic lupus erythematosus. For example, in a biological sample obtained from a person suspected of suffering from systemic lupus erythematosus ("the subject") can be analyzed with respect to the relative expression levels of Neutrokine-alpha polynucleotides and / or polypeptides and / or Neutrocin-alphaSV of the present invention. The expression levels of one or more of these molecules of the invention are subsequently compared with the expression levels of the same molecules of the invention expressed in a panel of persons known to represent a range of severities of this disease. In accordance with this method, the coincidence of the level of expression with a characterized member of the panel indicates the severity of the disease. In another embodiment, Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides or Neutrocin-alpha and / or Neutrocin-alphaSV agonists or antagonists (eg, Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies) of the present invention , are used for treatment, diagnosis or prognosis of an individual suffering from rheumatoid arthritis or a variety of this disease. According to this embodiment, an individual suffering from rheumatoid arthritis or a variety of individuals suffering from rheumatoid arthritis, express aberrantly high levels of Neutrokine-alpha and / or Neutrocin-alphaSV, when compared to an individual who does not suffer from arthritis. rheumatoid or this variety of rheumatoid arthritis. Any means described herein or otherwise known in the art can be applied to detect the Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention (e.g., SCAF analysis or ELISA detection of the Neutrokine-alpha and / or Neutrocin-alphaSV polypeptides of the present invention and hybridization or PCR detection of Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides of the present invention) and for determining the expression profile of the Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides and / or polypeptides of the present invention, in a biological sample. A biological sample of people affected by rheumatoid arthritis, is characterized by high levels of expression of Neutrocina-alpha and / or Neutrocina-alfaSV when compared with the levels observed in individuals who do not suffer from rheumatoid arthritis. Thus, the Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides and / or polypeptides of the present invention, and / or agonists or antagonists thereof, can be used in accordance with the methods of the present invention in diagnosis and / or prognosis of rheumatoid arthritis or a variant of rheumatoid arthritis. For example, a biological sample obtained from a person suspected of being affected by rheumatoid arthritis ("the subject") can be analyzed with respect to the relative expression levels of Neutrokine-alpha and / or polynucleotides and / or polypeptides. Neutrokine-alphaSV of the present invention. The levels of expression of one or more of these molecules of the invention, subsequently, are compared to the levels of -5-expression of the same molecules of the invention expressed in a person known to be unaffected by rheumatoid arthritis. A significant difference in the expression levels of the Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides and / or polypeptides of the present invention, and / or agonists and / or antagonists thereof, between samples obtained from the subject and from controls , suggests that the subject is affected by rheumatoid arthritis, or a variety of it. Thus, the present invention provides a diagnostic method useful for the diagnosis of an immune system disorder, including cancers of this system and immunodeficiency and / or autoimmune diseases, which includes measuring the level of expression of the gene encoding the polypeptide Neutrokine-alpha and / or Neutrocin-alphaSV in the tissue of the immune system or other cells or body fluids of an individual and compare the level of gene expression obtained with a standard gene expression level of Neutrocin-alpha and / or Neutrocin-alphaSV , whereby an increase or decrease in the level of gene expression, compared to the standard, is indicative of a disorder of the immune system. When a diagnosis of an immune system disorder, including but not limited to diagnosis of a tumor, diagnosis of an immunodeficiency and / or diagnosis of an autoimmune disease has already been made in accordance with conventional methods, the present invention is useful as an indicator of prognosis, by which patients who exhibit an increase or decrease in the expression of the gene Neutrocina-alpha and / or Neutrocina-alfaSV, will experience a more unfavorable clinical outcome in relation to patients who express the gene at levels closer to the standard. When analyzing or determining the level of expression of the gene coding for Neutrokine-alpha and / or Neutrokine-alphaSV, it is intended to measure qualitatively or quantitatively, or estimate, the level of the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide or the level of mRNA encoding Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide in a first biological sample, either directly (eg, by determining or estimating absolute protein concentration or mRNA concentration) or, relatively (eg , comparing with the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide concentration or the concentration of mRNA in a second biological sample). Preferably, the concentration of Neutrokine-alpha and / or Neutrocin-alphaSV polypeptide or the concentration of mRNA in the first biological sample, is measured or estimated and compared with a standard concentration of Neutrokine-alpha and / or Neutrocin-alphaSV polypeptide or a standard concentration of mRNA, where the standard is taken from a second biological sample obtained from an individual who does not have of the disorder or a given standard by averaging the concentrations from samples from a population of individuals who do not have the immune system disorder. As will be seen, once a standard level of Neutrokine-alpha and / or Neutrocin-alphaSV polypeptide or a standard level of mRNA is known, these can be used repeatedly as a standard for comparison. The term "biological sample" as used herein, means any biological sample obtained from an individual, body fluid, cell line, tissue culture or other source containing the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide or MRNA. As indicated, biological samples include bodily fluids (such as serum, plasma, urine, synovial fluid, and spinal fluid) that contain free extracellular domains of Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide, immune system tissue, and other sources. of tissue that is known to express Neutrokine-alpha and / or Neutrokine-full alphaSV or free extracellular domain, or a Neutrokine-alpha and / or Neutrocin-alphaSV receptor. Methods for obtaining tissue biopsies and body fluids from mammals are known in the art. When the biological sample does not include mRNA, a tissue biopsy is the preferred source. The compounds of the present invention are useful for the diagnosis, prognosis or treatment of various disorders related to the immune system in mammals, preferably humans. Such disorders include, but are not limited to, tumors (eg, B cell leukemias and monocytic cells and lymphomas) and tumor metastases, bacterial infections, viruses and other parasites, immunodeficiencies, inflammatory diseases, lymphadenopathy, autoimmune diseases (eg, arthritis). rheumatoid, systemic lupus erythematosus, Sjogren's syndrome, mixed connective tissue disease and inflammatory myopathies), and graft versus host disease. Total cellular RNA can be isolated from a biological sample using any suie technique, for example the one-step guanidinium-phenol-chloroform thiolate method described by Chomczynski and Sacchi, Anal. Biochem. 162: 156-159 (1987). The levels of mRNA encoding the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide are determined using any appropriate method. These methods include Northern blot analysis, nuclease mapping, polymerase chain reaction (PCR) reverse transcription combined with polymerase chain reaction (PCR-TI) and combined reverse transcription. with the chain reaction catalyzed by ligase (RCL-TI). The Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide concentration assay in a biological sample can be carried out using antibody-based techniques. For example, the expression of Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide in tissues can be studied by classical immunohistological methods (Jalkanen, M., et al., J. Cell, Biol. 101: 916-985 ( 1985); Jalkanen, M., et al., J. Cell. Biol. 105: 3081-3096 (1987)). Other methods based on antibodies useful for the detection of Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide gene expression include immunoassays such as the enzyme-linked immunosorbent assay (ELISA) and the radioimmunoassay (RIE). Some suitable antibody labels are known in the art and include enzymatic labels such as glucose oxidase and radioisotopes such as iodine (131I, 125I, 1 3I, 1-1I), carbon (1C), sulfur (35S), tritium (3H) ), indium (115mIn, 113mIn, 112In, nin) and technetium (99Tc, 99mTc), thallium (20iTi), gallium (68Ga, 67Ga), palladium (103Pd), molybdenum (99Mo), xenon (133Xe), fluorine ( 18F), 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 186Re, 188Re, 142Pr, 105Rh, 97Ru; luminescent labels such as luminol; and fluorescent labels such as fluorescein and rhodamine and biotin. The techniques known in the art can be applied to label the antibodies of the present invention. Such techniques include, but are not limited to, the use of bifunctional conjugating agents (see, US Patents 5,756,065, 5,714,631, 5,696,239, 5,652,361, 5,505,931, 5,489,425, 5,435,990, 5,428,139, 5,342,604, 5,274,119, 4,994,560 and 5,808,003; which is incorporated herein by reference in its entirety). The type of tissue or cell to be analyzed, will generally include those that are known or suspected to express the Neutrokine-alpha gene (such as for example cells of the monocytic line) or cells or tissues that are known or suspected to be expressed. Suspect that they express the Neutrokine-alpha receptor gene (such as for example) cells of the B-cell line and the spleen). Methods of isolation of proteins employed herein, for example, may be such as those described in Harlow, E. and Lane, D., 1988, "Antibodies: A Laboratory Manual," Cold Spring Harbor Laboratory Press, Cold Spring Harbor , New York), which are incorporated herein by reference in their entirety. The isolated cells can be isolated from a cell culture or from a patient. The analysis of cells from a culture may be a necessary step in the evaluation of cells that could be used as part of a cell-based gene therapy technique or, alternatively, to test the effect of the compounds on the expression of the Neutrokine-alpha gene or Neutrokine-alpha receptor gene. For example, antibodies, or ***** fragments of antibodies, such as those described herein, may be used to quantitatively or qualitatively detect the presence of Neutrocin-alpha gene products or conserved variants or peptide fragments thereof. This can be carried out, for example, by immunofluorescence techniques, using an antibody with a fluorescent label coupled with microscopic light, flow cytometry or fluorimetric detection. The antibodies (or fragments thereof) or Neutrokine-alpha polypeptides or polypeptides of the present invention, additionally, can be used histologically for example in immunofluorescence, in immunoelectron microscopy or in non-immunological assays, for the in-situ detection of the gene of NeutjLOcina-alpha or conserved variants or peptide fragments thereof, or for the binding of Neutrocin-alpha to the Neutrocin-alpha receptor. The detection in si tu can be carried out by removing a histological sample from a patient and applying a labeled antibody or a Neutrocin-alpha antibody of the present invention. The antibody (or fragment) or the Neutrocin-alpha polypeptide is preferably applied to the labeled antibody (or fragment) in a biological sample. By using such a method, it is possible to determine not only the presence of the Neutrocin-alpha gene product or conserved variants or peptide fragments, or the binding of Neutrocin-alpha polypeptide, but also its distribution in the examined tissue. Employing the present invention, those skilled in the art will readily perceive that any of a wide variety of histological methods (such as staining procedures) can be modified in order to achieve this detection in itself. Immunoassays and non-immunoassays for the detection of Neutrocin-alpha gene products or conserved variants or peptide fragments thereof, will typically comprise incubating a sample, such as a biological fluid, a tissue extract, freshly harvested cells or cell lysates that have were incubated in cell culture, in the presence of an antibody with a detectable label capable of identifying the Neutrocin-alpha gene products or conserved variants or peptide fragments thereof, and detecting the bound antibody by any of a number of techniques known in the art. countryside. Immunoassays and non-immunoassays for the detection of Neutrocin-alpha receptor gene products or conserved variants or peptide fragments thereof, will typically comprise incubating a sample, such as a biological fluid, a tissue extract, freshly harvested cells or cell lysates. which have been incubated in cell culture, in the presence of a Neutrocin-alpha polypeptide with a detectable tag capable of identifying Neutrocin-alpha gene products or conserved variants or peptide fragments thereof, and detecting the bound Neutrocin-alpha polypeptide by any of a number of techniques known in the art. The biological sample may be contacted with a solid phase support or carrier and immobilized therein, such as nitrocellulose or other solid support which is capable of immobilizing cell particles or soluble proteins. Thereafter, the support can be washed with suitable buffer solutions, followed by a treatment with the antibody Antineutrocin-alpha carrying a detectable label or a detectable Neutrocin-alpha polypeptide. The solid phase support, then, can be washed with a buffer solution a second time to remove the antibody or polypeptide that did not bind. Optionally, the antibody is then labeled. Subsequently, the amount of mark attached to the solid support is detected by conventional methods. The term "solid phase carrier or carrier" as used herein, means any carrier capable of binding an antigen or an antibody. Known supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros and magnetite. The nature of the carrier can be soluble to a degree or insoluble for the purposes of the present invention. The support material can have virtually any possible structural configuration, as long as the coupled molecule is capable of binding to an antigen or antibody. Thus, the configuration of the support can be spherical, for example a bead, or cylindrical, for example the inner surface of a test tube, or the external surface of a rod. Alternatively, the surface may be flat such as a sheet, a test strip, etc. Preferred supports include polystyrene beads. Those skilled in the art will know other suitable carriers to bind the antigen or antibody or will be able to determine them by routine experimentation. The binding activity of a given batch of Antineutrocin-alpha antibody or Neutrocin-alpha polypeptide can be determined in accordance with known methods. Those skilled in the art will be able to determine the optimum operating and testing conditions for each determination, through routine experimentation. In addition, assaying Neutrokine-alpha and / or Neutrocin-alphaSV polypeptide levels or levels of the polypeptide in a biological sample obtained from an individual, Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides can also be detected in vivo by imaging. For example, in one embodiment of the present invention, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide or Antineutrocin-alpha antibody is used to image B-cell lymphoreses. In one embodiment, the Neutrocin-alpha polypeptides and / or Neutrocin-alphaSV and / or Antineutrocin-alpha antibodies and / or Neutrocin-alpha polynucleotides of the present invention (eg, polynucleotides complementary to all or a portion of the Neutrocin-alpha and / or Neutrocin-alphaSV mRNA), they are used to obtain images of lymphoras (eg, monocyte and B cell lympholas). Markings of antibodies or markers for in vivo imaging of the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides include those labels or markers detectable by X-ray radiography, MRI, MRI, Scan-TAC or Reaction Scheme. For X-ray radiographs, suitable labels include radioisotopes such as barium or cesium, which emit detectable radiation but are not overtly dangerous to the subject. Suitable markers for NMR and Reaction Scheme include those with a detectable characteristic spin, such as deuterium, which can be incorporated into the antibody by labeling nutrients for the relevant hybridoma. When in vi vo images are used to detect increased levels of the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide for diagnosis in humans, human antibodies or "humanized" chimeric monoclonal antibodies would be preferable. Such antibodies can be produced using the techniques described herein or otherwise known in the art. For example, methods for the production of chimeric antibodies in the art are known. See, for a review, - 51 Morrison, Science 229: 1202 (1985); Oi et al., Biotechniques 4: 214 (1986); Cabilly et al., United States Patent US 4,816,567; Taniguchi et al., European Patent EP 171,496; Morrison et al., European Patent EP 173,494; Neuberger et al., International Publication WO 8,601,533; Robinson et al. , International Publication WO 8,702,671; Boulianne et al., Nature 312: 643 (1984); Neuberger et al., Nature 314: 268 (1985). Additionally, any Neutrocin-alpha polypeptide whose presence can be detected can be administered. for example, Neutrocin-alpha polypeptides labeled with radiopaque compounds or other appropriate compounds can be administered and visualized in vi, as described above for the labeled antibodies. In addition, such Neutrocin-alpha polypeptides can be used in vi tro for diagnostic procedures. A specific antibody against Neutrokine-alpha and / or Neutrocin-alphaSV polypeptide or an antibody fragment that has been labeled with an appropriate detectable image portion, such as a radioisotope (eg, 131I, 112In, 99mTc, (131I 125I , 123I, 121I), carbon (14C), sulfur (35S), tritium (3H), indium (115mIn, 113mIn, 112In, X11ln) and technetium (99Tc, 99mTc), thallium (201Ti), gallium (58Ga, d7Ga) , palladium (103Pd., molybdenum (99Mo), xenon (133Xe), fluorine (18F), 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 186Re, 188Re, 1 2Pr, 105Rh, 97Ru) , a radiopaque substance or a material detectable by nuclear magnetic resonance, is introduced (for example, parenterally, subcutaneously or intraperitoneally) in the mammal to be examined with respect to a disorder of the immune system. subject and the system of obtaining the images used, will determine the amount of image portion needed for to produce diagnostic images. In the case of an isotope portion for a human subject, the amount of radioactivity injected will usually vary in the range of about 5 to 20 millicuries of 99rnTc. The antibody or labeled antibody fragment, then, will preferably accumulate at the location of cells containing the Neutrocin-alpha protein. In vivo tumor images are described in S.W. Burchiel et al., "Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments" (Chapter 13 in Tumor Imaging: The Radiochemical Detection of Cancer, S.W. Burchiel and B.A. Rhodes, eds., Masson Publishing Inc. (1982)). With respect to antibodies, one of the ways in which the Antineutrocin-alpha antibody can be detectably labeled is by ligating it to an enzyme and using the bound product in an enzyme immunoassay (EIE) (Vollder, A., "The Enzyme Linked Immunosorbent Assay (ELISA) ", 1978, Diagnostic Horizons 2: 1-7, Microbiological Associates Quarterly Publication, Walkersville, MD); Voller et al., J. Clin. Pathol. 31: 507-520 (1978); Butler, J. E., Meth. Enzymol. 73: 482-523 (1981); Maggio, E. (ed.), 1980, Enzyme Immunoassay, CRC Press, Boca Raton, Fl.; Ishikawa, E. et al. , (eds.), 1981, Enzyme Immunoassay, Kgaku Shoin, Tokyo). The enzyme that is bound to the antibody will react with an appropriate substrate, preferably a chromogenic substrate, in such a way as to produce a chemical moiety that can be detected, for example, by spectrophotometry, fluorometry or by visual means. Enzymes that can be used to detectably label the antibody, include but are not limited to, malate dehydrogenase, staphylococcal nuclease, delta-5-steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate dehydrogenase, triosephosphate isomerase, horseradish peroxidase, phosphatase alkaline, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase and acetyl cholinesterase. Additionally, detection can be carried out by colorimetric methods that employ a chromogenic substrate for the enzyme. Detection can also be achieved by visual comparison of the degree of enzymatic reaction of a substrate, compared to standards prepared in a similar way. Detection can also be carried out using any of a variety of other immunoassays. For example by radioactive labeling of antibodies or antibody fragments, it is possible to detect Neutrocin-alpha in a radioimmunoassay (RIE) (see for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March 1986, which is incorporated herein by reference). The radioactive isotope can be detected by means including, but not limited to, gamma counters, a scintillation counter or by autoradiography. It is also possible to label the antibody with a fluorescent compound. When the fluorescent-labeled antibody is exposed to a light of the appropriate wavelength, its presence can be detected due to fluorescence. Among the most commonly used fluorescent label compounds are fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, ophthaldehyde and fluorescamine. The antibody can also be detectably labeled using fluorescence emitting metals, such as those of the lanthanide series, which can be bound to the antibody using metal chelating groups such as diethylenetriamine acetic acid (ADTP) or ethylenediamine tetraacetic acid (EDTA) The antibody can also be detectably labeled by coupling it with a chemiluminescent compound The presence of the antibody labeled with a chemiluminescent compound is subsequently determined by detecting the presence of luminescence that arises during the course of a reaction Examples of particularly useful chemiluminescent labeling compounds are luminol, isoluminol, acrominic ester, imidazole, acridinium salt, and oxalate ester.A similarly, a bioluminescent compound can be used to label the antibody of the present invention The bioluminescence is a type of imioluminescence found in biological systems, in which a catalytic protein increases the efficiency of the chemiluminescent reaction. The presence of a bioluminescent protein is determined by detecting the presence of luminescence. Some important bioluminescent compounds for labeling purposes include, but are not limited to, luciferin, luciferase and aequorin. Treatment of Disorders Related to the Immune System - 52 - As noted above, Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides and polypeptides and Antineutrocin-alpha antibodies are useful for the diagnosis of disorders involving abnormally low or high expression of Neutrocin-alpha activity and / or Neutrocin-alfaSV. Given the cells and tissues in which Neutrokine-alpha and / or Neutrokine-alphaSV are expressed, as well as the activities modulated by Neutrokine-alpha and / or Neutrokine-alphaSV, it is evident that a substantially altered level of expression (increased or decreased) of Neutrokine-alpha and / or Neutrokine-alphaSV in an individual, compared to the standard or "normal" level, produces pathological disorders related to the body systems in which Neutrocin-alpha and / or Neutrocin-alphaSV is expressed and / or where it is active. It will also be apparent to a person skilled in the art, since the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides of the present invention are members of the TNF family, the extracellular domains of the respective proteins can be released in soluble form from the cells expressing Neutrokine-alpha and / or Neutrokine-alphaSV, by a proteolytic cleavage and, therefore, when the Neutrokine-alpha and / or Neutrokine-alphaSV polypeptide (particularly a soluble form of the respective extracellular domains) is added from an exogenous source to the cells, tissues or body of an individual, the polypeptide will exert its modulating activities on any of its target cells within said individual. Likewise, cells expressing this type of transmembrane II protein can be added to the cells, tissues or body of an individual, whereby the aggregated cells will bind to the cells expressing the Neutrocin-alpha receptor and / or Neutrokine-alphaSV, whereby cells expressing Neutrocin-alpha and / or Neutrocin-alphaSV can cause actions (eg, proliferation or cytotoxicity) in target cells carrying the receptor. In one embodiment, the present invention provides a method for administering compositions containing the polypeptides of the invention (eg, compositions containing Neutrokine-alpha and / or Neutrocin-alphaSV polypeptides or Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies, associated with heterologous polypeptides, heterologous nucleic acids, toxins or prodrugs) to target cells, such as, for example, B cells expressing the Neutrokine-alpha and / or Neutrocin-alphaSV receptor, or monocytes that express the form bound to the cell surface of Neutrokine-alpha and / or Neutrocin-alphaSV, polypeptides of - 4 - Neutrokine-alpha and / or Neutrocin-alphaSV or antibodies Antineutrocin-alpha and / or Antineutrocin-alphaSV of the present invention, can be associated with heterologous polypeptides, heterologous nucleic acids, toxins or prodrugs, through hydrophobic, hydrophilic, ionic and / or ionic interactions. covalent In one embodiment, the present invention provides a method for the specific administration of compositions of the present invention to cells, by administering the polypeptides of the present invention (eg, Neutrokine-alpha and / or Neutrocin-alphaSV polypeptides or Antineutrocin-alpha and / or Antineutrocin-alphaSV), which are associated with heterologous polypeptides or nucleic acids. In one example, the present invention provides a method for administering a therapeutic protein in the target cell. In another example, the present invention provides a method for delivering a single-stranded nucleic acid (eg, antisense or ribozymes) or a double-stranded nucleic acid (eg, DNA that can be integrated into the genome of the cell or that can be replicate episomally and can be transcribed) in the target cell. In another embodiment, the present invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells), - - by administration of the polypeptides of the present invention (e.g., Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides or Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies) in association or cytotoxic toxins or prodrugs. In a specific embodiment, the present invention provides a method for the specific destruction of cells from the B-cell line (eg, leukemias or B cell-related lymphomas) by administration of Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides in association with toxins or cytotoxic prodrugs. In another specific embodiment, the present invention provides a method for the specific destruction of monocytic line cells (e.g., monocytic leukemias or lymphomas), by administering Antineutrocin-alpha antibodies and / or Antineutrocin-alfaSV, in association with toxins or • cytotoxic prodrugs. The term "toxin" as used herein, means compounds that bind to and activate endogenous cytotoxic effector systems, radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, cytotoxins (cytotoxic agents) or any molecule or enzyme that normally does not it is present inside or on the surface of a cell that, under defined conditions, causes cell death. Toxins that can be used in accordance with the methods of the present invention include, but are not limited to, radioisotopes known in the art, compounds such as for example antibodies (or portions containing complement fixatives thereof) that bind to an inherent or induced endogenous cytotoxic effector system, thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saporin, momordin, gelonin, radish antiviral protein, alpha-sarcin and cholera toxin. The term "toxin" also includes a cytostatic or cytocidal agent, a therapeutic agent or radioactive metal ion, e.g., alpha emitters such as for example 213Bi or other radioisotopes such as for example 103Pd, 133Xe, 131I, d8Ge, 57, Co, 65Zr "n, 85Sr ,,, 32-Pn, 35Se, 90vY, 153S0wm ,, 153Gr.dj, 169vYb, 75 S0el ,, 113So.n ,, 90tI.t? _. Ri • o", 117 .E-.st.year, 186DRe ", m, • o,, y, 188-Rr > e__m.; o,.; _ luminescent labels such as luminol and fluorescent labels such as fluorescein and rhodamine and biotin. The techniques known in the art can be applied to label the antibodies of the present invention. Such techniques include, but are not limited to, the use of bifunctional conjugating agents (see e.g., U.S. Patent Nos. 5,756,065; 5,714,631; 5,696,239; - ,652,361; 5,505,931; 5,489,425; 5,435,990; 5,428,139; 5,342,604; 5,274,119; 4,994,560 and 5,808,003; the content of each of them is incorporated herein in its entirety as a reference). A cytotoxin or cytotoxic agent includes any agent that is harmful to the cells. Some examples include paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthrocinone, nitroxanthone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine , tetracaine, lidocaine, propranolol and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolite agents (eg, methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil-decarbazine), alkylating agents (eg, mechlorethamine, chlorambucilothioepa, melphalan, carmustine (BSNU), and lomustine (CCNU), cyclophosphamide, busulfan, dibromomanitol, streptozotocin, mitomycin C and cis-dichlorodiamine platinum (II) (DDP), cis-platinum), anthracyclines (eg, daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (eg, dactinomycin ( previously actxnomycin), bleomycin, mithramycin and anthramycin (AMC)) and antimytosis agents (eg, vincristine and vinblastine). The term "cytotoxic prodrug" as used herein, refers to a non-toxic compound that is transformed by an enzyme, normally present in the cell, into a cytotoxic compound. Cytotoxic prodrugs that can be used in accordance with the methods of the present invention include, but are not limited to, glutamyl derivatives of the benzoic acid mustard alkylating agent, etoposide phosphate derivatives or mitomycin C, cytosine arabinoside, daunorubisin and derivatives phenoxyacetamide of doxorubicin. It will be noted that disorders caused by a decrease in the normal or standard level of activity of Neutrokine-alpha and / or Neutrokine-alphaSV in an individual, particularly disorders of the immune system, can be treated by administration of the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide (in the form of a soluble extracellular domain or cells expressing the entire protein) or an agonist. Thus, the present invention also provides a method of treating an individual in need of an increased level of activity of Neutrokine-alpha and / or Neutrocin-alphaSV, which comprises administering to such an individual a pharmaceutical composition comprising a amount of a Neutrokine-alpha and / or Neutrocin-alphaSV polypeptide of the present invention, or an agonist thereof, effective to increase the activity of Neutrokine-alpha and / or Neutrocin-alphaSV in such an individual. It will also be noted that disorders caused by an increase in the standard or normal level of Neutrokine-alpha and / or Neutrokine-alphaSV activity in an individual, particularly disorders of the immune system, can be treated by administration of the Neutrocin- alpha and / or Neutrocin-alphaSV (in the form of a soluble extracellular domain or cells expressing the entire protein) or an antagonist (eg, an Antineutrocin-alpha antibody). Thus, the present invention also provides a method of treating an individual that needs a decrease in the activity level of Neutrokine-alpha and / or Neutrocin-alphaSV, which comprises administering to such an individual a pharmaceutical composition comprising a amount of a polypeptide isolated from Neutrocin-alpha and / or Neutrocin-alphaSV of the present invention, or an antagonist thereof, effective to decrease the activity level of Neutrocin-alpha and / or Neutrocin-alphaSV in said individual. The Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention, or Neutrokine-alpha and / or Neutrocin-al-TaSV agonists, can be used in the treatment of infectious agents.

For example, by increasing the immune response, particularly by increasing the proliferation and differentiation of B cells, infectious diseases can be treated. The immune response can be increased either by increasing the existing immune response, or by initiating a new immune response. Alternatively, Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides, or Neutrocin-alpha and / or Neutrocin-alphaSV agonists, may also directly inhibit the infectious agent, without the need to induce an immune response. The viruses are an example of an infectious agent that can cause diseases or symptoms that can be treated with Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides, or Neutrocin-alpha and / or Neutrocin-alphaSV agonists. Some examples of viruses include but are not limited to, the following viruses, DNA and RNA, and viral families: Arboviruses, Adenoviridae, Arenaviridae, Arterivirus, Birnaviridae, Bunyaviridae, Cali civiridae, Circoviridae, Coronaviridae, Dengue, EBV, HIV, Flaviviridae, Hepadnaviridae ( Hepatitis), Herpesviridae (such as cytomegalovirus, herpes simplex, herpes zoster), mononegavirus (eg, Paramyxoviridae, Morbilli virus, Rhabdoviridae), Orthomyxoviridae (eg, Influenza A, Influenza B and parainfluenza), papilloma virus, Papovaviridae, Parvoviridae, Picornaviridae, Poxviridae (such as as varicella or vaccinia) Reoviridae (eg, rotavirus), retroviridae (HTLV-I, HTLV-II, Lentivirus) and Togaviridae (eg, Rubivirus). Viruses within these families can cause a variety of diseases or symptoms, including but not limited to: arthritis, bronchiolitis, respiratory syncytial virus, encephalitis, eye infections (eg, conjunctivitis, keratitis), chronic fatigue syndrome, hepatitis (A, B , C, E, Active Chronicle, Delta), Japanese B encephalitis, Junin, Chicungunia, Rift Valley fever, yellow fever, meningitis, opportunistic infections (eg, AIDS), pneumonia, Burkitt's lymphoma, varicella, hemorrhagic fever, measles, mumps, parainfluenza, rabies, common catarrh, polio, leukemia, rubella, sexually transmitted diseases, skin diseases (eg, Kaposi's sarcoma, warts) and viremia. The Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides, or Neutrocin-alpha and / or Neutrocin-alphaSV agonists or antagonists, can be used for the treatment, prevention, diagnosis and / or detection of any of these symptoms or diseases. In specific embodiments, Neutrocin-alpha polynucleotides, polypeptides or agonists are used for the treatment, prevention and / or diagnosis of: meningitis, dengue, EBV and / or hepatitis (e.g., hepatitis B). In a further specific embodiment, Neutrocin-alpha polynucleotides, polypeptides or agonists are used for the treatment of patients who do not respond to one or more other commercially available vaccines against hepatitis. In a further specific embodiment, Neutrokine-alpha polynucleotides, polypeptides or agonists are used for the treatment, prevention and / or diagnosis of AIDS. In a further specific embodiment, the Neutrokine-alpha and / or Neutrocin-alphaSV and / or Neutrokine-alpha receptor polynucleotides, polypeptides, agonists and / or antagonists are used for the treatment, prevention and / or diagnosis of patients with cryptosporidiosis. Similarly, bacterial or fungal agents that can cause diseases or symptoms and that can be treated with the neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides or agonists or antagonists, include but are not limited to the following bacteria Gram-negative and Gram-positive and families of bacteria and fungi: actinomycetales (eg, Corynebacterium, Mycobacterium, Norcardia), Cryptococcus neoformans, Aspergillosis, Bacillaceae (e.g., anthrax, clostridium), Bacteroidaceae, Blastomycosis, Bordetella, Borrelia (eg, Borrelia burgdoiferi), brucellosis, candidiasis, campylobacter, Coccidioidomycosis, Cryptococcosis, - 33 - dermatomycosis, E. coli (eg, enterotoxigenic E. coli and enterohemorrhagic E. coli), Enterobacteriaceae (Klebsiella, Salmonella (eg, Salmonella typhi and Salmonella partyphi), Serratia, Yersinia), Erysipelothrix, Helicobacter, Legionellosis, Leptospirosis, Listeria (eg, Listeria monocytogenes), mycoplasmas, Mycobacterium um leprae, Vibrio cholerae, Neisseriaceae (eg, Acinetobacter, gonorrhea, meningococci), Neisseria meningi tidis , infections by Pasteurellacea (eg, Actinobacillus, Heamophilus (eg, Heamophilus influenza type B), Pasteurella), pseudomonas, Rickettsiaceae, Chlamydiaceae, syphilis, Shigella spp., staphylococcal, meningococcal, pneumococcal and streptococcal (eg, Streptococcus pneumoniae and Streptococcus Group B). These families of bacteria or fungi can cause the following diseases or symptoms, including but not limited to: bacteremia, endocarditis, eye infections (conjunctivitis, tuberculosis, uveitis), gingivitis, opportunistic infections (eg, AIDS-related infections), paronychia , prosthetic-related infections, Reiter's disease, respiratory tract infections such as whooping cough or empyema, sepsis, Lyme disease, cat scratch disease, dysentery, paratyphoid fever, food poisoning, typhoid, pneumonia, gonorrhea, meningitis ( eg, meningitis types A and B), - 4 - chlamydia, syphilis, diphtheria, leprosy, paratuverculosis, tuberculosis, lupus, botulism, gangrene, tetanus, impetigo, rheumatic fever, scarlet fever, sexually transmitted diseases, skin diseases (eg, cellulitis, dermatocytosis), toxemia, urinary tract infections, wound infections. The Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides, or Neutrocin-alpha and / or Neutrocin-alphaSV agonists or antagonists, can be used for the treatment, prevention, diagnosis and / or detection of any of these symptoms or diseases. In specific embodiments, Neutrokine-alpha polynucleotides or polypeptides or agonists thereof are used for the treatment and / or diagnosis of: tetanus, diphtheria, botulism and / or type B meningitis. In addition, parasitic agents can be treated cause diseases or symptoms by Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides, or Neutrocin-alpha and / or Neutrocin-alphaSV agonists, which include but are not limited to the following families or classes: amoebiasis, babesiosis , coccidiosis, cryptosporidiosis, dientamoeviasis, dourine, ectoparasites, Giardiasis, helminthiasis, leishmaniasis, teileriasis, toxoplasmosis, trypanosomiasis and trichomonas and sporozoa (eg, Plasmodium um virax, Plasmodium um falciparium, Plasmodium - malariae and Plasmodium um ovale). These parasites can cause a variety of diseases or symptoms, including but not limited to: scabies, thrombiculiasis, eye infections, intestinal disease (eg, dysentery, giardiasis), liver disease, lung disease, opportunistic infections (eg, AIDS-related) ), malaria or malaria, complications of pregnancy and toxoplasmosis. Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides, or Neutrokine-alpha agonists or antagonists and / or Neutrocin-alphaSV, can be used for the treatment, prevention, diagnosis and / or detection of any of these symptoms or diseases. In specific embodiments, the polynucleotides, Neutrocin-alpha polypeptides, or agonists thereof, are used for the treatment, prevention, and / or diagnosis of malaria or malaria. In another embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention, and / or agonists and / or antagonists thereof, are used for the treatment, prevention and / or diagnosis of ear infections. internal (such as for example, otitis media), as well as other infections characterized by Streptococcus pneumoniae and other pathogenic microorganisms. In a specific embodiment, Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides or agonists or antagonists thereof (eg, Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies), are used for the treatment or prevention of disorders characterized by a deficient production of serum immunoglobulins, recurrent infections and / or immune system dysfunction. In addition, Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides, or agonists or antagonists thereof (eg, Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies), can be used for the treatment or prevention of infections of joints, bones, skin and / or parotid glands, blood infections (eg, sepsis, meningitis, septic arthritis and / or osteomyelitis), autoimmune diseases (eg, those described herein), inflammatory disorders and malignancies and / or any disease or disorder or condition associated with these infections, diseases, disorders and / or malignancies, include but are not limited to, EIVC, other primary immunodeficiencies, HIV disease, LLC, recurrent bronchitis, sinusitis, otitis media, conjunctivitis, pneumonia, hepatitis, meningitis, herpes zoster (e.g., severe herpes zoster) and / or pneumoci sti s carnii. The Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention, or agonists or antagonists thereof, can be used for the diagnosis, prognosis, treatment or prevention of one or more of the following diseases or disorders or conditions associated with them: primary immunodeficiencies, immune-mediated thrombocytopenia, Kawasaki syndrome, bone marrow transplantation (eg, recent bone marrow transplantation in adults or children), chronic B-cell lymphocytic leukemia, HIV infection (eg , HIV infection in adults or pediatric), chronic inflammatory demyelinating polyneuropathy and purpura after a transfusion. Additionally, the Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention, or agonists or antagonists thereof, can be used for the diagnosis, prognosis, treatment or prevention of one or more of the following diseases, disorders or conditions associated therewith, Guillain-Barre syndrome, anemia (eg, anemia associated with parvovirus B19), patients with stable multiple myeloma who are at high risk of infection (eg, recurrent infections), autoimmune hemolytic anemia (eg , fever-type autoimmune emollient anemia), thrombocytopenia (eg, neonatal thrombocytopenia) and immune-mediated neutropenia), transplants (eg, cytomegalovirus-negative (CMV) or CMV-positive organ receptors), hypogammaglobulinemia (eg, hypogammaglobulinemic neonates with risk factors for infections or morbidity), epilepsy (eg, intractable epilepsy), syndromes systemic culitics, myasthenia gravis (e.g., decompensation in myasthenia gravis) dermatomyositis and polymyositis. Additional preferred embodiments of the present invention, include but are not limited to, the use of the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides, Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides and functional agonists thereof, in the following applications: Administration in animals (eg, mice, rats, rabbits, hamsters, guinea pigs, pigs, dwarf pigs, chickens, camels, goats, horses, cows, sheep, dogs, cats, non-human primates and humans, preferably humans) to reinforce the immune system to produce greater amounts of one or more antibodies (eg, IgG, IgA, IgM and IgE), to induce the production of higher affinity antibodies (eg, IgG, IgA, IgM and IgE) and / or to increase the immune response. In a specific non-exclusive embodiment, the Neutrocin-alpha polypeptides of the present invention and / or agonists thereof, are administered to boost the immune system to produce greater amounts of IgG. In another specific non-exclusive embodiment, the Neutrocin-alpha polypeptides of the present invention and / or agonists thereof, are administered to boost the immune system to produce greater amounts of IgA. In another non-exclusive specific embodiment, the Neutrocin-alpha polypeptides of the present invention and / or agonists thereof, are administered to boost the immune system to produce greater amounts of IgM. Administration to an animal (including but not limited to those listed above and also including transgenic animals) incapable of producing functional endogenous antibody molecules or having an endogenous immune system compromised in some other way, but which is capable of producing human immunoglobulins by means of a reconstituted or partially reconstituted immune system from another animal (see, eg, PCT International Publications WO 98/24893, WO 96/34096, WO 96/33735 and WO 91/10741). A vaccine adjuvant that enhances the immune response against a specific antigen. In a specific modality, the vaccine adjuvant is a Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide described herein. In another specific embodiment, the vaccine adjuvant is a Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotide described herein (ie, the Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotide is a genetic vaccine adjuvant) . As described herein, Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides can be administered using techniques known in the art, including but not limited to, liposomal administration, distribution of recombinant vectors, naked DNA injection and distribution. with a gene gun. An adjuvant to enhance tumor-specific immune responses. An adjuvant to intensify antiviral immune responses. Antiviral immune responses that can be enhanced using the compositions of the present invention as adjuvants, include but are not limited to, viruses and diseases associated with viruses or symptoms described herein or otherwise known in the art. In specific embodiments, the compositions of the present invention are used as an adjuvant to enhance an immune response against a virus, disease or symptom that is selected from the group consisting of: AIDS, meningitis, dengue, EBV and hepatitis (eg, hepatitis B) . In another specific embodiment, the compositions of the present invention are used as an adjuvant to enhance an immune response against a virus, disease or symptom that is selected from the group consisting of: HIV / AIDS, respiratory syncytial virus, dengue, rotavirus, encephalitis B Japanese, influenza A and B, parainfluenza, measles, cytomegalovirus, rabies, junin, chicungunia, Rift Valley fever, herpes simplex and yellow fever. In another specific embodiment, the compositions of the present invention are used as an adjuvant to enhance an immune response against the HIV gpl20 antigen. An adjuvant to enhance antibacterial or antifungal immune responses. Antibacterial or antifungal immune responses that can be enhanced using the compositions of the present invention as an adjuvant, include bacteria or fungi and diseases or symptoms associated with bacteria or fungi described herein or otherwise known in the art. In specific embodiments the compositions of the present invention are used as an adjuvant to enhance an immune response against a bacterium or fungus, disease or symptom that is selected from the group consisting of: tetanus, diphtheria, botulism and type B meningitis. In another specific embodiment , the compositions of the present invention are used as an adjuvant to enhance an immune response against a bacterium or fungus, disease or symptom that is selected from the group consisting of: Vibrio cholerae, Mycobacterium leprae, Salmonella typhi, Salmonella paratyphi, Meisseria meningitidis, Streptococcus pneumoniae, group B streptococcus, Shigella spp., enterotoxigenic E. coli, enterohemorrhagic E. coli, Borrelia burgdorfen and Plasmodium um (malaria or malaria). An adjuvant to intensify immune responses against parasites. Immune responses against parasites that can be intensified using the compositions of the present invention as an adjuvant, include parasites and diseases or symptoms associated with parasites described herein or otherwise known in the art. In specific embodiments, the compositions of the present invention are used as an adjuvant to enhance an immune response against a parasite. In another specific embodiment, the compositions of the present invention are used as an adjuvant to enhance an immune response against plasmodium (malaria or malaria). As a stimulator of B cell response against pathogens. As an agent that raises the immune status of an individual before receiving an immunosuppressive therapy. As an agent to induce high affinity antibodies.

As an agent to increase the serum concentration of immunoglobulins. As an agent to accelerate the recovery of immunocompromised individuals. As an agent to strengthen the immune response in elderly populations. As an enhancer of the immune system before, during or after a bone marrow transplant and / or other transplants (e.g., allogeneic or transplants of genogenic organs). With respect to transplants, the compositions of the present invention can be administered before, concomitantly and / or after transplantation. In a specific embodiment, the compositions of the present invention are administered after transplantation, prior to the start of recovery of the T cell populations. In another specific embodiment, the compositions of the present invention are administered for the first time after transplantation after of the recovery of the T cells, but before the complete recovery of the B cell population. As an agent for reinforcing the immune response in immunodeficient B cell subjects, such as, for example, an individual who has undergone a splenectomy partial or total. Immunodeficiencies of B cells that can be improved or treated by administration of Neutrokine-alpha and / or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, include but are not limited to, severe combined immunodeficiency (IDCG) linked to sex, autosomal IDCG, adenosine deaminase deficiency (ADA deficiency), sex-linked agammaglobulinemia (XLA), Bruton's disease, congenital agammaglobulinemia, sex-linked infantile agammaglobulinemia, acquired agamaglobulinemia, adult agamaglobulinemia, agamaglobulinemia of late onset, dysgammaglobulinemia, hypogammaglobulinemia, transient hypogammaglobulinemia of childhood, nonspecific hypogammaglobulinemia, agamaglobulinemia, common variable immunodeficiency (EIVC) (acquired), Wiskott-Aldrich syndrome (SWA), sex-linked immunodeficiency with hyper IgM, immunodeficiency not linked to sex with hyper IgM, selective IgA deficiency , deficiency of IgG subclasses (with or without IgA deficiency), deficiency of antibodies with normal or elevated levels of Ig, immunodeficiency with thymoma, Ig heavy chain deletions, kappa chain deficiency, B cell lymphoproliferative disorders (BLPD) , selective immunodeficiency of IgM, recessive agammaglobulinemia (of Swiss type), reticular dysgenesis, neonatal neutropenia, severe congenital leukopenia, alinfoplasia-thymic aplasia or dysplasia with immunodeficiency, ataxia-telangiectasia, short limb dwarfism, sex-linked lymphoproliferative syndrome (XLP) , combined immunodeficiency with Nezelof syndrome with Igs, purine deficiency, nucleoside phosphorylase (PNP), MHC class II deficiency (scarce lymphocyte syndrome) and severe combined immunodeficiency. As an agent for enhancing the immune response in individuals having an acquired loss of B cell function. Disorders resulting from an acquired loss of B cell function can be improved or treated by administering the polypeptides and Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides of the present invention, or agonists thereof, including but not limited to, HIV infection, AIDS, bone marrow transplantation and B-cell chronic lymphocytic leukemia (CLL). As an agent to strengthen the immune response in individuals who have a temporary immunodeficiency. Disorders that result in a temporary immunodeficiency that can be improved or can be treated by administration of the Neutrokine-alpha and / or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, include but are not limited to , recovery from viral infections (e.g., influenza), disorders associated with malnutrition, recovery of infectious mononucleosis or disorders associated with stress, recovery of measles, recovery of blood transfusions, recovery of surgeries. As a regulator of the presentation of antigens by monocytes, dendritic cells and / or B cells. In one embodiment, the polypeptides (in soluble form, membrane-bound or transmembrane) or Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides, intensify the presentation of the antigen or antagonize the presentation in vivo or in vi tro. In addition, in related modalities, this intensification or antagonism of antigen presentation may be useful in antitumor treatment or to modulate the immune system. As a mediator of mucosal immune responses. The expression of Neutrocin-alpha by monocytes and the response of B cells to this factor suggest that it could be involved in the exchange of signals between B cells and monocytes or their differentiated progeny. This activity in many ways is analogous to the CD40-CD154 signaling between B cells and T cells. Therefore, Neutrocin-alpha can be an important regulator of immune responses independent of T cells against environmental pathogens. In particular, non-conventional populations of B cells (CD5 +) that are associated with mucosal sites and that are responsible for a large part of innate immunity in humans, can respond to Neutrocin-alpha, thus intensifying the protective immune status. of an individual. As an agent to direct the immune system of an individual towards the development of a humoral response (i.e., TH2), as opposed to a TH1 cellular response. As a means to induce the proliferation of tumors and in this way make them more susceptible to antineoplastic agents. For example, multiple myeloma is a slow-dividing disease and therefore refractory to virtually all antineoplastic regimens. If these cells were forced to proliferate more rapidly, their susceptibility profile would change. As a specific binding protein to B cells to which specific activators or inhibitors of cell growth can bind. The result would be to focus the activity of such activators or inhibitors on normal, diseased or neoplastic B cell populations. As a means to detect B cell lines by virtue of their specificity. This application may require labeling the protein with biotin or other agents (e.g., as described herein) to obtain a detection means. As a stimulator of the production of B cells in pathologies such as AIDS, chronic lymphocytic disease and / or common variable immunodeficiency. As part of a B cell selection device whose function would be to isolate B cells from a heterogeneous mixture of cell types. Neutrokine-alpha could be coupled with a solid support to which B cells, then, would bind specifically. The unbound cells would be washed out and the joined cells, subsequently, would be eluted. A non-limiting use of this selection would be to allow the purging of tumor cells from, for example, bone marrow or peripheral blood, before a transplant. As a therapy for the generation and / or regeneration of lymphoid tissues after a surgery, trauma or genetic defect. As gene-based therapy for genetically inherited disorders that cause immunocompetence, such as those observed in patients with IDCG. As an antigen for the generation of antibodies to inhibit or intensify the responses mediated by Neutrocin-alpha.

- - As a means to activate monocytes / macrophages to defend against parasitic diseases affecting monocytes, such as lesmania. As a pre-treatment of bone marrow samples before a transplant. Where such treatment would increase the representation of B cells and thus accelerate recovery. As a means to regulate secreted cytokines that are induced by Neutrocin-alpha. The Neutrocin-alpha or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, can be used to modulate IgE concentrations in vi tro or in vivo. Additionally, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, can be used for the treatment, prevention and / or diagnosis of IgE-mediated allergic reactions. Such allergic reactions include, but are not limited to, asthma, rhinitis and eczema. In a specific embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, are administered for the treatment, prevention, diagnosis and / or improvement of selective IgA deficiency. .

In another specific embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, are administered for the treatment, prevention, diagnosis and / or improvement of ataxia-telangiectasia. In another specific embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, are administered for the treatment, prevention, diagnosis and / or improvement of the common variable immunodeficiency. In another specific embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, are administered for the treatment, prevention, diagnosis and / or amelioration of sex-linked agammaglobulinemia. In another specific embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, are administered for the treatment, prevention, diagnosis and / or improvement of Wiskott-Aldrich syndrome. In another specific embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, are administered for the treatment, prevention, diagnosis and / or amelioration of Ig deficiency linked to the sex with hyperIgM. In another specific embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or agonists or antagonists thereof (eg, Antineutrocin-alpha antibodies), are administered for the treatment, prevention and / or diagnosis of chronic myelogenous leukemia, acute myelogenous leukemia, leukemia, histiocytic leukemia, monocytic leukemia (eg, acute monocytic leukemia), leukemic reticulosis, monocytic leukemia of Shilling type and / or other leukemias derived from monocytes and / or monocytic cells and / or tissues . In another specific embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, are administered for the treatment, prevention, diagnosis and / or enhancement of the monocytic leukemoid reaction, such as seen, for example, in tuberculosis. In another specific embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or agonists thereof, are administered for the treatment, prevention, diagnosis and / or amelioration of monocytic leukocytosis, monocytic leukopenia, monocytopenia and / or monocytosis. In a specific embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention and / or antibodies to antineutrocin-alpha antibodies and / or agonists or antagonists thereof, are used for the treatment, prevention, detection and / or diagnosis of primary B lymphocyte disorders and / or diseases and / or conditions associated therewith. In one embodiment, such primary B lymphocyte disorders, diseases and / or conditions are characterized by a complete or partial loss of humoral immunity. Primary B lymphocyte disorders, diseases and / or conditions associated therewith, which are characterized by a complete or partial humoral immunity and which can be prevented treated and / or diagnosed with the compositions of the present invention include, but are not limited to, are limited to, sex-linked agammaglobulinemia (XLA), severe combined immunodeficiency disease (IDCG) and selective IgA deficiency. In a preferred embodiment, Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides and polypeptides, and / or agonists and / or antagonists thereof, are used for the treatment, prevention and / or diagnosis of diseases or disorders that affect or conditions associated with any one or more of the various mucous membranes of the body. Such diseases or disorders include but are not limited to, for example, mucositis, mucoclasia, mucocolitis, mucocutaneous leishmaniasis (such as for example, American leishmaniasis, American leishmaniasis, nasopharyngeal leishmaniasis and New World leishmaniasis), mucocutaneous lymph node syndrome (e.g. , Kawasaki disease), mucoenteritis, mucoepidermoid carcinoma, mucoepidermoid tumor, mucoepithelial dysplasia, mucoid adenocarcinoma, mucoid degeneration, myxoid degeneration; myxomatous degeneration; myxomatosis, mucoid medial degeneration (eg medial cystic necrosis), mucolipidosis (including, for example, mucolipidosis I, mucolipidosis II, mucolipidosis III and mucolipidosis IV), mucolysis disorders, mucomembranous enteritis, mucoenteritis, mucopolysaccharidosis (such as, for example, , mucopolysaccharidosis type I (ie, Hurler's syndrome), mucopolysaccharidosis type IS (ie, Scheie's syndrome or mucopolysaccharidosis type V), mucopolysaccharidosis type II (i.e., Hunter syndrome), mucopolysaccharidosis type III (i.e., Sanfilippo syndrome), mucopolysaccharidosis type IV (ie, Morquio syndrome), mucopolysaccharidosis type VI (ie, Maroteaux-Lamy syndrome), mucopolysaccharidosis type VII (ie, mucopolysaccharidosis due to beta-glucuronidase deficiency) and mucosulfatidosis), mucopolysaccharideuria, mucopurulent conjunctivitis, mucopus, mucormycosis (ie, zygomycosis), mucosal disease (ie, bovine virus diarrhea), mucosal colitis (such as, for example, mucocolitis and myxomembrane colitis) and mucoviscidosis (such as, for example, cystic fibrosis, cystic fibrosis of the pancreas, Clarke-Hadfield syndrome) Fibrocystic disease of the pancreas, mucoviscidosis and viscidosis). In a highly preferred embodiment, Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides and polypeptides, and / or agonists and / or antagonists thereof, are used for the treatment, prevention and / or diagnosis of mucositis, especially associated with chemotherapy. In a preferred embodiment, Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides and polypeptides, and / or agonists and / or antagonists thereof, are used for the treatment, prevention and / or diagnosis of disorders or diseases or associated conditions with sinusitis An additional disorder, disease or symptom that can be treated, prevented and / or diagnosed with Neutrokine-alpha polynucleotides or polypeptides and / or Neutrokine-alphaSV, or Neutrokine-alpha agonists and / or Neutrocin-alphaSV, is osteomyelitis. An additional disorder, disease or symptom that can be treated, prevented and / or diagnosed with Neutrokine-alpha polynucleotides or polypeptides and / or Neutrokine-alphaSV, or Neutrokine-alpha and / or Neutrocin-alphaSV agonists, is endocarditis.

All the applications described above can be applied to veterinary medicine. Antagonists of Neutrokine-alpha include binding and / or inhibitory antibodies, antisense nucleic acids, ribozymes and Neutrokine-alpha polypeptides of the present invention. These would be expected to reverse many of the activities of the ligand described above, as well as to find clinical or practical application as: A means to block various aspects of immune responses against foreign or self agents. Some examples include autoimmune disorders such as lupus and arthritis, as well as immune responses to skin allergies, inflammation, intestinal disease, injuries and pathogens. Although the current data directly refer to the potential function of Neutrokine-alpha in pathology related to B-cells and monocytes, it is still possible that other cell types might have expression or response to Neutroc-alpha. Thus, Neutrocin-alpha, similar to CD40 and its ligand, could be regulated by the state of the immune system and the microenvironment in which the cell is located. A therapy to prevent B cell proliferation and Ig secretion associated with autoimmune diseases, such as idiopathic thrombocytopenic purpura, systemic lupus erythematosus and MS. An inhibitor of graft versus host disease or transplant rejection. A therapy for malignant diseases of cells B, such as ALL, Hodgkins disease, non-Hodgkins lymphoma, chronic lymphocytic leukemia, plasmacytomas, multiple myeloma, Burkitt's lymphoma and diseases transformed by EBV. A therapy for chronic hypergammaglobulinemia evident in diseases such as monoclonal gammopathy of undetermined significance (MGUS), Waldenstrom's disease, related idiopathic monoclonal gammopathies and plasmacytomas. A therapy to decrease the cellular proliferation of large B-cell lymphomas. A means to decrease the participation of B cells and Ig associated with chronic myelogenous leukemia. An immunosuppressive agent or agents. The Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or antagonists thereof, can be used to modulate IgE concentrations in vi tro or in vivo. In another embodiment, the administration of Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides or polynucleotides of the present invention, or antagonists thereof, can be used for the treatment, prevention and / or diagnosis of IgE-mediated allergic reactions. , including but not limited to asthma, rhinitis and eczema. An inhibitor of signaling pathways involving ERK1, C0X2 and cyclin D2 that have been associated with B cell activation induced by Neutrocin-alpha. The aforementioned applications can be used in a variety of guests. Such hosts include, but are not limited to, humans, mice and rats, rabbits, goats, cows, sheep, guinea pigs, camels, horses, mice, rats, hamsters, pigs, dwarf pigs, chickens, goats, cows, sheep, dogs , cats, non-human primates and humans. In specific modalities, the host is a mouse, rabbit, goat, guinea pig, chicken, rat, hamster, pig, sheep, dog or cat. In preferred embodiments, the host is a mammal. In more preferred embodiments, the host is a human being. The agonists and antagonists can be employed in a composition with a pharmaceutically acceptable carrier, e.g., as described herein. The antagonists can be used for example to inhibit the chemotaxis and activation of macrophages and their precursors mediated by Neutrocin-alpha and / or Neutrocin-alphaSV, and that of neutrophils, basophils, B lymphocytes and some subpopulations of T cells, eg, T cells. activated and cytotoxic CD8 and natural killer cells, in certain autoimmune, chronic inflammatory and infectious diseases. Examples of autoimmune diseases include multiple sclerosis and insulin-dependent diabetes. The antagonists can also be used for the treatment, prevention and / or diagnosis of infectious diseases, including silicosis, sarcoidosis, idiopathic pulmonary fibrosis and the prevention of the recruitment and activation of mononuclear phagocytes. These can also be used for the treatment, prevention and / or diagnosis of idiopathic hypereosinophilic syndrome by preventing the production and migration of eosinophils. The endotoxide shock can also be treated with the antagonists by preventing the migration of the macrophages and their production of the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides of the present invention. Antagonists can also be used for the treatment of atherosclerosis by preventing the infiltration of monocytes into the arterial walls. The antagonists can also be used for the treatment, prevention and / or diagnosis of histamine-mediated allergic reactions and immunological disorders including late-stage allergic reactions, chronic urticaria and atopic dermatitis, by inhibiting the chemokine and basophil-induced degranulation of mast cells and basophils. the release of histamine. IgE-mediated allergic reactions, such as allergic asthma, rhinitis and eczema, can also be treated. Antagonists can also be used for the treatment, prevention and / or diagnosis of chronic and acute inflammation by preventing the attraction of monocytes to the injured area. They can also be used to regulate populations of normal lung macrophages, since chronic and acute pulmonary inflammatory diseases are associated with the sequestration of mononuclear phagocytes in the lungs. Antagonists can also be used for the treatment, prevention and / or diagnosis of rheumatoid arthritis by preventing the attraction of monocytes to synovial fluid in the patient's joints. The influx of monocytes and activation play a significant role in the pathogenesis of degenerative and inflammatory arthropathies. Antagonists can be used to interfere with harmful cascades attributed mainly to IL-1 and TNF, which prevents the biosynthesis of other inflammatory cytokines. In this way, antagonists can be used to prevent inflammation. Antagonists can also be used to inhibit prostaglandin-independent fever induced by Neutrocin-alpha and / or Neutrocin-alphaSV. Antagonists can also be used for treatment, prevention and / or diagnosis of bone marrow failure, for example aplastic anemia and myelodysplastic syndrome. The antagonists can also be used for the treatment, prevention and / or diagnosis of asthma and allergy, by preventing the accumulation of eosinophils in the lungs. The antagonists can also be used for the treatment, prevention and / or diagnosis of subepithelial basement membrane fibrosis, which is a prominent feature of the asthmatic lung. Antagonists can also be used for the treatment, prevention and / or diagnosis of lymphomas (e.g., one or more of the extensive but non-limiting list of lymphomas provided herein). All the applications described above can be applied to veterinary medicine. In addition, all applications described herein can also be applied to veterinary medicine. The Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention and / or agonists and / or antagonists thereof, can be used for the treatment, prevention and / or diagnosis of various disorders related to the immune system. and / or conditions associated with these disorders, in mammals, preferably humans. Many autoimmune disorders result in inappropriate recognition of both the own and foreign material by immune cells. This inappropriate recognition causes an immune response that causes the destruction of host tissue. Therefore, administration of the Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention and / or agonists and / or antagonists thereof, can inhibit an immune response, particularly the proliferation of B cells and / or the production of immunoglobulins, can be an effective therapy in the treatment and / or prevention of autoimmune disorders.

Thus, in preferred embodiments, antagonists of Neutrocin-alpha and / or Neutrocin-alfaSV of the present • invention (e.g., polypeptide fragments of Neutrocin-alpha and / or Neutrocin-alphaSV and Antineutrocin-alpha antibodies) are used for the treatment, prevention and / or diagnosis of an autoimmune disorder. Autoimmune disorders and conditions associated with such disorders, which can be treated, prevented and / or diagnosed with the Neutrokine-alpha polynucleotides and polypeptides and / or antagonists of the present invention (eg, Antineutrocin-alpha antibodies), include but are not limit, autoimmune hemolytic anemia, autoimmune neonatal thrombocytopenia, idiopathic thrombocytopenic purpura, autoimmunocytopenia, hemolytic anemia, antiphospholipid syndrome, dermatitis, allergic encephalomyelitis, myocarditis, recurrent polychondritis, rheumatic heart disease, glomerulonephritis (eg, IgA nephropathy), multiple sclerosis, neuritis, uveitis, ophthalmia, polyendocrinopathies, purpura (eg, Henloch-Scoenlein purpura), Reiter's disease, Stiff-Man syndrome, autoimmune pulmonary inflammation, Guillain-Barre syndrome, insulin-dependent diabetes mellitus, and autoimmune inflammatory eye disease. Some autoimmune disorders (which are highly probable) that can be treated, prevented and / or diagnosed with the compositions of the present invention, include but are not limited to, autoimmune thyroiditis, hypothyroidism (ie, Hashimoto's thyroiditis), (often characterized , eg, by cell-mediated thyroid cytotoxicity and humoral), systemic lupus erythematosus (often characterized, eg, by circulating and locally generated immune complexes), Goodpasture syndrome (often characterized, eg, by antibodies against the basement membrane) , pemphigus (often characterized, eg, by epidermal acantholytic antibodies), autoimmunity of receptors such as, for example, (a) Graves' disease (often characterized, eg, by antibodies against the TSH receptor), (b) ) myasthenia gravis (often characterized, eg, by antibodies to acetylcholine receptors) and (c) insulin resistance (often characterized, eg, by antibodies against the insulin receptor), autoimmune hemolytic anemia (often characterized, e.g., by phagocytosis of erythrocytes sensitized by antibodies), autoimmune thrombocytopenic purpura (often characterized, e.g., by phagocytosis of platelets sensitized by antibodies). Additional autoimmune disorders (which are likely) that can be treated, prevented and / or diagnosed with the compositions of the present invention, include but are not limited to, rheumatoid arthritis (often characterized, eg, by immune complexes in the joints), scleroderma with anti-collagen antibodies (often characterized, eg, by nucleolar antibodies and other nuclear antibodies), mixed connective tissue disease (often characterized, eg, by antibodies against extractable nuclear antigens (ribonucleoprotein)), polymyositis / dermatosis (often characterized , eg, by ANA not histone), pernicious anemia (often characterized, eg, by antiparietal cells, microsomes and antibodies against intrinsic factor), idiopathic Addison's disease (often characterized, eg, by humoral and cell-mediated adrenal cytotoxicity) ), infertility (often characterized, eg, by anti-sperm antibodies), glom erulonephritis (often characterized, e. g. , by antibodies against the glomerular basement membrane or immune complexes) such as primary glomerulonephritis and IgA nephropathy, pemphigus bullosa (often characterized, eg, by IgG and complement in the basement membrane), Sjogren's syndrome (often characterized, eg, by antibodies in multiple tissues and / or non-histone specific ANA (SS-B)), diabetes mellitus (often characterized, eg, by antibodies against cell-mediated and humoral islet cells) and resistance to adrenergic drugs (including resistance) to adrenergic drugs with asthma or cystic fibrosis) (often characterized, e.g., by antibodies against beta-adrenergic receptors). Additional autoimmune disorders (which are possible) that can be treated, prevented and / or diagnosed with the compositions of the present invention, include but are not limited to chronic active hepatitis (often characterized, eg, by antibodies against smooth muscle), primary biliary cirrhosis (often characterized, eg, by mitochondrial antibodies), endocrine gland insufficiency (often characterized, eg, by tissue-specific antibodies in some cases), vitiligo (often characterized, eg, by antibodies against melanocytes), vasculitis (often characterized, eg, by Ig and complement in vessel walls and / or low serum concentration of complement), post-MI (often characterized, eg, by myocardial antibodies), cardiotomy syndrome (often characterized, eg, by antibodies against myocardium), urticaria (often characterized, eg, by IgG and IgM antibodies against IgE), atopic dermatitis (a men characterized, e.g., by IgG and IgM antibodies against IgE), asthma (often characterized, e.g., by IgG and IgM antibodies against IgE), inflammatory myopathies and many other inflammatory, granulomatous, degenerative and atrophic diseases). In a preferred embodiment, the autoimmune diseases and disorders and / or conditions associated with said diseases and disorders, mentioned above, can be treated, prevented and / or diagnosed using Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies. In a specific embodiment, rheumatoid arthritis is treated, prevented and / or diagnosed using Antineutrocin-alpha antibodies and / or Antineutrocin-alphaSV antibodies and / or other antagonists of the present invention. In a specific embodiment, lupus is treated, prevented and / or diagnosed using Antineutrocin-alpha antibodies and / or Antineutrocin-alphaSV antibodies and / or other antagonists of the present invention. In a specific embodiment, nephritis associated with lupus is treated, prevented and / or diagnosed using Antineutrocin-alpha antibodies and / or Antineutrocin-alphaSV antibodies and / or other antagonists of the present invention. In a specific embodiment, Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides, or antagonists thereof (eg, Antineutrocin-alpha antibodies and / or Antineutrocin-alphaSV antibodies) are used for the treatment or prevention of lupus erythematosus. systemic and / or diseases, disorders or conditions associated with it. Diseases, disorders or conditions associated with lupus that can be treated or prevented with the Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention, or antagonists thereof, include but are not limited to haematological (eg, hemolytic anemia, leukopenia, lymphopenia and thrombocytopenia), immunological disorders (eg, anti7? DN antibodies and antiSm antibodies), rashes, photosensitivity, oral ulcers, arthritis, fever, fatigue, weight loss, serositis (eg, pleuritis) (pleurisy)), kidney disorders (eg, nephritis), neurological disorders (eg, 'convulsions, peripheral neuropathy, CNS-related disorders), gastrointestinal disorders, Raynaud's phenomenon and pericarditis. In a preferred embodiment, Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides, or antagonists thereof (eg, Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies), are used for the treatment or prevention of renal disorders associated with systemic lupus erythematosus. In a more preferred embodiment, Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides, or antagonists thereof (eg, Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies), are used for the treatment or prevention of nephritis associated with systemic lupus erythematosus. In a similar way, allergic reactions and conditions such as asthma (particularly allergic asthma) or other respiratory problems, can also be treated with the Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention, and / or agonists and / or antagonists of the same. In addition, these molecules can be used for the treatment, prevention and / or diagnosis of anaphylaxis, hypersensitivity against antigenic molecules or incompatibility of blood groups. The Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention and / or agonists and / or antagonists thereof, can also be used for the treatment, prevention and / or diagnosis of organ rejection or against graft disease host verses (EIVH) and / or conditions associated with them. The rejection of organs occurs by the destruction, by the immune cells of the host, of the transplanted tissue through an immune response. Similarly, an immune response also participates in EIVH, but in this case, foreign transplanted immune cells destroy host tissues. The administration of Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention, and / or agonists and / or antagonists thereof that inhibit an immune response, particularly the proliferation, differentiation or chemotaxis of T cells, It can be an effective therapy in the prevention of organ rejection or EIVH. Similarly, Neutrokine-alpha and /? Polynucleotides or polypeptides Neutrokine-alphaSV of the present invention and / or agonists and / or antagonists thereof, can also be used to modulate inflammation. For example, the Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention and / or agonists and / or antagonists thereof, can inhibit the proliferation and differentiation of cells involved in an inflammatory response. These molecules can be used for the treatment, prevention and / or diagnosis of inflammatory disorders, chronic and acute conditions, including chronic prostatitis, granulomatous prostatitis and malakoplakia, inflammation associated with infection (eg, septic shock, sepsis or systemic inflammatory response syndrome ( SRIS)), reperfusion injury after ischemia, endotoxin lethality, arthritis, hyperacute rejection mediated by complement, nephritis, lung injury induced by cytokines or chemokines, inflammatory bowel disease, Crohn's disease or resulting from excessive production of cytokines (eg, TNF or IL-1). In a specific embodiment, the Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies of the present invention are used for the treatment, prevention, modulation, detection and / or diagnosis of inflammation. In a specific embodiment, the Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies of the present invention are used for the treatment, prevention, modulation, detection and / or diagnosis of inflammatory disorders. In another specific embodiment, the Antineutrocin-alpha and / or Antineutrocin-alphaSV antibodies of the present invention are used for the treatment, prevention, modulation, detection and / or diagnosis of allergy and / or hypersensitivity. Antibodies against Neutrocin-alpha and / or Neutrocin-alphaSV can be used to bind and inhibit the activity of Neutrokine-alpha and / or Neutrocin-alphaSV, for the treatment prevention and / or diagnosis of ARDS, preventing the infiltration of neutrophils in the lung after the injury. The agonists and antagonists of the present invention can be employed in a composition with a pharmaceutically acceptable carrier, e.g., as described below. Neutrokine-alpha and / or Neutrocin-alphaSV and / or Neutrocin-alpha receptor polynucleotides or polypeptides of the present invention and / or agonists and / or antagonists thereof, are used for the treatment, prevention and / or diagnosis of diseases and disorders of the pulmonary system (e.g., bronchi, such as for example, sinopulmonary and bronchial infections) and conditions associated with such diseases and disorders and other respiratory disorders and diseases. In specific modalities, such diseases and disorders include, but are not limited to, bronchial adenoma, bronchial asthma, pneumonia (such as, bronchial pneumonia, bronchopneumonia and tuberculous bronchopneumonia), chronic obstructive pulmonary disease (COPD), bronchial polyps, bronchiectasis ( such as eg, dry bronchiectasis, cylindrical bronchiectasis and saccular bronchiectasis), bronchiolar adenocarcinoma, bronchiolar carcinoma, bronchiolitis (such as eg, exudative bronchiolitis, fibrous obliterans bronchiolitis and proliferative bronchiolitis), bronchiole alveolar carcinoma, bronchitic asthma, bronchitis' (such as eg , asthmatic bronchitis, Castellani bronchitis, chronic bronchitis, croup bronchitis, fibrous bronchitis, hemorrhagic bronchitis, infectious avian bronchitis, bronchitis obliterans, plastic bronchitis, pseudomembranous bronchitis, putrid bronchitis and verminose bronchitis), bronchocentric granulomatosis, bronchoedema, bronchial fistula phage, bronchogenic carcinoma, bronchogenic cyst, broncholithiasis, bronchophalasia, bronchomycosis (such as eg, bronchopulmonary aspergillosis), bronchopulmonary spirochetosis, hemorrhagic bronchitis, bronchorrhea, bronchospasm, bronchostaxis, bronchostenosis, Biot respiration, bronchial breathing, Kussmaul breathing, Kussmaul-Kien respiration, respiratory acidosis, respiratory alkalosis, respiratory distress syndrome of the newborn, respiratory insufficiency, respiratory scleroma, respiratory syncytial virus and the like. In a specific embodiment, the Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polynucleotides of the present invention, and / or agonists and / or antagonists thereof, are used for the treatment, prevention and / or diagnosis of the disease Chronic obstructive (COPD). In another embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention and / or agonists and / or antagonists thereof, are used for the treatment, prevention and / or diagnosis of fibrosis and conditions associated with fibrosis, such as, but not limited to, cystic fibrosis (including fibrosis such as cystic fibrosis of the pancreas, Clark-Hadfiel syndrome, fibrocystic disease of the pancreas, mucoviscidosis and viscidosis), endomyocardial fibrosis, idiopathic retroperitoneal fibrosis, leptomeningeal fibrosis, mediastinal fibrosis, subepidermal nodular fibrosis, pericentral fibrosis, perimuscular fibrosis, replacement fibrosis, subadventive fibrosis and Symmers fiorosis. Ligands of the TNF family are known to be among pleiotropic cytokines, inducing a large number of cellular responses, including cytotoxicity, antiviral activity, immunoregulatory activities and the transcriptional regulation of several genes (DV Goeddel et al., "Tumor Necrosis Factors: Gene Structure and Biological Activities, "Symp.Quant. Biol. 51: 597-609 (1986), Cold Spring Harbor, B. Beutler and A. Cerami, Annu., Rev. Biochem. 57: 505-518 (1988; LJ Old Sci. Am. 258: 59-75 (1988), W. Fiers, FEBS Lett 285: -199-224 (1991).) Ligands of the TNF family, including Neutrocin-alpha and / or Neutrocin-alphaSV of the present invention induces several cellular responses by binding to the receptors of the TNF family Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides are thought to induce a potent cellular response, including any genotypic, phenotypic and / or morphological changes for the cell, cell line, tissue, tissue culture or As indicated, such cellular responses include not only normal physiological responses to ligands of the TNF family, but also associated diseases that increase apoptosis or inhibition of apoptosis. Programmed cell death or apoptosis, is a physiological mechanism involved in the deletion of B and / or T lymphocytes from peripheral blood of the immune system and its deregulation can lead to a number of different pathogenic processes (J.

C. Ameisen, AIDS 8: 1197-1213 (1994); P.H. Krammer et al. , Curr. Opin. Immunol. 6: 279-289 (1994)). Diseases associated with an increase in cell survival or inhibition of apoptosis that could be diagnosed, treated or prevented with the Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention and agonists and antagonists of the same, include cancers (such as follicular lymphomas, carcinomas with p53 mutations and hormone-dependent tumors, including, but not limited to, colon cancer, cardiac tumors, pancreatic cancer, melanoma, retinoblastoma, glioblastoma, lung cancer, intestinal cancer, Testicular cancer, stomach cancer, neuroblastoma, myxoma, myoma, lymphoma, endothelioma, osteoblastoma, osteoclastoma, osteosarcoma, chondrosarcoma, adenoma, breast cancer, prostate cancer, Kaposi's sarcoma and ovarian cancer); autoimmune disorders (such as systemic lupus erythematosus and glomerulonephritis related to the immune system, rheumatoid arthritis); viral infections (such as herpes virus, pox virus and adenovirus); inflammation; graft disease vs. Guest; rejection of acute grafts and rejection of chronic grafts. Thus, in preferred embodiments, the Neutrocin-c-lfa and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention, and / or agonists or antagonists thereof, are used for the treatment, prevention and / or diagnosis of autoimmune diseases and / or to inhibit the growth, progress and / or metastasis of cancer, including but not limited to, those in the present, such as, for example, lymphocytic leukemias (including, for example, MLL and chronic lymphocytic leukemia (CLL)) and follicular lymphomas. In another embodiment the Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention are used to activate, differentiate or proliferate cancerous cells or tissue (eg, cancers related to the B cell line (eg, LLC and MLL), lymphocytic leukemia or lymphoma) and in this way make the cells more vulnerable to cancer therapy (eg, chemotherapy or radiation therapy). In addition, in other embodiments, the Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention or agonists or antagonists thereof, are used to inhibit the growth, progress and / or metastasis of malignancies and related disorders. such as leukemia (including acute leukemia (eg, water lymphocytic leukemia, acute myelocytic leukemia (including myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia)) and chronic leukemia (eg, chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia)), polycythemia vera, lymphomas (eg, Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease and solid tumors, including but not limited to, sarcomas and carcinomas such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma, lymph ngiosarcoma, lymphangioendotheliosarcoma, synovitis, mesothelioma, Ewings tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, carcinoma of sweat glands, carcinoma of sebaceous glands, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, carcinoma of the bile duct, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, and angioblastoma, acoustic neuroma, oligodendroglioma, menangioma-, melanoma, neuroblastoma and retinoblastoma.

- - Diseases associated with an increase in apoptosis that can be diagnosed, treated or prevented with the Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention and agonists and antagonists thereof, include AIDS, neurodegenerative disorders ( such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, cerebellar degeneration); myelodysplastic syndromes (such as aplastic anemia), ischemic lesions (such as those caused by myocardial infarction, fulminant attack, and reperfusion injury), toxin-induced liver disease (such as that caused by alcohol), septic shock, cachexia, and anorexia . Thus, in preferred embodiments, Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides, and / or agonists or antagonists thereof, are used for the treatment, prevention and / or diagnosis of diseases and disorders above. listings. In preferred embodiments, the polypeptides of Neutrokine-alpha and / or Neutrocin-alphaSV of the present invention and / or agonists or antagonists thereof (eg, Antineutrocin-alpha antibodies), inhibit the growth of human histiocytic lymphoid cells U-937, in a dose-dependent manner . In further preferred embodiments, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides of the present invention and / or agonists or antagonists thereof (eg, Antineutrocin-alpha antibodies), inhibit the growth of PC-3 cells, HT cells. -29, HeLa cells, MCF-7 cells and A293 cells. In highly preferred embodiments, the Neutrocin-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides of the present invention and / or agonists or antagonists thereof (eg, Antineutrocin-alpha antibodies) are used to inhibit growth, progress and / or or metastasis of prostate cancer, colon cancer, cervical carcinoma and breast carcinoma. Thus, in further preferred embodiments, the present invention relates to a method for increasing apoptosis induced by a ligand of the TNF family, which includes administration to a cell that expresses a Neutrokine-alpha and / or Neutrocin- receptor. alphaSV, an effective amount of Neutrocin-alpha and / or Neutrocin-alphaSV or an agonist or antagonist thereof, capable of increasing or decreasing signaling mediated by Neutrocin-alpha and / or Neutrocin-alphaSV. Preferably, Neutrocin-alpha and / or Neutrocin-alphaSV-mediated signaling is increased or decreased to treat, prevent and / or diagnose a disease in which apoptosis is decreased or cytokines are decreased and an expression of adhesion molecules is exhibited . An agonist or antagonist may include soluble forms of Neutrokine-alpha and / or Neutrocin-alphaSV and monoclonal antibodies directed against the Neutrokine-alpha and / or Neutrocin-alphaSV polypeptide. In a further aspect, the present invention relates to a method for inhibiting apoptosis induced by a ligand of the TNF family, which includes administering to a cell expressing the Neutrokine-alpha and / or Neutrocin-alphaSV receptor, an amount effective of an agonist or antagonist capable of increasing or decreasing signaling mediated by Neutrocin-alpha and / or Neutrocin-alphaSV. Preferably, Neutrocin-alpha and / or Neutrocin-alphaSV-mediated signaling is increased or decreased to treat, prevent and / or diagnose a disease where increased apoptosis or NF-kappaB expression is exhibited. An agonist or antagonist may include soluble forms of Neutrokine-alpha and / or Neutrocin-alphaSV and monoclonal antibodies directed against the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide. Because Neutrocin-alpha and / or Neutrocin-alphaSV belong to the? NF superfamily, polypeptides must also modulate angiogenesis.

In addition, since Neutrocin-alpha and / or Neutrocin-alphaSV inhibits the functions of immune cells, the polypeptides will have a wide range of anti-inflammatory activities. Neutrokine-alpha and / or Neutrocin-alphaSV can be used as an antineovascularizing agent for the treatment prevention and / or diagnosis of solid tumors, by stimulating the invasion and activation of host defense cells, eg, cytotoxic T cells and macrophages, and by inhibiting the angiogenesis of the tumors. Those skilled in the art will recognize other indications that are not for cancer, where the proliferation of blood vessels is not desirable. They could also be used to increase the host's defenses against chronic and acute resistant infections, for example, mycobacterial infections, by attracting and activating microbicidal leukocytes. Neutrokine-alpha and / or Neutrocin-alphaSV can also be used to inhibit the proliferation of T cells, by inhibiting the biosynthesis of IL-2, for the treatment of autoimmune diseases mediated by T cells and lymphocytic leukemias (including, for example, chronic lymphocytic leukemia (CLL)). Neutrokine-alpha and / or Neutrocin-alphaSV can also be used to stimulate wound healing, both by the recruitment of residual debris cells and by the recruitment of inflammatory cells that promote connective tissue. In the same way, Neutrocin-alpha and / or Neutrocin-alphaSV can also be used for the treatment, prevention and / or diagnosis of other fibrotic disorders, including liver cirrhosis, osteoarthritis and pulmonary fibrosis. Neutrokine-alpha and / or Neutrocin-alphaSV also increases the presence of eosinophils that have the distinctive function of killing parasite larvae that invade tissues, such as schistosomiasis, trichinosis and ascariasis. They can also be used to regulate hematopoiesis, by regulating the activation and differentiation of various hematopoietic progenitor cells, for example, to release mature leukocytes from the bone marrow after chemotherapy, i.e., in the mobilization of stem cells. Neutrokine-alpha and / or Neutrocin-alphaSV can also be used for the treatment, prevention and / or diagnosis of sepsis. The polynucleotides and / or polypeptides of the present invention and / or agonists and / or antagonists thereof, are useful in the diagnosis and treatment or prevention of a wide range of diseases and / or disorders. Such diseases and disorders include, but are not limited to, cancer (eg, cancers related to cells of the immune system, breast cancer, prostate cancer, ovarian cancer, follicular lymphoma, cancer associated with mutations or alterations of p53, brain tumor, cancer. bladder, uterine cervical cancer, colon cancer, colorectal cancer, non-small cell lung carcinoma, small cell lung carcinoma, stomach cancer, etc.), lymphoproliferative disorders (eg, lymphadenopathy), microbial infections, (eg, viral, bacterial, etc.) (eg, HIV-1 infection, HIV-2 infection, herpesvirus infection (including, but not limited to, HSV-1, HSV-2, CMV, VZV, HHV-6, HHV -7, EBV), adenovirus infection, poxvirus infection, human papilloma virus infection, hepatitis infection (eg, HAV, HBV, HCV, etc.), infection by Helicobacter pylori infection, invasive staphylococci , etc.), parasitic infections, nephritis, bone disease (eg, osteoporosis), atherosclerosis, pain, cardiovascular disorders (eg, neovascularization, hypovascularization or reduced circulation (eg, ischemic disease (eg, myocardial infarction, massive heart attack, etc. .)), AIDS, allergy, inflammation, neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, cerebellar degeneration, etc.), graft rejections (acute and chronic), graft disease vs . host, diseases due to osteomyelodysplasia (e.g., aplastic anemia, etc.), joint tissue destruction in rheumatism, liver diseases (eg, acute and chronic hepatitis, liver injury and cirrhosis), autoimmune diseases (eg, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, glomerulonephritis immune complexes, autoimmune diabetes, autoimmune thrombocytopenic purpura, Graves' disease, Hashimoto's thyroiditis, etc.), cardiomyopathy (eg, dilated cardiomyopathy), diabetes, diabetic complications (eg, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy), influenza, asthma , psoriasis, glomerulonephritis, septic shock and ulcerative colitis. The polynucleotides and / or polypeptides of the present invention and / or agonists and / or antagonists thereof, are useful in promoting angiogenesis, healing (e.g., wounds, burns and bone fractures). The polynucleotides and polypeptides of the present invention and / or agonists and / or antagonists thereof, are also useful as adjuvants for enhancing the immune response against specific antigens and antiviral immune responses. More generally, the polynucleotides and / or polypeptides of the present invention and / or agonists and / or antagonists thereof, are useful in the regulation (i.e., raising or reducing) of the immune response. For example, the polynucleotides and / or polypeptides of the present invention may be useful in the preparation or recovery of surgery, trauma, radiation therapy, chemotherapy and transplants, or may be used to boost the immune response and / or to recover in individuals. elderly and immunocompromised. Alternatively, the polynucleotides and / or polypeptides of the present invention and / or agonists and / or antagonists thereof, are useful as immunosuppressive agents, for example in the treatment or prevention of autoimmune disorders. In specific embodiments, the polynucleotides and / or polypeptides of the present invention are used for the treatment or prevention of chronic inflammatory, allergic or autoimmune disorders, such as those described herein or otherwise known in the art. Preferably, the treatment using the Neutrokine-alpha and / or Neutrocin-alphaSV polynucleotides or polypeptides and / or Neutrocin-alpha and / or Neutrocin-alphaSV agonists or antagonists (eg, Antineutrocin-alpha antibodies), could be carried out by the administration of an effective amount of the Neutrokine-alpha and / or Neutrocin-alphaSV polypeptide of the present invention, or an agonist or antagonist thereof, to the patient, or by removing the patient's cells, then they are supplied with the Neutrokine polynucleotide -alpha and / or Neutrocin-alphaSV and the engineered cells are returned to the patient (ex vivo therapy). In addition, as will be described below, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide or polynucleotide can be used as an adjuvant in a vaccine to induce an immune response against infectious diseases. Formulations and Administration The Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide composition (preferably containing a polypeptide that is a soluble form of the extracellular domains of Neutrokine-alpha and / or Neutrocin-alphaSV), will be formulated and will dose in a manner consistent with good medical practice, taking into consideration the clinical condition of the individual patient (especially the side effects of treatment with • the Neutrokine-alpha and / or Neutrocin-alphaSV polypeptide alone), the Neutrokine-alpha and / or Neutrocin-alphaSV polypeptide composition distribution site, the method of administration, the administration schedule and other known factors for the practitioners of medicine. The term "effective amount" of Neutrokine-alpha and / or Neutrocin-alphaSV polypeptide, for the purposes of the present, is determined by such considerations. As a general proposition, the total effective pharmaceutical amount of Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide administered parenterally per dose, will be in the range of about 1 microgram / kg / day to 10 mg / kg / day of body weight of the patient, although, as noted above, it will be subject to therapeutic discretion. Preferably, this dose is 0.01 mg / kg / day and more preferably for humans between 0.01 and 1 mg / kg / day. In another embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide of the present invention is administered to a human at a dose between 0.0001 and 0.045 mg / kg / day, preferably at a dose between 0.0045 and 0.045 mg / kg / day and more preferably at a dose of approximately 45 micrograms / kg / day in humans; and at a dose of about 3 mg / kg / day in mice. If administered continuously, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide is typically administered at the dose rate of about 1 microgram / kg / hour to about 50 micrograms / kg / hour, either through 1-4 injections daily or by continuous subcutaneous infusion, for example, using a minipump. An intravenous solution bag can also be used.

The duration of treatment necessary to observe changes and the intervals after treatment for responses to occur seem to vary depending on the desired effect. In a specific embodiment, the total pharmaceutically effective amount of the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide administered parenterally per dose will be in the range of about 0.1 microgram / kg / day to 45 microgram / kg / day of body weight of the patient, although, as noted above, it will be subject to therapeutic discretion. Preferably, this dose is at least 0.1 micrograms / kg / day and more preferably for humans between about 0.01 and 50 micrograms / kg / day for the protein. Neutrocin-alpha and / or Neutrocin-alfaSV can be administered by continuous infusion, with multiple direct injections per day (eg, three or more times a day or twice a day), a single injection a day, or as intermittent discrete injections (eg, twice a day, once a day, every third day, twice a week, weekly, every two weeks, monthly, bi-monthly and quarterly). If administered continuously, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide is typically administered at a dose rate of about 0.001 to 10 micrograms / kg / hour at about 50 micrograms / kg / hour, either by 1 to 4 injections per day or by continuous subcutaneous infusion, for example, using a minipump. Effective dosages of the compositions of the present invention to be administered can be determined by methods known to those skilled in the art, which take into account parameters such as biological half-life, bioavailability and toxicity. Such determination will be within the ability of those skilled in the art, especially in light of the detailed description provided herein. The bioexposure of an organism to Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide during therapy may also play an important role in determining a therapeutic and / or pharmacologically effective dose regimen. Dosage variations, such as repeated administrations of a relatively low dose of the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide for a prolonged period, can have an effect that is therapeutically and / or pharmacologically distinguishable from that achieved with repeated administrations of a relatively high dose of Neutrocin-alpha and / or Neutrocin-alphaSV for a relatively short period of time. See, for example, the immunoglobulin serum concentration experiments presented in Example 6. Using the dose conversion factors per equivalent surface area provided by Freireich, EJ, et al., (Cancer Chemotherapy Reports 50 (4): 219- 44 (1966)), a person skilled in the art is able to conveniently convert data obtained from the use of Neutrocin-alpha and / or Neutrocin-alphaSV in an experimental system, into an accurate estimate of a pharmaceutically effective amount of the polypeptide of Neutrokine-alpha and / or Neutrocin-alphaSV to be administered by dose in another experimental system i Experimental data obtained by administering Neutrocin-alpha in mice (see, for example, Example 6), can be converted, by factors of conversion of Freireich et al. , in accurate estimates of the pharmaceutically effective doses of Neutrocin-alpha in rats, monkeys, dogs and humans. The following conversion table (Table III) is a summary of the data provided by Freireich et al. Table III provides approximate factors for converting doses expressed in terms of mg / kg of a species to one dose per equivalent surface area expressed as mg / kg in another tabulated species.

Table III. Factors of Conversion of Dose by Area of Equivalent Surface. - A - Mouse Rat Monkey Human Dog - DE - (20 g) (150 g) (3 .5 kg) (8 kg) (60 kg) Mouse 1 1/2 1/4 1/6 1/12 Rat 2 1 1/2 1/4 1/7 Mono 4 2 1 3/5 1/3 Dog 6 4 5/3 1 1/2 Human 12 7 3 2 1 Thus, for example, using the conversion factors provided in Table III, a dose of 50 mg / kg in mice is converted to an appropriate dose of 12.5 mg / kg in monkeys, because (50 mg / kg) x (1/4) = 12.5 mg / kg. As an additional example, doses of 0.02, 0.08, 0.8, 2 and 8 mg / kg in mice equal the dose effect of 1667, 6.67, 66.7, 166.7 micrograms / kg and 0.667 mg / kg, respectively, in humans. Pharmaceutical compositions containing the Neutrokine-alpha and / or Neutrocin-alphaSV polypeptides of the present invention can be administered orally, parenterally, subcutaneously, intramuscularly, intravaginally, intraperitoneally, topically (in the form of powders, ointments, drops or transdermal patches), buccal or as oral or nasal spray (eg, via inhalation of a vapor or powder). In one embodiment, the term "pharmaceutically acceptable carrier" means a non-toxic filler, diluent, encapsulant, solid, semi-solid or liquid, or auxiliary formulation • of any type. In a specific embodiment, the term "pharmaceutically acceptable" means approved by a regulatory institution of the federal government or a state government, or that is listed in the United States Pharmacopoeia or in another pharmacopoeia generally recognized for use in animals and more particularly in humans. Some non-limiting examples of pharmaceutically suitable carriers according to this embodiment are provided in EW Martin's "Rmington's Pharmaceutical Sciences" and include sterile liquids such as water and oils, including those of petroleum, of natural, vegetable or synthetic origin. , such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred vehicle when the pharmaceutical composition is administered intravenously. Saline and aqueous solutions of dextrose and glycerol can be used as liquid carriers, particularly for injectable solutions. The composition, if desired, may also contain minor amounts of wetting agents or emulsifiers, or pH regulating agents. These compositions may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations and the like. The term "parenteral" as used herein, refers to modes of administration by intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion. In a preferred embodiment, the compositions of Neutrokine-alpha and / or Neutrocin-alphaSV of the present invention (including polypeptides, polynucleotides and antibodies, and agonists and / or antagonists thereof), are administered subcutaneously. In another preferred embodiment, the compositions of Neutrokine-alpha and / or Neutrocin-alphaSV of the present invention (including polypeptides, polynucleotides and antibodies, and agonists and / or antagonists thereof), are administered intravenously. The compositions of Neutrocin-alpha and / or Neutrokine-alphaSV of the present invention are also suitably administered by sustained release systems. Suitable examples of sustained release compositions include suitable polymeric materials, such as, for example, semipermeable polymer matrices in the form of shaped articles, e. g. , films or microcapsules), suitable hydrophobic materials (for example emulsions in an acceptable oil) or ion exchange resins and sparingly soluble derivatives (such as, for example, sparingly soluble salt). Sustained-release matrices include polylactides (US Patent US 3, 773,919, European Patent EP 58,881), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U. et al., Biopolymers 22: 547-556 (1983)), poly- (2-hydroxyethyl methacrylate) (R. Langer et al., J. Biomed, Mater. Res. 15: 167-277 (1981) and R. Langer, Chem. Tech. 12: 98-105 (1982)), ethylene vinylacetate (R. Langer. et al., Id.) or poly-D- (-) -3-hydroxybutyric acid (European Patent EP 133,988). Sustained-release compositions also include compositions of the present invention entrapped in liposomes (see generally, Langer, Science 249: 1527-1533 (1990)).; Treat et al., In Liposomes in the Therapy of Infectious Disease and Cancer, López-Berestein and Fidler (eds.), Liss, New York, pp. 317-327 and 353-365 (1989)). Liposomes containing the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide can be prepared by known methods: German Patent DE 3,218,121; Epstein et al., Proc. Nati Acad. Sci (USA) 82: C688-3692 (1985); Hwang et al. , Proc. Nati Acad. Sci. (USA) 77: 4030-4034 (1980); European Patent EP 52,322; European Patent EP 36,676; European Patent EP 88,046; European Patent EP 143,949; European Patent EP 142,641; Japanese Patent Application 83-118008; U.S. Patent Nos. 4,485,045 and 4,544,545; and European Patent EP 102,324. Ordinarily, the liposomes are of the small unilamellar type (approximately 200 to 800 Angstroms) in which the lipid content is greater than about 30 mole percent of cholesterol, wherein the selected ratio is adjusted for optimal therapy with the polypeptide of Neutrocin-alpha and / or Neutrocin-alfaSV. In another embodiment, the sustained release compositions of the present invention include crystal formulations, known in the art. In yet a further embodiment, the compositions of the present invention are administered by means of a pump (see Langer, supra; Sefton, CRC Crit Ref Biomed, Eng. 14: 201 (1987); Buchwald et al., Surgery 88 : 507 (1980), Saudek et al., N. Engl. J. Med. 321: 574 (1989)). Other controlled-release systems are described in Langer's review (Science 249: 1527-1533 (1990)). For parenteral administration, in one embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide is generally formulated by mixing it in the desired degree of purity, in an injectable pharmaceutical form (solution, suspension or emulsion), with a pharmaceutically acceptable carrier, ie , one that is not toxic to the recipient at the doses and concentrations used and that is compatible with the other ingredients of the formulation. For example, the preferred formulation does not include oxidizing agents and other compounds that are known to be harmful to the polypeptides. In general, the formulations are prepared by contacting the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide uniformly and intimately with liquid carriers or with finely powdered solid carriers, or both. Then, if necessary, the product is shaped into the desired formulation. Preferably the vehicle is a parenteral vehicle, more preferably a solution that is isotonic to the blood of the recipient. Some examples of such vehicles include water, saline, Ringer's solution and dextrose solution. Nonaqueous vehicles such as fixed oils and ethyl oleate are also useful, as are liposomes. The vehicle suitably contains minor amounts of additives, such as substances that increase isotonicity and chemical stability. Such materials are not toxic to the recipient at the doses and concentrations employed and include regulatory solutions such as phosphate, citrate, succinate, acetic acid and other organic acids or their salts regulatory solution; antioxidants such as ascorbic acid; low molecular weight polypeptides (less than about ten residues), e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinyl pyrrolidone, amino acids such as glycine, glutamic acid, aspartic acid or arginine, monosaccharides, disaccharides, and other carbohydrates, including cellulose or its derivatives, glucose, mannose, sucrose or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium, preservatives, such as cresol, phenol, chlorobutanol, benzyl alcohol and parabens and / or nonionic surfactants such as polysorbates, poloxamers or PEG. The Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide is typically formulated in such vehicles at a concentration of about 0.001 to 100 mg / ml or 0.1 to 100 mg / ml, preferably 1 to 10 mg / ml, to a pH of about 3 to 10 or 3 to 8, preferably 5 to 8, more preferably 6 to 7. It will be understood that the use of certain excipients, vehicles or stabilizers of the above, will result in the formation of salts of Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide. The Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide to be used for therapeutic administrationIt must be sterile. Sterility is easily achieved by filtration through sterile filtration membranes (e.g., 0.2 micron membranes). The Neutrocin-alpha and / or Neutrocin-alphaSV therapeutic polypeptide compositions are generally placed in a container having a sterile access port, for example, an intravenous solution bag or a bottle having a stopper that can be punctured by a hypodermic injection needle. The Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide will normally be stored in multi-dose or multi-dose containers, for example, sealed vials or bottles in the form of an aqueous solution, or in the form of a lyophilized formulation to be reconstituted. . As an example of a lyophilized formulation, 10 ml vials are filled with 5 ml sterile Neutrokine-alpha and / or sterile Neutrokine-alphaSV polypeptide aqueous solution filtered at 1% (w / v) and the mixture is lyophilized. The infusion solution is prepared by reconstituting the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide using bacteriostatic injectable water. Alternatively, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide is stored in single dose containers in lyophilized form. The infusion selection is reconstituted using a sterile vehicle for injection. The present invention also provides a pharmaceutical package or kit containing one or more containers that are filled with one or more of the ingredients of the pharmaceutical compositions of the present invention. Optionally, associated with such containers there is a notification in the form prescribed by a governmental regulatory institution of the manufacture, use or sale of pharmaceutical or biological products, wherein said notification reflects the approval by said institution, for the manufacture, use or sale for administration in humans. In addition, the polypeptides of the present invention can be used in conjunction with other therapeutic compounds. The compositions of the present invention can be administered alone or in combination with other adjuvants. Adjuvants that can be administered with the compositions of the present invention include, but are not limited to, alum, alum plus deoxycholate (ImmunoAg), MTP-PE (Biocine Corp.), QS21 (Genetech, Inc.), BCG and MPL. In a specific embodiment, the compositions of the present invention are administered in combination with alum. In another specific embodiment, the compositions of the present invention are administered in combination with QS21. Other adjuvants that can be administered with the compositions of the present invention include, but are not limited to, monophosphoryl lipid immunomodulator, Adju Vax 100a, QS-21, QS-18, CRL 1005, aluminum salts, MF-59 and technology. of virosomal adjuvant. Vaccines that can be administered with the compositions of the present invention include but are not limited to, vaccines directed toward protection against MMR (measles, mumps, rubella), polio, varicella, tetanus / diphtheria, hepatitis A, hepatitis B, Haemophil Us Infl uenzae B, whooping cough, pneumonia, influenza, Lyme disease, rotavirus, cholera, yellow fever, Japanese encephalitis, poliomyelitis, rabies, typhoid and pertussis, and / or PNEUMOVAX-23 ™. Combinations may be administered either concomitantly, e.g., in the form of a mixture, separately but simultaneously or concurrently; or sequentially. This includes presentations in which the combined agents are administered together in the form of a therapeutic mixture, and also methods in which the combined agents are administered separately but simultaneously, e. g. , through separate intravenous lines in the same individual. Administration "in combination" further includes the separate administration of one of the compounds or agents to be administered first, followed by the second. In another specific embodiment, the compositions of the present invention are used in combination with PNEUMOVAX-23 for the treatment, prevention and / or diagnosis of infections and / or any disease, disorder and / or condition associated therewith. In one embodiment, the compositions of the present invention are used in combination with PNEUMOVAX-23 for the treatment, prevention and / or diagnosis of infections with Great Positive bacteria and / or any disease, disorders and / or condition associated therewith. In another specific embodiment, the compositions of the present invention are used in combination with PNEUMOVAX-23 for the treatment, prevention and / or diagnosis of infections and / or any disease, disorder and / or condition associated therewith. In one embodiment, the compositions of the present invention are used in combination with TM PNEUMOVAX-23 for the treatment, prevention and / or diagnosis of infections by bacteria Great positive and / or any disease, disorder and / or condition associated therewith. In another embodiment, the compositions of the present invention are used in combination with TM PNEUMOVAX-23 for the treatment, prevention and / or diagnosis of infections and / or any disease, disorder and / or condition associated with one or more members of the genus Enterococcus and / or of the genus Streptococcus. In another embodiment, the compositions of the present invention are used in combination with PNEUMOVAX-23 ™ for the treatment, prevention and / or diagnosis of infections and / or any disease, disorder and / or condition associated with one or more members of streptococci. Group B. In another embodiment, the compositions of the present invention are used in combination with PNEUMOVAX-23 for the treatment, prevention and / or diagnosis of infections and / or any disease, disorder and / or condition associated with Streptococcus pneumoniae. The compositions of the present invention may be administered alone or with other therapeutic agents, including but not limited to, chemotherapeutic agents, antibiotics, antivirals, steroidal and non-steroidal anti-inflammatory agents, conventional immunotherapeutic agents and cytokines. The combinations can be administered either concomitantly, e.g., in the form of a mixture, separately but simultaneously or concurrently; or sequentially. This includes presentations in which the combined agents are administered together in the form of a therapeutic mixture and also methods in which the combined agents are administered separately but simultaneously, e.g., through separate intravenous lines in the same individual. Administration "in combination" further includes administration of one of the compounds or agents that is administered first, followed by the second. In one embodiment, the compositions of the present invention are administered in combination with other members of the TNF family. TNF, TNF-related or TNF-like molecules that can be administered with the compositions of the present invention include, but are not limited to, the soluble forms of TNF-alpha, lymphotoxin alfa (LT-alpha, also known as TNF). -beta), LT-beta (found in the heterotrimeric complex LT-alpha2-beta) OPGL, FasL, CD27L, CD30L, CD40L, 4-1BBL, DcR3, OX40L, TNGgamma (International Publication WO 96/14328), AIM-I (International Publication WO 97/33899), AIM-II (International Publication WO 97/34911), APRIL (J. Exp. Med. 188 (6): 1185-1190), endocina-alpha (International Publication WO 98/07880). , TR6 (International Publication WO 98/30694), OPG and Neutrocin-alpha (International Publication WO 98/18921), OX40 and neural growth factor (FCN) and soluble forms of Fas, CD30, CD27, CD40 and 4-IBB, TR2 (International Publication WO 96/34095), DR3 (International Publication WO 97/33904), DR4 (International Publication WO 98/32856), TR5 (International Publication ional WO 98/30693, TR6 (International Publication WO 98/30694), TR7 (International Publication WO 98/41629), TRANK, TR9 (International Publication WO 98/56892), TRIO (International Publication WO 98/54202), 312C2 ( International Publication WO 98/06842) and TR12. In a preferred embodiment, the compositions of the present invention are administered in combination with the ligand CD40 (CD40L), a soluble form of CD40L (eg, AVREND ™), biologically active fragments, variants or derivatives of CD40L, antiCD40L antibodies (eg, agonist or antagonist antibodies), and / or antiCD40 antibodies (eg, agonist or antagonist antibodies). In certain embodiments, the compositions of the present invention are administered in combination with antiretroviral agents, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and / or protease inhibitors. Nucleoside reverse transcriptase inhibitors that can be administered in combination with the compositions of the present invention, include but are not limited to, TM, TM TU RETROVIR (zidovudine / AZT), VIDEX (didanosine / ddl), HIVID (zalcitabine / ddC), ZERIT ™ (stavudine / d4T), EPIVIR ™ (lamivudine / 3TC) and COMBIVIR ™ (zidovudine / lamivudine). Non-nucleoside reverse transcriptase inhibitors that can be administered in combination with the compositions of the present invention, include but are not limited to, VIRAMUNE ™ (nevirapine), RESCRIPTOR ™ (delavirdine) and SUSTIVA ™ (efavirenz). The protease inhibitors that can be administered in combination with the compositions of the present invention, include but are not limited to, TM TM TM CRIXIVAN (mdinavir),? ORVIR (ptonavir), INVIRASE TM (saquinavir) and VIRACEPT (nelfinavir). In a specific embodiment, antiretroviral agents, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and / or protease inhibitors, can be used in any combination with the compositions of the present invention for the treatment, prevention and / or or diagnoses of AIDS and / or for the treatment, prevention and / or diagnosis of HIV infections. In other embodiments, the compositions of the present invention may be administered in combination with agents against opportunistic infections. Agents against opportunistic infections that can be administered in combination with the compositions of the present invention, include but are not limited to, TRIMETHOPRIM-SULFAMETHOXAZOLE ™, DAPSO ™ E ™, PE ™ TAMIDI ™ A ™, ATOVAQUO ™ E ™, TU ™ TM T ISONIAZID, RIFAMPIN, PYRAZINAMIDE, ETAMBUTOL, RIFABUTIN ™, CLARITHROMICIN11, AZITHROMYCIN ™, GANCICLOVIR ™, TM TM TM "™ FOSCARNET, CIDOFOVIR, FLUCONAZOLE, ITRACONAZOLE, TM TM TM TM KETOCONAZOLE, ACICLOVIR, FAMCICLOVIR, PYRIMETHAMINE, TM LEUCOVORIN ™, NEUPOGEN ™ (filgrastim / FEC-G) and LEUKINE (sargramostim / FEC-GM). In a specific embodiment, the compositions of the present invention are used in combination with TRIMETHOPRIM-SULFAMETHOXAZOLE ™, DAPSONE ™, PENTAMIDINA ™ and / or ATOVAQUONE ™, for the prophylactic treatment, prevention and / or diagnosis of an opportunistic Pneumocystis carinii pneumonia infection. In another embodiment, the compositions of the present invention are used in any combination with ISONIAZID, RIFAMPIN ™, PYRAZINAMIDE ™ and / or ETHAMBUTOL ™ for the prophylactic treatment, treatment, prevention and / or diagnosis of an opportunistic infection by the Mycobacterium avium complex. . In another specific embodiment, the compositions of the present invention are used in TM TM any combination with RIFABUTIN, CLARITHROMYCINE, and / or TM AZITHROMYCIN for the prophylactic treatment, prevention and / or diagnosis of an opportunistic infection by Mycobacterium tuberculosis. In another specific embodiment, the compositions of the present invention are used in TM TM any combination with GANCICLOVIR, FOSCARNET and / or CIDOFOVIR ™ for the prophylactic treatment, prevention and / or diagnosis of an opportunistic cytomegalovirus infection. In another specific embodiment, the compositions of the present invention are used in TM ™, any combination with FLUCONAZOLE, ITRACONAZOLE and / or KETOCONAZOLE ™ for the prophylactic treatment, prevention and / or diagnosis of an opportunistic fungal infection. In another specific embodiment, the compositions of the present invention are used in any combination with ACICLOVIR ™ and / or FAMCICLOVIR ™ for the prophylactic treatment, prevention and / or diagnosis of an opportunistic infection by herpes simplex type I and / or type II. In another specific embodiment, the compositions of the present invention are used in any combination with PIRIMETHAMIME ™ and / or LEUCOVORIN ™ for the prophylactic treatment, prevention and / or diagnosis of an opportunistic Toxoplasma gondii infection. In another specific embodiment, the compositions of the present invention are used in any combination with LEUCOVORIN and / or NEUPOGEN for the prophylactic treatment, prevention and / or diagnosis of a bacterial opportunistic infection. In an additional mode, the compositions of the present invention are administered in combination with an antiviral agent. Antiviral agents that can be administered with the compositions of the present invention, include but are not limited to, acyclovir, ribavirin, amantadine and remantidine. In a further embodiment, the compositions of the present invention are administered in combination with an antibiotic agent. Antibiotic agents that can be administered with the compositions of the present invention include, but are not limited to, amoxicillin, aminoglycosides, beta-lactam (glycopeptide), beta-lactamases, clindamycin, chloramphenicol, cephalosporin, ciprofloxacin, erythromycin, fluoroquinolones, macrolides , metronidazole, penicillins, quinolones, rifampin, streptomycin, sulfonamide, tetracyclines, trimethoprim, trimethoprim-sulfamethoxazole and vancomycin. Conventional nonspecific immunosuppressive agents that can be administered in combination with the compositions of the present invention include, but are not limited to, steroids, cyclosporin, cyclosporin analogs, cyclophosphamide, cyclophosphamide IV, methylprednisolone, prednisolone, azathioprine, FK-506, 15-deoxyspergualin and other immunosuppressive agents that act by suppressing the function of T cells that manifest response. In specific embodiments, the compositions of the present invention are administered in combination with immunosuppressants. Immunosuppressant preparations that can be administered with the compositions of the present invention include, but are not limited to, TM TM, TM. TM ORTHOCLONE (OKT3), SANDIMMUNE / NEORAL / SANGDYA TM TM (ciclosporin), PROGRAF (tacrolimus), CELLCEPT TM (mycophenolate), Azathioprine, glucocorticoids and RAPAMUNE (sirolimus). In a specific modality, immunosuppressants can be used to prevent rejection of transplanted organs or bone marrow. In a preferred embodiment, the compositions of the present invention are administered in combination with a steroid therapy. Steroids that can be administered in combination with the compositions of the present invention include, but are not limited to, oral corticosteroids, prednisone, and methylprednisolone (e.g., methylprednisolone IV). In a specific embodiment, the compositions of the present invention are administered in combination with prednisone. In another specific embodiment, the compositions of the present invention are administered in combination with prednisone and an immunosuppressive agent. The immunosuppressive agents that can be administered with the compositions of the present invention and prednisone are those described herein and include, but are not limited to, azathioprine, cyclophosphamide and cyclophosphamide IV. In another specific embodiment, the compositions of the present invention are administered in combination with methylprednisolone. In a further specific embodiment, the compositions of the present invention are administered in combination with methylprednisolone and an immunosuppressive agent. The immunosuppressive agents that can be administered with the compositions of the present invention and methylprednisolone are those described herein and include, but are not limited to, azathioprine, cyclophosphamide and cyclophosphamide IV. In a preferred embodiment, the compositions of the present invention are administered in combination with an antimalarial agent. Antimalarial agents that can be administered with the compositions of the present invention include, but are not limited to, hydroxychloroquine, chloroquine and / or quinacrine. In a preferred embodiment, the compositions of the present invention are administered in combination with a nonsteroidal anti-inflammatory drug (NSAID). In a non-exclusive embodiment, the compositions of the present invention are administered in combination with one, two, three, four, five, ten or more of the following drugs: NRD-101 (Hoechst Marion Roussell), diclofenac (Dimethaid), oxaprozin potassium (Monsanto), mecasermin (Chiron), T-614 (Toyama), pemetrexed disodium (Eli Lilly), atreleuton (Abbott), valdecoxib (Monsanto), eltenac (Byk Gulden), campat, AGM-1470 (Takeda), CDP-571 (Celltech Chiroscience), CM-101 (CarboMed), ML-3000 (Merckle), CB-2431 (KS Biomedix), CBF-BS2 (KS Biomedix), gene therapy IL-IRa (Valentis), JTE-522 (Japan Tobacco), paclitaxel (Angiotech), DW-166HC (Dong Wha), darbufelone mesylate (Warner-Lambert), receptor 1 of soluble TNF (synergen: Amgen), IPR-6001 (Institute for Pharmaceutical Research), trocade (Hoffman-La Roche), EF-5 (Scotia Pharmaceuticals), BIIL-284 (Boehringer Ingelheim), BIIF-1149 (Boehringer Ingelheim), LeukoVax (Inflammatics), MK-663 (Merck), ST-1482 (Sigma-Tau) and butixocort propionate (WarnerLambert). In a preferred embodiment, the compositions of the present invention are administered in combination with one, two, three, four, five or more of the following drugs: methotrexate, sulfasalazine, sodium aurothiomalate, auranofin, cyclosporin, penicillamine, azathioprine and a drug antimalarial (eg, as described in TM present), cyclophosphamide, chlorambucil, gold, ENBREL (Etanercept), anti-TNF antibodies and prednisolone. In a more preferred embodiment, the compositions of the present invention are administered in combination with an antimalarial agent, methotrexate, an anti-TNF antibody, ENBREL ™ and / or sulfasalazine. In one embodiment, the compositions of the present invention are administered in combination with methotrexate. In another modality, the compositions of the present invention are administered in combination with anti-TNF antibodies. In one embodiment, the compositions of the present invention are administered in combination with methotrexate and anti-TNF antibodies. In one embodiment, the compositions of the present invention are administered in combination with sulfasalazine. In one embodiment, the compositions of the present invention are administered in combination with methotrexate, anti-TNF antibodies and sulfasalazine. In one embodiment, the compositions of the present invention are administered in combination with ENBREL TM. In one embodiment, the compositions of the present invention are administered in combination with ENBREL ™ and methotrexate. In one embodiment, the compositions of the present invention are administered TM in combination with ENBREL, methotrexate and sulfasalazine. In other embodiments, one or more antimalarial agents are combined with one of the combinations mentioned above. In a specific embodiment, the compositions of the present invention are administered in combination with an antimalarial agent (e.g., hydroxychloroquine), ENBREL ™, methotrexate and sulfasalazine.

In another specific embodiment, the compositions are administered in combination with an antimalarial agent (e.g., hydroxychloroquine), sulfasalazine, an anti-TNF antibody and methotrexate. In a further embodiment, the compositions of the present invention are administered alone or in combination with one or more preparations of intravenous immunoglobulins. Intravenous preparations of immunoglobulins that can be administered with the compositions of the present invention, include but are not limited to, GAMMAR ™, IVEEGAM ™, SANDOGLOBULIN ™, GAMMAGARD S / D ™ and GAMIMUNE ™. In a specific embodiment, the compositions of the present invention are administered in combination with intravenous immunoglobulin preparations in transplantation therapy (e.g., in bone marrow transplants). Ligand CD40 (CD40L), a soluble form of CD40L (eg, AVREND ™), biologically active fragments, variants or derivatives of CD40L, antiCD40L antibodies (eg, agonist or antagonist antibodies) and / or antiCD40 antibodies (eg, agonist or antagonists). In a further embodiment, the compositions of the present invention are administered alone or in combination with an anti-inflammatory agent. Anti-inflammatory agents that can be administered with the compositions of the present invention include but are not limited to, glucocorticoids and non-steroidal anti-inflammatories, aminoarylcarboxylic acid derivatives, arylacetic acid derivatives, arylbutyric acid derivatives, arylcarboxylic acid derivatives, acid derivatives arylpropionic, pyrazoles, pyrazolones, salicylic acid derivatives, thiazinecarboxamides, e-acetamidocaproic acid, S-adenosylmitionin, 3-amino-4-hydroxybutyric acid, amixetrin, bendazac, benzydamine, bucolone, diphenpyramide, ditazole, emorfazone, guayazulene, nabumetone, nimesulide , orgoteína, oxaceprol, paranilina, perisoxal, pifoxima, procuazona, proxazol and tenidap. In another embodiment, the compositions of the present invention are administered in combination with a chemotherapeutic agent. Chemotherapeutic agents that can be administered with the compositions of the present invention include, but are not limited to, antibiotic derivatives (e.g., doxorubicin, bleomycin, daunorubicin, and dactinomycin); antiestrogens (e.g., tamoxifen), antimetabolites (e.g., fluorouracil, 5-FU, methotrexate, floxuridine, interferon alfa-2b, glutamic acid, plicamycin, mercaptopurine and 6-thioguanine); cytotoxic agents (e.g., carmustine, BCNU, lomustine, CCNU, cytosine arabinoside, cyclophosphamide, estramustine, hydroxyurea, procarbazine, mitomycin, busulfan, cis-platinum and vincristine sulfate); hormones (e.g., medroxyprogesterone, estramustine sodium phosphate, ethinyl estradiol, estradiol, megestrol acetate, methyltestosterone, diethylstilbestrol diphosphate, chlorotrianisene and testolactone); Nitrogen derivatives of mustard (e.g., mefalén, chlorambucil, mechlorethamine (nitrogen mustard) and thiotepa); steroids and combinations (e.g., metametasone sodium phosphate); and others (e.g., dicarbazine, asparaginase, mitotane, vincristine sulfate, vinblastine sulfate and etoposide). In a specific embodiment, the compositions of the present invention are administered in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or any combination of CHOP components. In another embodiment, the compositions of the present invention are administered in combination with Rituxmab. In a further embodiment, the compositions of the present invention are administered with Rituxmab and CHOP or Rituxmab and any combination of the CHOP components. In a further embodiment, the compositions of the present invention are administered in combination with cytokines. Cytokines that can be administered with the compositions of the present invention, include but are not limited to, FEC-GM, FEC-G, IL-2, IL-3, IL-4, IL-5, IL-6, IL -7, IL-10, IL-12, IL-13, IL-15 antiCD40, DC40L, IFN-alpha, INF-beta, INF-gamma, TNF-alpha and TNF-beta. In another embodiment, the compositions of the present invention can be administered with any interleukin, including but not limited to, IL-lalpha, IL-lbeta, IL-2, IL-3, IL-4, IL-5, IL- 6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21 and IL-22. In preferred embodiments, the compositions of the present invention are administered in combination with IL-4 and IL-10. It has been observed that both IL-4 and IL-10 increase the proliferation of B cells mediated by Neutrocin-alpha. In a further embodiment, the compositions of the present invention is administered with a chemokine. In another embodiment, the compositions of the present invention are administered with chemokine beta-8, chemokine beta-1 and / or macrophage inflammatory protein-4. In a preferred embodiment, the compositions of the present invention are administered with beta-8 chemokine. In a further embodiment, the compositions of the present invention are administered in combination with an IL-4 antagonist. IL-4 antagonists that can be administered with the compositions of the present invention include, but are not limited to, soluble IL-4 receptor polypeptides, multimeric forms of soluble IL-4 receptor polypeptides, IL-4 antireceptor antibodies. that bind to the IL-4 receptor without transducing the biological signal induced by IL-4; anti-IL-4 antibodies that block the binding of IL-4 with one or more IL-4 receptors, and IL-4 muteins that bind to IL-4 receptors but do not transduce the biological signal induced by IL-4 . Preferably, the antibodies used according to this method are monoclonal antibodies (including fragments of antibodies, such as for example, those described herein). In a further embodiment, the compositions of the present invention are administered in combination with hematopoietic growth factors. Hematopoietic growth factors that can be administered with the compositions of the present invention, include but are not limited to, LEUCINE ™ (SARGRAMOSTIM ™) and NEUPOGEN ™ (FILGRASTIM ™). In a further embodiment, the compositions of the present invention are administered in combination with fibroblast growth factors. Fibroblast growth factors that can be administered with the compositions of the present invention, include but are not limited to, FGF-1, FGF-2, FGF-3, FGF-4, FGF-5, FGF-6, FGF -7, FGF-8, FGF-8, FGF-10, FGF-11, FGF-12, FGF-13, FGF-14 and FGF-15. Additionally, the compositions of the present invention may be administered alone or in combination with other therapeutic regimens, including but not limited to radiation therapy. Such combination therapy can be administered sequentially and / or concomitantly. Agonists and Antagonists - Assays and Molecules The present invention provides a method for selecting compounds to identify those that increase or block the action of Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide in cells, such as their interaction with Neutrocin binding molecules. -alpha and / or Neutrocin-alphaSV, such as receptor molecules. An agonist is a compound that increases the natural biological functions of Neutrokine-alpha and / or Neutrokine-alphaSV or that functions in a manner similar to Neutrocin-alpha and / or Neutrocin-alphaSV, while antagonists decrease or eliminate such functions. In another embodiment, the present invention provides a method for identifying a receptor protein or other ligand-binding protein that specifically binds to a Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide. For example, a cellular compartment, such as a membrane or preparation thereof, can be prepared from cells that express a molecule that binds to Neutrocin-alpha and / or Neutrocin-alphaSV. The preparation is incubated with Neutrokine-alpha and / or Neutrokine-alphaSV labeled and the Neutrokine-alpha and / or Neutrokine-alphaSV complexes bound to the receptor or other binding protein, are isolated and characterized in accordance with routine methods in this field. Alternatively, the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide can be attached to a solid support, such that the dissolved binding molecules from the cell are bound to the column and then eluted and characterized in accordance with the routine methods. In the assay of the present invention with respect to agonists and antagonists, a cellular compartment, such as a membrane or a preparation thereof, can be prepared from a cell that expresses a molecule that binds Neutrocin-alpha and / or Neutrocin-alphaSV, such as a molecule of a signaling or regulatory pathway modulated by Neutrocin-alpha and / or Neutrocin-alphaSV. The preparation is incubated with Neutrocin-alpha and / or Neutrocin-alphaSV labeled in the absence or presence of a candidate molecule, which may be an agonist or antagonist of Neutrocin-alpha and / or Neutrocin-alphaSV. The ability of the candidate molecule to bind to the binding molecule is reflected in a decreased binding of the labeled ligand. Molecules that bind free, i.e., without inducing the effects of Neutrocin-alpha or the Neutrocin-alpha and / or Neutrocin-alphaSV binding molecule, are more likely to be good antagonists. Molecules that bind well and induce effects that are equal or closely related to those of Neutrokine-alpha and / or Neutrocin-alphaSV, are considered as agonists. Neutrokine-alpha and / or Neutrocin-alphaSV-like effects of potential agonists and antagonists can be measured, for example, by determining the activity of a second messenger system after the interaction of the candidate molecule with a cell or cell preparation appropriate, and comparing the effect with that of Neutrocin-alpha and / or Neutrocin-alphaSV or with that of molecules that induce the same effects as Neutrocin-alpha and / or Neutrocin-alphaSV. A second messenger system which may be useful in this regard, include but is not limited to, the second AMP messenger systems guanylate cyclase, ion channel or hydrolysis with phosphoinositide. Another example of an assay for antagonists of Neutrokine-alpha and / or Neutrocin-alphaSV, is a competitive assay that combines Neutrokine-alpha and / or Neutrokine-alphaSV and a potential antagonist, with receptor molecules bound to the membrane or with Neutrokine-alpha and / or Neutrocin-alphaSV recombinant receptor molecules, under appropriate conditions to carry out a competitive inhibition assay. Neutrokine-alpha and / or Neutrocin-alphaSV can be labeled, for example by radioactivity, in such a way that the number of Neutrokine-alpha and / or Neutrokine-alphaSV molecules bound to a receptor molecule can be accurately determined, to evaluate the effectiveness of the potential antagonist. Potential antagonists include small organic molecules, peptides, polypeptides (e.g., IL-13) and antibodies that bind to a polypeptide of the present invention and thus inhibit or extinguish its activity. Potential antagonists can also be small organic molecules, a peptide, a polypeptide such as a closely related protein or antibody that binds to the same sites in a binding molecule, such as a receptor molecule, without inducing the activities induced by Neutrokine. -alpha and / or Neutrocin-alphaSV, thus avoiding the action of Neutrocin-alpha and / or Neutrocin-alphaSV by excluding or preventing the binding of Neutrocin-alpha and / or Neutrocin-alphaSV. Other potential antagonists include antisense molecules. Antisense technology can be used to control the expression of genes through antisense DNA or RNA or through the formation of triple helices. Antisense techniques are described, for example, in Okano, J. Neurochem. 56: 560 (1991): "Oligodeoxinucletides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, FL (1988) .The formation of triple helices is described, for example, in Lee et al., Nucleic Acids Research 6: 3073 (1979): Cooney et al., Science 241: 456 (1988); and Dervan et al., Science 251: 1360 (1991). The methods are based on the binding of a polypeptide to a complementary DNA or RNA. For example, the coding portion 51 of a polynucleotide that codes for the extracellular domain of the polypeptide of the present invention can be used to design an antisense RNA oligonucleotide of about 10 to 40 base pairs in length. An oligonucleotide of AD? complementary to a region of the gene involved in transcription, thus avoiding the transcription and production of? eutrocin-alpha and / or? eutrocin-alphaSV. The oligonucleotide of AR? antisense hybridizes to the AR? m in vivo and blocks the translation of the mRNA molecule into the? eutrokin-alpha and / or? eutrocin-alphaSV polypeptide. Oligonucleotides described above can also be administered to cells in such a way that the antisense RNA or DNA can be expressed in vivo to inhibit the production of Neutrocin-alpha and / or Neutrocin-alphaSV. In one embodiment, the Neutrocin-alpha and / or Neutrocin-alphaSV antisense nucleic acid of the present invention is produced intracellularly by transcription of an exogenous sequence. For example, a vector or a portion thereof, is transcribed, producing an antisense nucleic acid (RNA) of the present invention. Such a vector would contain an antisense nucleic acid sequence encoding Neutrocin-alpha and / or Neutrocin-alphaSV. Such a vector could remain episomal or could be integrated into the chromosome, as long as it can be transcribed to produce the desired antisense RNA. Such vectors can be constructed by standard methods of recombinant DNA technology. The vectors can be plasmids, viral or others known in the art, used for replication and expression in vertebrate cells. The expression of the Neutrocin-alpha and / or Neutrocin-alphaSV coding sequence or fragments thereof can be by any promoter known in the art known to act in vertebrate cells, preferably human cells. Such promoters may be inducible or constitutive. These promoters include, but are not limited to, the SV40 early promoter (Bernoist and Chambon, Nature 29: 304-310 (9181)), the promoter contained in the long terminal repeat of the Rous sarcoma virus (Yamamoto et al., Cell 22: 787-797 (1980)), the herpes thymidine promoter (Wargner et al., Proc. Nati, Acad. Sci. USA 78: 1441-1445 (1981)), the regulatory sequences of the metallothionein gene (Brinster et al., Nature 296: 39-42 (1982)), etc. The antisense nucleic acids of the present invention comprise a sequence complementary to when a portion of an RNA transcript of a Neutrocin-alpha and / or Neutrocin-alphaSV gene. However, absolute complementarity, although preferred, is not necessary. A sequence "complementary to at least a portion of RNA", as used herein, means a sequence that has sufficient complementarity to be able to hybridize with RNA, forming a stable duplex; in the case of Neutrocin-alpha and / or Neutrocin-alphaSV double-stranded antisense nucleic acids, a single strand of duplex DNA would then be tested, or the formation of a triplex could be tested. The ability to hybridize will depend both on the degree of complementarity and the length of the antisense nucleic acid. In general, the larger the hybridizing nucleic acid, the higher will be the unpaired bases with an RNA of Neutrocin-alpha and / or Neutrocin-alphaSV and in any case a stable duplex would be formed (or a triplex, as the case may be) . A person skilled in the art will be able to obtain a tolerable degree of mismatches by using standard procedures to determine the melting point of the hybridized complex. Oligonucleotides that are complementary to the 5 'end of the message, e.g., the 5' untranslated sequence up to and including the AUG start codon, they should work more efficiently by inhibiting translation. However, sequences complementary to the 3 'untranslated sequences of the mRNAs have been shown to be effective also in inhibiting the translation of mRNA. See generally, Wagner, R., 1994, Nature 372: 333-335. Thus, complementary oligonucleotides complementary to 5 'or 3' non-coding, non-translated regions of Neutrokine-alpha and / or Neutrocin-alphaSV, shown in Figures 1A-B and 5A-B, respectively, could be used in an antisense approach to inhibit translation of the endogenous mRNA of Neutrocin-alpha and / or Neutrocin-alphaSV. Oligonucleotides complementary to the 5 'untranslated region of the mRNA must include the complement of the AUG start codon. Antisense oligonucleotides complementary to mRNA coding regions are less effective inhibitors of translation, but could be used in accordance with the present invention. Regardless of whether they are designed to hybridize with the 5 ', 3' or coding region of the Neutrokine-alpha and / or Neutrocin-alphaSV mRNA, the antisense nucleotides must be at least 6 nucleotides in length and preferably the oligonucleotides vary from about to approximately 50 nucleotides in length. In specific aspects, the oligonucleotide has at least 10 nucleotides, at least 17 nucleotides, at least 25 nucleotides or at least 50 nucleotides. The polynucleotides can be DNA or RNA or chimeric mixtures or derivative or modified versions thereof, single chain or double chain. The oligonucleotide may be modified in the base portion, in the sugar portion or in the phosphate portion, for example, to improve the stability of the molecule, the hybridization, etc. The oligonucleotide may include other adjoining groups, such as peptides (e.g., to target receptors of host cells in vivo) or agents that facilitate transport across the cell membrane (See e.g., Letsinger et al., 1989, Proc. Nati. Acad. Sci.

USES. 86: 6553-6556; Lemaitre et al. , Proc. Nati Acad.

Sci. 84: 648-652 (1987); PCT International Publication WO 88/09810, published December 15, 1988) or to cross the blood-brain barrier (see, eg, PCT International Publication WO 89/10134, published April 25, 1988), hybridization-induced cleavage agents (see, eg, Krol et al., BioTechniques 6: 958-976 (1988)) or intercalating agents (see, eg, Zon, Pharm. Res. 5: 539-549 (1988)). For this purpose, the oligonucleotide can be conjugated with another molecule, e.g., a peptide, a cross-linking agent induced by hybridization, a transport agent, a breaking agent induced by hybridization, etc. The antisense oligonucleotide may comprise at least one modified base portion, which is selected from the group including but not limited to 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine , 5- (carboxyhydroxylmethyl) -uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2 -methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5-methoxycarboxymethyluracil, 5-methoxyuracil, 2 -methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wibutoxosine, psudouracil, kerosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, acid methyl ester uracil-5-oxyacetic acid, uracil-5-oxyacetic acid (v), 5-methyl-2-t iouracil, 3- (3-amino-3-N-2-carboxypropyl) -uracil, (acp3) w and 2,6-diaminopurine. The antisense oligonucleotide can also comprise at least a portion of modified sugar, which is selected from the group including, but not limited to, arabinose, 2-fluoroarabinose, xylulose and hexose. In yet another embodiment, the antisense oligonucleotide comprises at least one modified phosphate structure, which is selected from the group including but not limited to, a phosphorothioate, a phosphorodithioate, a phosphoramidothioate, a phosphoroamidate, a phosphorodiamidate, a methylphosphonate, a phosphotriester of alkyl and a formatetal or analogue thereof. In still another embodiment, the antisense oligonucleotide is an alpha-anomeric oligonucleotide. An alpha-anomeric oligonucleotide forms specific double-stranded hybrids with complementary RNA, in which, contrary to usual beta units, the filaments run parallel to one another (Gautier et al., Nucí Acids Res. 15: 6625-6641 (1987)). The oligonucleotide is a 2-0-methylribonucleotide (Inoue et al., Nucí Acids Res. 15: 6131-6148 (1987)), or a chimeric RNA-DNA analog (Inoue et al., FEBS Lett 215: 327- 330 (1997)). The polypeptides of the present invention can be synthesized by standard methods known in the art, e.g., by the use of an automated 7DNA synthesizer (such as those commercially available from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides can be synthesized by the method of Stein et al., (Nucí Acids Res. 16: 3209 (1988)), methylphosphonate oligonucleotides can be prepared by the use of controlled porous glass polymeric supports (Sarin. et al., Proc. Nati, Acad. Sci. USA 85: 7448-7451 (1988)), etc. While antisense nucleotides complementary to the Neutrocin-alpha and / or Neutrocin-alphaSV coding region sequence can be used, those that are complementary to the transcribed untranslated region are more preferred. Potential antagonists according to the present invention also include catalytic RNA or a ribozyme (see e.g., PCT International Publication WO 90/11364, published October 4, 1990).; Sarver et al. , Science 247: 1222-1225 (1990)). While ribozymes that break mRNA at specific recognition sites can be used to destroy Neutrokine-alpha and / or Neutrocin-alphaSV mRNAs, the use of "hammerhead" ribozymes is preferred. Hammerhead ribozymes break mRNAs at locations dictated by the flanking regions that form complementary base pairs with the target mRNA. The only requirement is that the white mRNA has the following sequence of two bases: 5'-UG-3 '. The construction and production of hammerhead ribozymes is known in the art and is described in greater detail in Haseloff and Gerlach, Nature 334: 585-591 (1988). There are numerous sites of potential hammerhead ribozyme cleavage in the nucleotide sequence of Neutrokine-alpha and Neutrokine-alphaSV (Figures 1A-B and 5A-B, respectively). Preferably, the ribozyme is engineered so that the break recognition site is located near the 5 'end of Neutrokine-alpha and / or Neutrocin-alphaSV mRNA, ie, to increase efficiency and minimize intracellular accumulation of non-functional mRNA transcripts. As in the antisense approach, the ribozymes of the present invention may be composed of modified oligonucleotides (eg, to improve stability, targeting, etc.) and must be distributed in cells expressing Neutrocin-alpha and / or Neutrocin-alfaSV in vivo. DNA constructs encoding the ribozyme can be introduced into the cell, in the same manner as described above for the production of the antisense encoding DNA. A preferred method for distribution includes using a "coding" DNA construct of the ribozyme under the control of a strong constitutive promoter, such as, for example, the pol III promoter or the pol II promoter, such that the transfected cells produce sufficient quantities of the ribozyme to destroy messages of endogenous Neutrokine-alpha and / or Neutrokine-alphaSV and inhibit translation. Since ribozymes, unlike antisense molecules are catalytic, a lower intracellular concentration is required to obtain efficiency. Endogenous gene expression can also be reduced by inactivating or "knocking out" the Neutrokine-alpha and / or Neutrocin-alphaSV gene and / or its promoter, using target-directed homologous recombination (eg, see Smithies et al., Nature 317 : 230-234 (1985), Thomas and Capecchi, Cell 51: 503-512 (1987), Thompson et al., Cell 5: 313-321 (1989), each of which is incorporated herein in its entirety. as reference) . For example, a non-functional mutant polynucleotide of the present invention (or a completely unrelated DNA sequence) flanked by DNA homologous to the sequence of the endogenous polynucleotide (either the coding regions, or, the regulatory regions of the gene) can be used with or without a selectable marker and / or a negative selectable marker, to transfect cells expressing the polypeptides of the present invention in vivo. In another embodiment, known techniques are used to generate "knockouts" in cells that contain but do not express the gene of interest. The insertion of the DNA construct, through target homologous recombination, results in the inactivation of the target gene. Such approaches are particularly suitable in research and in the agricultural field, where modifications to embryonic stem cells can be used to generate animal offspring with an inactive target gene (e.g., see Thomas and Capecchi 1987 and Thompson 1989, supra). However, this approach can be routinely adapted for use in humans, as long as the recombinant DNA constructs are administered directly or directed to the required site in vivo, employing appropriate viral vectors that will be apparent to those skilled in the art. The content of each of the documents cited in this paragraph, is incorporated herein by reference in its entirety. In other embodiments, antagonists according to the present invention include soluble forms of Neutrokine-alpha and / or Neutrocin-alphaSV (eg, Neutrokine-alpha fragments shown in Figures 1A-B that include the ligand binding domain. , the conserved domain TNF and / or the extracellular domain of Neutrokine-alpha and / or Neutrocin-alphaSV and fragments of Neutrokine-alphaSV shown in Figures 5A-B that include the ligand-binding domain, the conserved domain TNF and / or the extracellular domain of Neutrocin-alpha and / or Neutrocin-alphaSV). Such soluble forms of Neutrokine-alpha and / or Neutrocin-alphaSV, which may be of natural or synthetic origin, antagonize signaling mediated by Neutrocin-alpha and / or Neutrocin-alphaSV when competing with Neutrocin-alpha and / or Neutrocin- natural or native alphaSV by binding to Neutrokine-alpha and / or Neutrocin-alphaSV receptors (eg, DR5 (see International Publication WO 98/41629), TRIO (see International Publication WO 97/54202), 312C2 (see International Publication WO 98/06842) and TR11, TR11SV1 and TR11SV2 (see US Application Serial No. 09 / 176,200)) and / or forming a multimer that may or may not be capable of binding to the receptor, but which is incapable of Induce signal transduction. Preferably, these antagonists inhibit the stimulation of lymphocyte proliferation (e.g., B cells), differentiation and / or activation thereof, mediated by Neutrocin-alpha and / or Neutrocin-alphaSV. The antagonists of the present invention also include antibodies specific for the ligands of the TNF family (e.g., CD30) and fusion proteins of Neutrocin-alpha-FC and / or Neutrocin-alphaSV-Fc. The term "TNF family ligand" as used herein, refers to ligands of natural, recombinant and synthetic origin, which are capable of binding to a member of the TNF receptor family and induce and / or block the ligand / receptor signaling path. Members of the TNF ligand family include, but are not limited to, TNF-alpha, lymphotoxin-alpha (LT-alpha, also known as TNF-beta), LT-beta (found in the heterotrimeric LT-alpha2-beta complex ), FasL, CD40L, (TNF-gamma (International Publication WO 96/14328), AIM-I (International Publication WO 97/33899), AIM-II (International Publication WO 97/34911), APRIL (J. Exp. Med. 188 (6): 1185-1190), endocina-alpha (International Publication WO 98/07880), neutrocine-alpha (International Publication WO 98/18921), CD27L, CD30L, 4-1BBL, OX40L, CD27, CD30, 4 -1BB, OX40 and the neural growth factor (FCN). In preferred embodiments, the ligands of the TNF family of Neutrocin-alpha and / or Neutrocin-alphaSV of the present invention are DR5 (see Publication International WO 98/41629), TRIO (see International Publication WO 98/54202), 312C2 (see International Publication WO 98/06842) and TRll, TR22SV1 and TR11SV2 (see US Application Serial No. 09 / 176,200). The antagonists of the present invention also include antibodies specific for receptors of the TNF family or the Neutrocin-alpha and / or Neutrocin-alphaSV polypeptides of the present invention. The antibodies according to the present invention can be prepared by any of a variety of standard methods, employing Neutrokine-alpha and / or Neutrocin-alphaSV immunogens of the present invention. As indicated, such Neutrokine-alpha and / or Neutrocin-alphaSV immunogens include the complete Neutrokine-alpha and / or Neutrocin-alphaSV polypeptides illustrated in Figures 1A-B (SEQ ID No. 2) and Figures 5A-B (SEQ ID No. 19), respectively (which may or may not include the leader sequence) and fragments of Neutrokine-alpha and / or Neutrocin-alphaSV polypeptides comprising, for example, the ligand binding domain, the conserved domain TNF, the extracellular domain, the transmembrane domain and / or the intracellular domain, or any combination thereof. The polyclonal and monoclonal agonist or antagonist antibodies according to the present invention can be prepared according to the methods described in Tartaglia and Goeddle, J. Biol. Chem., 267/7): 4304-4307 (1992); Tartaglia et al. , Cell 73: 213-216 (1993)) and PCT Application WO 94/09137 and preferably are specific against (ie, they bind only to) the polypeptides of the present invention having the amino acid sequence of SEQ ID NO. : 2. The term "antibody" (Ab) or "monoclonal antibody" (mAb) as used herein, means that it includes intact molecules as well as fragments thereof (such as for example Fab and F fragments (ab ' )) that are capable of binding to an antigen. The Fab, Fab 'and F (ab') fragments lack the intact Fc fragment of the antibody, they are cleared more rapidly from the circulation and may present a less non-specific tissue binding compared to an intact antibody (Wahl et al., J. Nuci, Med.., 24: 316-325 (1983)). In a preferred method, the antibodies according to the present invention are mAbs. Such mAbs can be prepared using hybridoma technology (Kohier and Mlllstein, Nature 256: 495-497 (1975) and Patent North American No. 4,376,110; Harlow et al. , Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1988; Monocionai Antibodies and Hybridomas: A New Dimension in Biological Analyzes, Plenum Press, New York, NY, 1980; Campbell, "Monoclonal Antibody Technology," In: Laboratory Techniques in Biochemistry and Molecular Biology, Volume 13 (Burdon et al., Eds.), Elsevier, Amsterdam (1984)). Proteins and other compounds that bind to the neutrokine-alpha and / or neutrocine-alphaSV domains are also candidate agonists and antagonists in accordance with the present invention. Such binding compounds can be "captured" using the yeast two-hybrid system (Fields and Song, Nature 340: 245-246 (1989)). A modified version of the yeast two-hybrid system has been described by Roger Brent and colleagues (Gyuris, Ceii 75: 791-803 (1993); Zervos et al., Celi 72: 223-232 (1993)). Preferably, the yeast two-hybrid system is used in accordance with the present invention to capture compounds that bind to the ligand-binding domain, to the extracellular, intracellular, transmembrane and death domain of neutrokine-alpha and / or neutrocine. -alfaSV. Such compounds are good candidate agonists and antagonists of the present invention. For example, when using the two-hybrid assay mentioned above, the extracellular or intracellular domain of the neutrokine-alpha and / or neutrocin-alphaSV receptor, or a portion thereof, can be used to identify cellular proteins that interact with the neutrokine-alpha and / or neutrocine-alphaSV receptor in vivo. Such an assay can also be used to identify ligands with potential agonist or antagonist activity of neutrokine-alpha and / or neutrocine-alphaSV receptor function. This screening assay has previously been used to identify proteins that interact with the cytoplasmic domain of murine TNF-RII and led to the identification of two proteins associated with the receptor. Rothe et al., Ceil 78: 681 (1994). Such proteins and amino acid sequences that bind to the cytoplasmic domain of the neutrokine-alpha and / or neutrocine-alphaSV receptors are good candidate agonists and antagonists of the present invention. Other screening techniques include the use of cells expressing the polypeptide of the present invention (eg, transfected CHO cells) in a system that measures changes in extracellular pH caused by receptor activation, for example in the manner described in Science. , 246: 181-296 (1989). In another example, potential agonists or antagonists can be contacted with a cell expressing the polypeptide of the present invention and a second messenger response can be measured, e.g. signal transduction, to determine if the antagonist or potential agonist is effective. Agonists in accordance with the present invention include compounds of natural and synthetic origin such as, for example, fragments of the TNF family ligand peptide, transforming growth factor, neurotransmitters (such as glutamate, dopamine, N-methyl-D-aspartate) , tumor suppressors (p53), cytolytic T cells and antimetabolites. Preferred agonists include chemotherapeutic drugs such as, for example, cis-platinum, doxorubicin, bleomycin, cytosine arabinoside, nitrogen mustard, methotrexate and vincristine. Others include ethanol and amyloid peptide (Science 267: 1457-1458 (1995)). Preferred agonists are neutrokine-alpha and / or neutrocine-alphaSV polypeptide fragments of the present invention that stimulate the proliferation, differentiation and / or activation of lymphocytes (e.g., B cells). Other preferred agonists include polyclonal and monoclonal antibodies directed against the neutrokine-alpha and / or neutrocin-alphaSV polypeptides of the present invention, or a fragment thereof. Such agonist antibodies directed against a receptor of the TNF family are described in Tartaglia et al. , Proc. Nat 'l Acad. Sci. USA 88: 9292-9296 (1991), and Tartaglia et al. , J. Biol. Chem., 267: 4304-4307 (1992). See also PCT Application WO 94/09137. In a further embodiment, immunoregulatory molecules such as, for example, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13 can be used. , IL-15, anti-CD40, CD40L, IFN-gamma and TNF-alpha, as agonists of the neutrokine-alpha and / or neutrocine-alphaSV polypeptides of the present invention, which stimulate the proliferation, differentiation and / or activation of lymphocytes (eg, B cells). In a specific embodiment, IL-4 and / or IL-10 are used to increase the proliferation of B cells mediated by neutrocine-alpha and / or neutrocin-alphaSV. In additional embodiments of the present invention, cells that are engineered to express the polypeptides of the present invention, or alternatively, which are engineered so as not to express the polypeptides of the present invention (eg, knockouts) are administered to a patient in vivo. Such cells can be obtained from the patient (ie, an animal, including humans) or from a compatible MHC donor and can include, but are not limited to, fibroblasts, bone marrow cells, blood cells (eg, lymphocytes), adipocytes, cells muscular, endothelial cells, etc. The cells are engineered using the recombinant DNA techniques to introduce the coding sequence of the polypeptides of the present invention into the cells, or alternatively, to interrupt the coding sequence and / or the endogenous regulatory sequence associated with the cells. the polypeptides of the present invention, eg by transduction (using viral vectors and preferably vectors that integrate the transgene into the cell genome) or transfection procedures, including but not limited to the use of plasmids, cosmids, YACs, naked DNA, electroporation, liposomes, and so on. The coding sequence of the polypeptides of the present invention can be placed under the control of a strong constitutive or inducible promoter, or a promoter / enhancer to achieve the expression and preferably the secretion of the polypeptides of the present invention. Genetically engineered cells that express and preferably secrete the polypeptides of the present invention can be introduced systemically into the patient, e.g. in the blood circulation, or intraperitoneally. Alternatively, the cells can be incorporated into a matrix and implanted in the body, e.g., engineered fibroblasts can be implanted as part of a skin graft.; can be implanted endothelial cells manipulated by genetic engineering as part of a lymphatic or vascular graft (see, for example, Anderson et al., Patent North American No. 5,399,349; and Mulligan & Wilson, Patent North American No. 5,460,959 each of which is incorporated herein, in its entirety, as a reference). When the cells to be administered are not autologous or are not MHC compatible, they can be administered using known techniques that prevent the development of a host immune response against the introduced cells. For example, the cells can be introduced in an encapsulated form which, while allowing an exchange of components with the immediate extracellular environment, does not allow the introduced cells to be recognized by the host's immune system. In still another embodiment of the present invention, the activity of the neutrokine-alpha and / or neutrocine-alphaSV polypeptide can be reduced using a "negative dominant". For this purpose, constructs coding for a defective neutrocine-alpha and / or neutrocin-alphaSV polypeptide, such as for example, mutants lacking all or a portion of the conserved TNF domain, can be used in gene therapy to decrease the activity of neutrocin-alpha and / or neutrocin-alphaSV in appropriate target cells. For example, nucleotide sequences that direct expression in the host cell of the neutrocine-alpha and / or neutrocine-alphaSV polypeptide, in which all or a portion of the conserved domain TNF was altered or lost, can be introduced in monocytic cells or other cells or tissues (either by the in vivo or ex vivo gene therapy methods described herein, or in some manner known in the art). Alternatively, targeting homologous recombination can be used to introduce such deletions or mutations in the endogenous neutrokine-alpha gene and / or neutrokine-alphaSV in monocytes. Genetically engineered cells will express non-functional neutrophil-alpha and / or neutrocin-alphaSV polypeptides (i.e., a ligand (e.g., multimer) that may be capable of binding, but is not capable of inducing signal transduction). Chromosomal Assays The nucleic acid molecules of the present invention are also valuable for the identification of chromosomes. The sequence is specifically directed towards, and can hybridize to, a particular location on an individual human chromosome. In addition, there is a current need to identify particular sites on the chromosomes. Few chromosome labeling reagents based on real sequence data (repetitive polymorphisms) are currently available to mark chromosomal sites. The mapping of DNAs into chromosomes according to the present invention is a first important step in the correlation of those sequences with genes associated with a disease. In certain preferred embodiments in this regard, the cDNA and / or polynucleotides described herein are used to clone genomic DNA from a neutrocine-alpha and / or neutrocine-alphaSV gene. This can be accomplished using a variety of known techniques and libraries, which are generally available commercially. The genomic DNA, subsequently, is used for chromosome mapping in itself, using the techniques known for this purpose. In addition, in some cases, sequences on chromosomes can be mapped by preparing PCR primers (preferably 15 to 25 bp) from cDNA. Computer analysis of the 3 'untranslated region of the gene is used to rapidly select primers that do not extend beyond an exon in the genomic DNA, thus complicating the amplification process. Then, these primers are used for PCR screening assays of hybrid somatic cells containing individual human chromosomes. Hybridization with fluorescence in si tu ("FISH") from a cDNA clone to a metaphase chromosome, can be used to obtain a precise chromosomal location in a single stage. This technique can be used with probes from cDNAs as short as 50 or 60 bp. For a review of this technique, see Verma et al. , Human Chromosomes: A Manual of Basic Techniques, Pergamon Press, New York (1988). Once a sequence has been mapped to an accurate chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found, for example, in V. McKusick, Mendelian Inheritance In Nucleic Acid Molecule, available online at Johns Hopkins University, Welch Medical Library. The relationship between genes and diseases that have been mapped in the same chromosomal region is subsequently identified by linkage analysis (co-inheritance of physically adjacent genes). Next, it is necessary to determine the differences in cDNA or genomic sequence between affected and unaffected individuals. If a mutation is observed in some or all of the affected individuals, but in none of the normal individuals, then the mutation is likely to be the causative agent of the disease. With the current resolution of physical mapping and genetic mapping techniques, a cDNA precisely located in a chromosomal region associated with the disease, could be one of between 50 and 500 potential causal genes (this assumes a mapping resolution of 1 megabases and a gene per 20 kb). Using the previously described techniques, the chromosomal location of neutrokine-alpha and neutrocin-alphaSV was determined with high confidence, using a combination of hybrids of somatic and hybrid cells by radiation at position 13q34 of the chromosome. EXAMPLES Having generally described the present invention, it will be more readily understood by reference to the following examples, which are provided as an illustration and are not intended to be limiting. Many of the following examples are established by referring specifically to the neutrokine-alpha polynucleotides and polypeptides of the present invention. Each example can also be practiced to generate and / or examine neutrokine-alphaSV polynucleotides and / or polypeptides of the present invention. A person skilled in the art will easily be able to direct the following examples towards neutrocin-alphaSV. Example: Expression and Purification of Neutrocin-alpha with "His tag" in E. coli The bacterial expression vector pQE9 (pD10) is used for bacterial expression in this example (QIAGEN, Inc. supra). Plasmid pQE9 codes for resistance to the antibiotic ampicillin ("Ampr") and contains a bacterial origin of replication ("ori"), an inducible IPTG promoter, a ribosome binding site ("RBS"), six codons that encode residues of histidine that allow affinity purification using a nickel-nitrile-triacetic acid affinity resin ("Ni-NTA") marketed by QIAGEN, Inc., supra, and suitable restriction enzymatic cleavage sites. These elements are arranged in such a way that an inserted DNA fragment encoding a polypeptide, expresses that peptide with all six His residues (i.e., a "6 X His tag") covalently linked to the amino-terminus of that polypeptide. The DNA sequence encoding the desired portion of the neutrokine-alpha protein comprising the extracellular domain sequence is amplified from the deposited cDNA clone using PCR oligonucleotide primers, which pair with the amino acid sequences. terminals of the desired portion of the protein and sequences in the 3 'construct deposited to the cDNA coding sequence. Additional nucleotides containing restriction sites to facilitate cloning in the pQE9 vector are added to the 5 'and 3' primer sequences, respectively. To clone the extracellular domain of the protein, the 5 'primer has the sequence 5' -GTG GGA TCC AGC CTC CGG GCA GAG CTG-3 '(SEQ ID NO: 10) containing the underlined BamHl restriction site followed by 18 nucleotides of the amino-terminal coding sequence of the extracellular domain of the sequence of Figures IA and IB. A person skilled in the art would, of course, observe that the point in the protein coding sequence where the 5 'primer begins could be varied to amplify a segment of DNA that codes for any desired portion of the neutrocin complete a shorter protein or longer than the extracellular domain of the form. The 3 'primer has the sequence 5' -GTG AAG CTT TTA TTA CAG CAG TTT CAA TGC ACC-3 '(SEQ ID NO: 11) containing the underlined ffindlll restriction site followed by two stop codons and 18 nucleotides complementary to the 3 'end of the coding sequence of the DNA sequence of Figures IA and IB. The amplified DNA fragment and the vector pQE9 are digested with the enzymes .BamHl and ífindlll and the digested DNAs are ligated. The insertion of the DNA into the restricted pQE9 vector places the protein coding region downstream of the IPTG-inducible promoter and within the framework with a starter AUG and all six histidine codons. The ligation mixture is transformed into competent E. coli cells using standard procedures, such as those described in Sambrook et al. , Molecular Cloning: a Laboratory Manual, 2nd Ed.; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989). The ecoli strain M15 / rep4, which contains multiple copies of the plasmid pREP4 expressing the lac repressor and confers resistance to kanamycin ("Kanr"), is used to carry out the illustrative example described herein. This strain, which is only one of many that are suitable for expressing the protein, is commercially available from QIAGEN, Inc., supra. Transformants are identified by their ability to grow on plates of LB medium in the presence of ampicillin and kanamycin. The plasmid DNA is isolated from the resistant colonies and the identity of the cloned DNA is confirmed by restriction analysis, PCR and DNA sequencing. Clones containing the desired constructs are grown overnight ("O / N") in liquid LB medium supplemented with ampicillin (100 μg / mL) and kanamycin (25 μg / mL). The O / N culture is used to inoculate a large culture, at a dilution of about 1:25 to 1: 250. The cells are grown to an optical density, at 600 nm ("OD600") of between 0.4 and 0.6.

Then isopropyl-beta-D-thiogalactopyranoside ("IPTG") is added to a final concentration of 1 mM to induce transcription of the lac repressor responsive promoter, by inactivating the lacl repressor. The cells are subsequently incubated for 3 to 4 hours. Later they are harvested by centrifugation. The cells are then stirred for 3 to 4 hours at 4 ° C in 6M guanidine-HCl, pH 8. The cell debris is removed by centrifugation and the supernatant containing the proteins is loaded onto a column of nickel-affinity resin. nitrile triacetic acid ("NiNTA") (available from QIAGEN, Inc., supra). The proteins with a 6 x His tag bind to the Ni-NTA resin with high affinity and can be purified in a simple single step procedure (for more details see: The QIAexpressionist, 1995, QIAGEN, Inc., supra). Briefly, the supernatant is loaded onto the column in 6M guanidine-HCl, pH 8, the column is first washed with 10 volumes of 6M guanidine-HCl, pH 8, then washed with 10 volumes of 6M guanidine-HCl, pH 6 and finally the neutrocine-alpha and / or neutrocine-alphaSV polypeptide is eluted with 6M guanidine-HCl, pH 5. The purified protein is subsequently renatured by dialysis against a phosphate buffer solution (PBS) or 50 mM sodium acetate buffer. , pH 6 plus 200 mM NaCl. Alternatively, the protein can be renatured successfully immobilized on the Ni-NTA column. The recommended conditions are the following: renature using a linear gradient of 6M-1M urea in 500 mM NaCl, 20% glycerol, 20 mM Tris / HCl; pH 7.4, containing protease inhibitors. The renaturation must be carried out during a period of 1.5 hours or more. After renaturing the proteins, they can be eluted by the addition of 250 mM imidazole. The imidazole is removed by a final dialysis step against PBS or against buffer solution of 50 mM sodium acetate, pH 6, plus 200 mM NaCl. The purified protein is stored at 4 ° C or frozen at -80 ° C. Example Ib: Neutrocin-alpha expression and purification in E. coli The bacterial expression vector pQE60 is used for bacterial expression in this example (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, CA, 91311). PQE60 codes for resistance to the antibiotic ampicillin ("Ampr") and contains a bacterial origin of replication ("ori"), an IPTG-inducible promoter, a ribosome binding site ("RBS"), six codons that encode residues of histidine that allow affinity purification using a nickel-nitrile-triacetic acid affinity resin ("Ni-NTA") obtainable in QIAGEN, Inc., supra and unique cleavage sites by suitable restriction enzymes. These elements are arranged in such a way that a DNA fragment encoding a polypeptide can be inserted in such a way as to produce the polypeptide with the six His residues (i.e., a "6 X His tag") covalently linked to the carboxyl-terminal end of that polypeptide. However, in this example the coding sequence of the polypeptide is inserted in such a way that the translation of the six His codons is prevented and, therefore, the polypeptide is produced without the 6 X His tag. The DNA sequence encoding the desired portion of the protein comprising the extracellular domain sequence is amplified from the deposited cDNA clone using PCR primer oligonucleotides that pair with the amino-terminal sequences of the desired portion of the protein and sequences in the 3 'construct deposited from the cDNA coding sequence. Additional nucleotides containing restriction sites are added to facilitate cloning in the vector pQE60 to the 5 'and 3' sequence, respectively. To clone the extracellular domain of the protein, the 5 'primer has the sequence 5' -GTG TCA TGA GCC TCC GGG CAG AGC TG-3 '(SEQ ID NO: 12) containing the underlined BspHI restriction site followed by 17 nucleotides of the amino-terminal coding sequence of the extracellular domain of the sequence in Figures IA and IB. A person skilled in the art will, of course, observe that the point of the coding sequence of the protein at which the 5 'primer starts can be varied to amplify a desired portion of the complete protein, shorter or longer than the extracellular domain. Shape. The 3 'primer has the sequence 5'-AGTG AAG CTT TTA TTA CAG CAG TTT. CA. TGC ACC-3 '(SEQ ID NO: 13) containing the underlined restriction site iIndIII followed by two codons and 18 nucleotides complementary to the 3' end of the coding sequence in the DNA sequence of Figures IA and IB. The amplified DNA fragments and the vector pQE60 are digested with the enzymes BspHI and BindlII and the digested DNAs are subsequently ligated. The insertion of the DNA into the restricted pQE60 vector places the coding region of the protein including its associated stop codon downstream of the IPTG-inducible promoter and within the framework with a start AUG. The associated stop codon prevents translation of the six histidine codons downstream of the insertion site. The ligated mixture is transformed into competent E. coli cells using standard procedures, such as those described in Sambrook et al. Molecular Cloning: a Laboratory Manual, 2nd Ed.; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989). The E. coli strain M15 / rep4, which contains multiple copies of plasmid pREP4, which expresses the lac repressor and confers resistance to kanamycin ("Kanr"), is used to carry out the illustrative example described herein. This strain, which is only one of many that are suitable for expressing the protein, is commercially available from QIAGEN, Inc., supra. Transformants are identified by their ability to grow on plates of LB medium in the presence of ampicillin and kanamycin. The plasmid DNA is isolated from the resistant colonies and the identity of the cloned DNA is confirmed by restriction analysis, PCR and DNA sequencing. A person skilled in the art will recognize that any of a number of bacterial expression vectors may be useful for placing pQE9 and pQE60 in the expression protocols presented in this example. For example, the new pHE4 series of bacterial expression vectors, in particular the vector pHE4-5, can be used for bacterial expression in this example (Accession number ATCC 209311, and variations thereof).

The DNA plasmid designated pHE4-5 / MPIFD23 with the deposit number ATCC 209311 is a plasmid DNA vector containing an insert coding for another ORF. The construction was deposited in the American Type Culture Collection, 10801 University Boulevard, Manassas, Virginia 20110-2209, on September 30, 1997. Using the Ndel and Asp718 restriction sites that flank the MPIF ORF insertion irrelevant, a person skilled in the art could easily use current molecular biology techniques to replace the irrelevant ORF of the vector pHE4-5 by the neutrokine-alpha ORF of the present invention. The bacterial expression vector pHE4-5 includes a neomycin phosphotransferase gene for selection, an origin of replication of E. coli, a promoter sequence of phage T5, two lac operator sequences, a sequence of Shine-Delgarno and the repressor gene of the operon. of lactose (laclq). These elements are arranged in such a way that a fragment of AD? inserted that encodes a peptide expresses that peptide with all six His residues (i.e., a "6 X His tag") covalently linked to the amino-terminal end of that polypeptide. The promoter and operator sequences of the vector pHE4-5 were prepared synthetically. The synthetic production of nucleic acid sequences is known in the art (CLO? ETECH 95/96 Catalog, pages 215-216, CLO? ETECH, 1020 East Meadow Circle, Palo Alto, CA 94303). Clones containing the desired neutrokine-alpha constructs are grown overnight ("O / N") in liquid LB culture medium supplemented with ampicillin (100 μg / mL) and kanamycin (25 μg / mL). The O / N culture is used to inoculate a large culture, at a dilution of about 1:25 to 1: 250. The cells are grown to an optical density, at 600 nm ("OD600"), between 0.4 and 0.6. Subsequently, isopropyl-beta-D-thiogalactopyranoside ("IPTG") is added to a final concentration of 1 mM to induce transcription of the lac repressor responsive promoter, by inactivating the lacl repressor. The cells are subsequently incubated for another 3 to 4 hours. Afterwards, the cells are harvested by centrifugation. Subsequently, the cells are shaken for 3 to 4 hours at 4 ° C in 6M guanidine-HCl, pH 8. The cell debris is removed by centrifugation and the supernatant containing the neutrokine is dialyzed against a buffer solution of 50 mM sodium acetate. pH 6, supplemented with 200 mM NaCl. Alternatively, the protein can be renatured successfully by dialyzing against 500 mM NaCl, 20% glycerol, 25 mM Tris / HCl, pH 7.4, containing protease inhibitors. After renaturing the protein, it can be purified by ion exchange, hydrophobic interaction and size exclusion chromatography. Alternatively, an affinity chromatography step, such as a column with antibodies, can be used to obtain the pure protein. The purified protein is stored at 4 ° C or frozen at -80 ° C. In certain embodiments, it is preferred to generate expression constructs such as those detailed in this Example to mutate one or more of the three cysteine residues in the neutrocine-alpha polypeptide sequence. The cysteine residues of the neutrokine-alpha polypeptide sequence are located at positions 147, 232 and 245, as shown in SEQ ID NO: 2, and at positions 213 and 226 of the neutrokine polypeptide sequence -alpha as shown in SEQ ID NO: 19 (there is no cysteine in the neutrokine-alphaSV polypeptide sequence corresponding to the Cys-147 of the neutrokine-alpha polypeptide sequence, because the amino acid residues from 143 to 160 of the neutrokine-alpha polypeptide sequence are not present in the neutrokine-alphaSV polypeptide sequence). Example 2: Cloning, Expression and Purification of the Neutrokine-alpha Protein in a Baculovirus Expression System In this illustrative example, the plasmid vector pA2GP is used to insert the cloned DNA encoding the extracellular domain of the protein, which lacks its intracellular and transmembrane naturally associated in a baculovirus to express the extracellular domain of the neutrocin-alpha protein, employing a baculovirus leader sequence and standard methods such as those described in Summers et al. , A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures, Texas Agricultural Experimental Station, Bulletin No. 1555 (1987). This expression vector contains the potent polyhedrin promoter of Autographa californica nuclear polyhedrosis virus (AcMNPV), followed by the secretory signal peptide (leader) of baculovirus gp67 protein and convenient restriction sites such as BamHl, Xbal and Asp718. The simian virus polyadenylation site 40 ("SV40") is used to obtain efficient polyadenylation. For easy selection of the recombinant virus, the plasmid contains the E. coli beta-galactosidase gene, under the control of a weak Drosophila promoter in the same orientation, followed by the polyadenylation signal of the polyhedrin gene. The inserted genes are flanked on both sides by viral sequences for cell-mediated homologous recombination with the wild type viral DNA, to generate viable viruses that express the cloned polynucleotide. Many other baculovirus vectors can be used in place of the above vector, such as pAc373, pVL941 and pAcIMl, as will be appreciated by one skilled in the art, so long as the construction provides the signals appropriately located for transcription, translation, secretion and the like. , including a signal peptide and an AUG within the framework, as required. Such vectors are described, for example, in Luckow et al. , Virology 170: 31-39 (1989). The DNA sequence coding for a N-terminally deleted form of the extracellular domain of the neutrocin-alpha protein in the deposited clone lacks the AUG start codon, the sequences of the naturally associated intracellular and transmembrane domains and the amino acids Gln-73 to Leu-79 shown in Figures la and IB (SEQ ID NO: 2), this sequence is amplified using oligonucleotides PCR primers corresponding to the 5 'and 3' sequences of the gene. The 5 'primer has the sequence 5' -GTG GGA TCC CCG GGC AGA GCT GCA GGG C-3 '(SEQ ID NO: 14) containing the site of the restriction enzyme BamHl underlined followed by 18 nucleotides of the sequence of the domain extracellular protein of the neutrokine-alpha protein shown in Figures IA and IB, starting with the indicated N-terminus of the extracellular domain of the protein. The 3 'primer has the sequence 5' -GTG GGA TCC TTA TTA CAG CAG TTT CAA TGC ACC-3 '(SEQ ID NO: 15) containing the BamHl underlined restriction site followed by two stop codons and 18 nucleotides complementary to the coding sequence 3 'of Figures IA and IB. In certain other embodiments, constructs designed to express the predicted extracellular domain of neutrokine-alpha (i.e., the amino acid residues of Gln-73 to Leu-285) are preferred. A technique in the art would be able to use the polynucleotide and polypeptide sequences provided by SEQ ID NO: 1 and SEQ ID NO: 2, respectively, to design polynucleotide primers to generate such clones. In a preferred embodiment, an expression construct pA2GP codes for the amino acid residues of Leu-112 to Leu-285 of the neutrocin-alpha polypeptide sequence as shown in SEQ ID NO: 2. In another preferred embodiment, a expression construct pA2GP codes for the amino acid residues of Ser-78 to Leu-285 of the neutrokine-alpha polypeptide sequence as shown in SEQ ID NO: 2. The amplified fragment is isolated from an agarose gel at 1% using a commercially available package ("Geneclean" BIO 101 Inc., La Jolla, CA). The fragment is then digested with BamHI and again purified on a 1% agarose gel. This fragment is designated herein as Fl.

The plasmid is digested with the BamHI restriction enzymes and optionally dephosphorylated using calf intestinal phosphatase, using routine procedures known in the art. Subsequently, the DNA is isolated from a 1% agarose gel using a commercially available packet ("Geneclean" BIO 101 Inc., La Jolla, CA). This vector DNA is referred to herein as "VI". The fragment Fl and the dephosphorylated plasmid VI are ligated with the T4 DNA ligase. Hosts such as E. coli HB101 or other suitable E. coli hosts such as XL-1 Blue (Stratagene Clning Systems, La Jolla, CA) are transformed with the ligation mixture and inoculated into culture dishes. Bacteria containing the plasmid are identified with the human gene by digestion of DNA from individual colonies with the restriction enzyme BamHI and then analyzing the digestion product by gel electrophoresis. The sequence of the cloned fragment is confirmed by DNA sequencing. This plasmid is designated herein as pA2GP-neutrocin-alpha. Five micrograms of the pA2GP-neutrocin-alpha plasmid are cotransfected with 1.0 microgram of commercial linearized baculovirus DNA ("BaculoGold ™ baculovirus DNA", Pharmingen, San Diego, CA), using the lipofection method described by Felgner et al. , Proc. Nat 'l Acad. Sci. USA 84: 7413-7417 (1987). 1 μg of BaculoGold ™ virus DNA and 5 μg of plasmid pA2GP-neutrocin-alpha are mixed in a sterile well of a microplate containing 50 microliters of Grace's medium without serum (Life Technologies Inc., Gaithersburg, MD). Then, 10 microliters of Lipofrectin plus 90 microliters of Grace's medium are added, mixed and incubated for 15 minutes at room temperature. Subsequently, the transfection mixture is added dropwise to Sf9 insect cells (ATCC CRL 1711) seeded on a 35 mm tissue culture plate with 1 mL of Grace's medium without serum.

The plates are then incubated for 5 hours at 27 ° C.

Subsequently, the transfection solution is removed from the plate and 1 mL of Grace's insect medium supplemented with 10% fetal calf serum is added. Subsequently the culture is continued at 27 ° C for four days. After four days, the supernatant is collected and plaque assayed, in the manner described by Summers and Smith, supra. An agarose gel with "Blue Gal" (Life Technologies Inc., Rockville, Maryland) is used to allow easy identification and isolation of gal-expressing clones, which produce blue-stained plates (a detailed description of an "assay"). of plates "of this type, can be found in the user's guide for insect cell cultures and baculovirology, distributed by Life Technologies Inc., Rockville, MD, pages 9-10.After an appropriate incubation, the plates stained with blue are stung with the tip of a micropipette (eg, an Eppendorf pipette) The agar containing the recombinant viruses is resuspended in a microcentrifuge tube containing 200 μL of Grace's medium and the suspension containing the recombinant baculovirus is used to infecting Sf9 cells seeded in 35 mm plates Four days later, the supernatants of these culture plates are harvested and then stored at 4 ° C. The recombinant virus is named V-neutrocine-alpha. To verify the expression of the neutrokine-alpha gene, Sf9 cells are grown in Grace's medium supplemented with 10% SFT (Fetal Calf Serum) inactivated by heat. Cells are infected with recombinant baculovirus V-neutrocin alfa at a multiplicity of infection ("MDI") of about 2. If radiolabeled proteins are desired, 6 hours later the medium is removed and replaced with SF900 II medium without methionine and cysteine (available from Life Technologies Inc., Rockville, MD). After 42 hours, 5 microcuries of 35S-methionine and 5 microcuries of 3-cysteine (available from Amercham) are added. The cells are incubated for another 16 hours and then harvested by centrifugation. The proteins of the supernatant, as well as intracellular proteins, are analyzed by SDS-PAGE, followed by autoradiography (if radiolabeled). Microsequencing of the amino acid sequence of the amino-terminus of the purified protein can be used to determine the amino terminal sequence of the extracellular domain of the protein and thus the breaking point and the length of the secretory signal peptide. In a specific experimental example, recombinant neutrocin-alpha was purified from supernatants of Sf9 cells infected with baculovirus, in the following manner. The insect cells were grown in EXCEL401 medium (JRH Scientific) with 1% (v / v) fetal bovine serum. At 92 hours after infection, the supernatant was harvested and clarified by centrifugation at 18,000 x g, followed by a membrane of 0.45 um. The filtration stage can also be used to remove contaminating lipids and, in turn, to improve the initial capture of the neutrocyan-alpha protein. The supernatant was loaded into a Pros HS-50 / HQ-50 in tandem mode. As an alternative, Toyopearl QAE, Toyopearl Super Q (Tosohass), Q-Sepharose (Pharmacia) and equivalent resins can be used.

This stage is used as a negative purification to remove anionic contaminants that bind strongly. The HS7HQ flow through the material was adjusted to pH 7.5 with 1M Tris-HCl, pH 8, diluted with an equal volume of 50 mM Tris-HCl, pH 8 and loaded onto a pore column PI-20 or PI-50 . The PI column was first washed with 4 column volumes of 75 mM sodium chloride in 50 mM Tris-HCl, at pH 7.5, then eluted using 3 to 5 column volumes of a gradient per 300 mM portions of sodium chloride. , 750 mM, 1500 mM in 50 mM Tris-HCl, pH 7.5. The protein neutrocin-alpha appears as a band of 17 kDa in an electrophoresis of the EGPA-DSS and is presented in the fractions 0.75M to 1.5M of sodium chloride. The Pl fraction was further purified through a column of size exclusion Sephacryl S100 HR (Pharmacia), equilibrated with 0.15M sodium chloride, 50 mM sodium acetate, at pH 6. The S200 fractions were mixed with sodium chloride to a final concentration of 3M and loaded onto a Toyopearl Hexyl 650C column (Tosohass). The Hexyl column was eluted with a linear gradient of 3M to 0.05M sodium chloride in 50mM sodium acetate, pH 6, in an amount of 5 to 15 column volumes. The sodium chloride gradient can also be replaced by a gradient of 1M to 0M ammonium sulfate in 50 mM sodium acetate, pH 6, in the chromatographic step with Hexyl. Fractions containing purified neutrocin-alpha, analyzed by SDS-PAGE, were combined and dialyzed against a buffer solution containing 150 mM sodium chloride, 50 mM sodium acetate, pH 6. The final purified neutrocin-alpha protein, expressed in a baculovirus system as explained herein, has an N-terminal sequence that begins with an amino acid residue Ala-134 of SEQ ID NO: 2. An analysis by CLAR-FR demonstrated a single peak greater than 95 % purity The level of endotoxin was below the limit of detection in an LAL trial. In another example, recombinant neutrocin-alpha was purified from supernatants of Sf9 cells infected with baculovirus containing 0.25% bovine serum, as follows. The supernatant of the Sf9 cell culture was harvested by centrifugation at 18,000 x g. The supernatant was then treated with 10 mM calcium chloride under slightly alkaline conditions for 10 to 15 minutes, followed by centrifugation and then filtration in a 0.22 micrometer membrane. The resulting Sf9 cell supernatant was diluted twice and loaded onto a Poros PI-50 column (available from PE Biosystems). The column was equilibrated with 50 mM Tris (pH = 7.4). The PI-50 column was washed with 1 column volume (VC) of 50 mM Tris (pH = 7.4) and then eluted with 1.5 M NaCl in 50 mM NaOAc (pH = 6) by more than 3 VC. The Pl fraction was loaded onto a Sephacryl S200 column equilibrated with 50 mM NaOAc (pH = 6), 125 mM NaCl. Fraction S200 was mixed with salts to a final concentration of 0.7M ammonium sulfate and NaCl 0.6M and loaded onto a Toyopearl Hexyl 650C column (available from Toso Haas) which had been equilibrated with a buffer solution containing 0.6M NaCl, 0.7M ammonium sulfate in 50 mM NaOAc (pH = 6). Then the column was washed with 2 VC of the same buffer. Subsequently, the recombinant neutrocin-alpha was eluted in steps with 3 VC of 50 mM NaOAc (pH = 6), followed by 2 VC of a wash with 20% ethanol. The recombinant neutrokine-alpha protein was eluted at the end of the ammonium sulfate gradient (from 0.3 to 0M salt). Appropriate fractions were mixed and dialysed against a buffer solution containing 50 mM NaOAc (pH = 6) and then passed through a Poros 50 HQ column. The HQ column flow was diluted to 4 ms and loaded onto a Toyopearl DEAD 650M column and then eluted with 25mM sodium citrate, 125mM NaCl. In another example, recombinant neutrocin-alpha was expressed and purified using a baculoviral vector system in Sf + insect cells.

First, a polynucleotide encoding the amino acid residues of Ser-78 to Leu-285 of the neutrokine-alpha polypeptide sequence shown in Figures IA and IB (which is exactly identical to the amino acid residues of Ser-78 to Leu-285 of the neutrokine-alpha polypeptide sequence as shown in SEQ ID NO: 2), was subcloned into the PSC baculovirus transfer construct, to generate a baculovirus expression plasmid. The pA2GP transfer vector, derived from pVL941, contains the gp67 signal peptide, a modified multiple cloning site and the lac Z gene cloned downstream of the Drosophila term shock promoter for selection of blue plates. Using the neutrocin-alpha sequence (SEQ ID NO: 2) and the sequence of the vector pA2GP, a cloning strategy was designed to continuously fuse the coding sequence of the PSC signal peptide to the coding sequence for neutrocin-alpha, in the Ala-134 position (SEQ ID NO: 2 and Figures IA and IB) and inserting it in the baculovirus transfer plasmid PSC. The strategy involved the use of a two-step polymerase catalyzed chain reaction (PCR) procedure. First, primers were designed to amplify the neutrokine-alpha sequences. The 5 'primer consisted of the coding sequence of Ala-134 and the following residues (5' -GGT CGC CGT TTC TAA CGC GGC CGT TCA GGG TCC AGA AG-3 ', SEQ ID NO: 31), preceded by the dodifying sequence of the PSC signal peptide from the C-terminal end. The 3 'primer (5' -CTG GTT CGG CCC AAG GTA CCA AGC TTG CT CTT AGA TCT TTT CTA GAT C-3 ', SEQ ID NO: 32) consisted of the inverse complement of the vector sequence pA2GP immediately downstream of the coding sequence of neutrocine-alpha, preceded by a restriction endonuclease site fpnl and a separating sequence (to increase the efficiency of the cut by the enzyme Kpnl). PCR was performed with the plasmid template pA2GP containing the neutrokine-alpha plasmid and the primers O-1887 and 0-1888, and the resulting PCR product was purified using standard techniques. i An additional PCR reaction was performed using the PSC baculovirus transfer plasmid pMGS12 as template. The plasmid pMGS12 consists of the AcNPV fragment coRI "I" inserted into pUC8, with the polyhedrin coding sequences after the start codon i ATG replaced by the PSC signal peptide and a i polylinker site. The PCR reaction used pMGS12 as a template, a 5 'primer (5' -CTG GTA GTT CTT CGG AGT i GTG-3 ', SEQ ID NO: 33) which was paired with AcNPV ORF603 i upstream of the unique sites NgoM IV and EcoR V, and the 3 'primer (5' -CGC GTT AGA AAC GGC GAC C-3 '; SEQ ID? O: 34), which was paired with the 3' end of the coding sequence of the PSC signal. To generate a PCR product in which the PSC signal peptide was fused without patches into the coding sequence Ala-134 of neutrocin-alpha, the PCR product was combined with the signal peptide-PCR product from the upstream region of polyhedrin and underwent an additional round of CPR. Because the 3 'end of the PSC signal peptide produced by PCR (pMGS12 / O-959 / O-1044) was overlapped with the 5' end of the neutrocine-alpha PCR product prepared with primers 0-1887 / 0 -1888, the two PCR products were combined and overlapped and extended by PCR using primers 0-959 and 0-1888. The resulting extended overlapping PCR product contained the PSC signal peptide fused to the neutrocin-alpha sequence and subsequently inserted into the baculovirus transfer plasmid pMGS12. The PCR product was digested with NgoM IV and Kpn I, and the fragment was purified and ligated into the pMGS12 subjected to a cut with NgoM IV-Kpn I. After transformation of competent E. coli DH5alpha cells with the linkage mixture, colonies were stung and AD mini-preparations were prepared? plasmid Several positive clones of each linkage were identified by a restriction digest analysis of the plasmid DNA and three clones (pAcC9669, pAcC9671 and pAcC9672) were selected for large-scale purification of the plasmid. The resulting plasmid DNA was subjected to a DNA sequence analysis to confirm and sequence the neutrokine-alpha insert. The following steps describe the process of recovery and purification of recombinant neutrocin-alpha from Sf + insect cells. Unless stated otherwise, the process is carried out at a temperature of 2-8 ° C. Recovery Stage 1. Treatment with CaCl2 The supernatant of an Sf + cell culture was harvested by centrifugation at 8,000 x g. Recovery buffer-1 (1M CaCl 2) was added to the supernatant until the final concentration of CaCl 2 was 10 mM (in a preferred additional mode, 1 M ZnCl 2 was used instead of CaCl 2). The pH of the solution was adjusted to 7.7 ± with buffer-2 recovery (Tris 1M pH 8 (± 0.2)). The solution was incubated for 15 minutes and then centrifuged at 8,000 x g. Purification Step 1. Chromatography in Poros PISO Column The supernatant of a culture of Sf + cells was loaded on a Poros PI-50 column (PE Biosystem). The column was equilibrated with PI-1 buffer (50 mM Tris, 50 mM NaCl, pH 7.4 (± 0.2)). The PI-50 column was washed with 1-2 VC of PI-1 buffer and then eluted with PI-2 buffer (50 mM sodium citrate, pH 6 (± 0.2)) in a linear gradient for more than 3 VC. The elution was monitored by ultraviolet (UV) absorbance at 280 nm. Fractions were collected through the eluate peak and analyzed by SDS-PAGE. The appropriate fractions were mixed. Stage 2. Chromatography in Toyopearl Column Hexyl 650C The Pl mixture was mixed with salts to a final concentration of 0.7M (NH4) S04 and loaded onto a Toyopearl Hexyl 650C (Toso Haas) column equilibrated with HIC-1 buffer (50 mM NaOAc, 0.6M NaCl, ( NH4) 2S04 0.7M, pH 6 (± 0.2)). The column was then washed with 2 VC of HIV-1 buffer. Subsequently, the recombinant neutrocin-alpha was eluted in portions with 3 to 5 VC of HIC-2 buffer (50 mM NaOAc, pH 6.0 (± 0.2), followed by a wash with 2 VC of 20% ethanol.

The elution was monitored by UV absorbance at 280 nm and conductivity. Fractions were collected through the eluate peak and analyzed by SDS-PAGE. Then the appropriate fractions were mixed.

Stage 3. Chromatography in SP Sepharose FF The Hexyl fraction was dialyzed and adjusted to pH 4.5 with buffer SP-1 (50 mM sodium acetate, pH 4. 5 (± 0.2)), diluted to 4 ms and loaded onto a SP sepharose column (cation exchanger, Pharmacia) balanced with regulatory solution SP-1 (50 mM sodium acetate, pH 4.5 (± 0.2)). Then the recombinant neutrocin-alpha protein was eluted from the SP column with buffer solution SP-2 (50 mM sodium acetate, pH 5.5 (± 0.2)) at pH 5.5. Then the elution was monitored by ultraviolet (UV) absorbance at 280 nm.

Fractions were collected through the eluate peak and analyzed by SDS-PAGE. The appropriate fractions were mixed. Stage 4. Neutrocin-alpha dialysis Recombinant SP fractions were placed on a 6 to 8 kd cutoff membrane and then dialyzed or diafiltered into dialysis buffer (10 mM sodium citrate, 140 mM sodium chloride, pH 6 (± 0.2)) during one night. Step 5. Filtration and Filling The protein concentration of the recombinant neutrokine-alpha solution of step 6 was determined by the protein assay with bicinchoninic acid (BCA). The recombinant neutrocin-alpha formulation was adjusted to a final protein concentration with an appropriate buffer and filtered under controlled conditions. The filtrate (bulk substance) was stored in suitable sterilized containers at -20 ° C. In a specific embodiment, the neutrocin-alpha protein of the present invention produced in a described manner was adjusted to a final protein concentration of 1 to 5 mg / mL and 10 mM sodium citrate buffer, 140 sodium chloride, was added thereto. mM, pH = 6.0 ± (0.4) and stored at -20 ° C or less in glass jars type 1. In the chromatography tests, the process was monitored by UV absorbance at 280 nm. When applicable, intermediates of in-process chromatography were tested for conductivity, pH and monitored by SDS and / or CLAR-FR. The columns and the purification equipment were cleaned and sanitized with 0.2 or 0.5M NaOH, followed by deionized water and then 0.1 or 0.5M acetic acid. The column and purification equipment were rinsed with deionized water and, if necessary, stored in an appropriate storage solution. Prior to use, the equipment was equilibrated with appropriate regulatory solutions (in the manner described herein or in a manner known in the art).

In a further preferred embodiment, 1M ZnCl 2 is used in place of 1M CaCl 2 in step 1 of the Recovery section described above. Likewise, in this modality a combination of ZnCl2 and CaCl2 can be used. Numerous combinations of 0.1M ZnCl2 and 0.9M CaCl2 can be used in the recovery process of the recombinant neutrokine-alpha protein, such as, for example, but not limited to, a combination of 0.1M ZnCl2 and 0.9M CaCl2, ZnCl2 0.2. M and CaCl2 0.8M, ZnCl2 0.3M and CaCl2 0.7M, ZnCl2 0.4M and CaCl2 0.6M, ZnCl2 0.5M and CaCl2 0.5M, ZnCl2 0.6M and CaCl2 0.4M, ZnCl2 0.7M and CaCl2 0.3M, ZnCl2 0.8M and 0.2M CaCl2, 0.9M ZnCl2 and 0.1M CaCl2 and others. However, the presence of AEDT will inhibit the recovery process. In addition, the presence of ZnCl2 and / or CaCl2 in the buffer solution of Recovery-1 will induce the formation of large amounts of neutrocine-alpha multimers of higher molecular weight (or molecular mass). Example 3: Cloning and Expression of Neutrocin-alpha in Mammalian Cells A typical mammalian expression vector contains the promoter element, which regulates the initiation of mRNA transcription, the protein coding sequence and the signals required for the termination of transcription and polyadenylation of transcription.

Additional elements include enhancers, Kozak sequences and intervening sequences flanked by donor and receptor sites for RNA splicing. Highly efficient transcription can be achieved with the SV40 early and late promoters, the long terminal repeats (LTRs) of Retroviruses, e.g., RSV, HTLVI, HIV-I and the cytomegalovirus early promoter (CMV). However, cellular elements can also be used (e.g., the human actin promoter). Some expression vectors suitable for use in the practice of the present invention, include for example vectors such as pSVL and pMSG (Pharmacia, Uppsala, Sweden), pRSV cat (ATCC 37152), pSV'dhfr (ATCC 37146) and pBC12MI (ATCC 67109). Mammalian host cells that can be used include, human HeLa cells, 293, H9 and Jurkat cells, murine NIH-3T3 cells and C127 cells, Cos 1, Cos 7 and CVl, QC1-3 quail cells, mouse L cells , Chinese hamster ovary cells (CHO) and HEK 293 cells. Alternatively, the gene can be expressed in stable cell lines containing the gene integrated into a chromosome. Co-transfection with a selectable marker, such as dhfr, gpt, nemocin, hygromycin, allows the identification and isolation of the transfected cells.

The transfected gene can also be amplified to express large amounts of the encoded protein. The DHFR (dihydrofolate reductase) marker is useful for developing cell lines that carry several hundred or even several thousand copies of the gene of interest. Another useful selection marker is the enzyme glutamine synthetase (GS) (Murphy et al., Biochem J. 227: 277-279 (1991), Bebbington et al., Bio / Technology 10: 169-175 (1992) 9. these markers, the mammalian cells are grown in a selective medium and the cells having the highest resistance are selected.These cell lines contain the amplified gene or genes integrated into a chromosome.Often the Chinese hamster ovary cells ( CHO) and NSO cells are used for the production of proteins.PCI and pC4 expression vectors contain the potent promoter (LTR) of the Rous Sarcoma Virus (Cullen et al., Molecular and Cellular Biology, 438-447 (March 1985)) plus a fragment of the CMV enhancer (Boshart et al., Cell 41: 521-530 (1985)). Multiple cloning sites, eg with the restriction enzyme cleavage sites BamHl, Xbal and Asp 718, facilitate the cloning of the gene of interest. the 3 'intron, the polyadenylation and termination signal and the rat preproinsulin gene.

Example 3 (a): Cloning and Expression in COS Cells The expression plasmid pNeutrocin-alpha-HA is prepared by cloning a portion of the deposited cDNA encoding the extracellular domain of the protein into the expression vector pcDNA / AMP or pcDNAIII (which can be obtained from Invitrogen, Inc.). To produce a soluble polypeptide, in secreted form, the extracellular domain is fused with the secretory leader sequence of the human IL-6 gene. The pcDNAI / amp expression vector contains: (1) an E. coli origin of replication effective for propagation in E. coli and other prokaryotic cells; (2) a gene for resistance to ampicillin for the secretion of prokaryotic cells containing the plasmid; (3) an SV40 origin of replication for propagation in eukaryotic cells; (4) a CMV promoter, a polylinker, an SV40 intron; (5) several codons encoding a fragment of hemagglutinin (ie, a "HA" tag to facilitate purification), followed by a stop codon and a polyadenylation signal arranged in such a way that the cDNA can conveniently be placed under the CMV promoter expression control and which can be operably linked to the SV40 intron and the polyadenylation signal by means of restriction sites in the polylinker. The HA mark corresponds to an epitope derived from the influenza hemagglutinin protein described by Wilson et al., Cell 37: 767 (1984). The fusion of the HA mark with the white protein allows the easy detection and recovery of the recombinant protein, with an antibody that recognizes the HA epitope. The pcDNAIII contains, in addition, the selectable marker neomycin. A DNA fragment encoding the extracellular domain of the neutrokine-alpha polypeptide is cloned into the vector polylinker region so that expression of the recombinant protein is driven by the SV promoter. The construction strategy of the plasmid is as follows. The neutrokine-alpha cDNA of the deposited clone is amplified using primers containing convenient restriction sites, much like the aforementioned for the construction of neutrocine-alpha expression vectors in E. coli. Suitable primers include the following, which are used in this example. The 5 'primer, which contains the underlined BamHI site, a Kozak sequence, an AUG start codon, a coding sequence, the secretory leader peptide of the human IL-6 gene and 18 nucleotides of the 5' coding region of the extracellular domain of the neutrokine-alpha protein, where the primer has the following sequence: 5 '-GCG GGA TCC GCC ACC ATG AAC TCC TTC TCC TCC TCC TCC TCC TCC TCC CTC CTG CTG CTG CTG GTG TTCC CCCT TCC CCT GCC CCA GTT GTG AGA CAA GGG GAC CTG GCC AGC-3 '(SEQ ID NO: 16). The 3 'primer contains the underlined BamHl restriction site and 18 nucleotides complementary to the 3' coding sequence immediately before the stop codon, wherein said primer has the following sequence: 5'-GTG GGA TCC TTA CAG CAG TTT CA. TGC ACC-3 '(SEQ ID NO: 17). The DNA fragment amplified by PCR and the pcDNAI / AMP vector are digested with BamHI and then ligated. The ligated mixture is transformed into the SURE E. coli strain (available from Stratagene Cloning Systems, 11099 North Torrey Pines Road, La Jolla, CA 92037), and the transformed culture is inoculated onto plates with ampicillin culture medium, which they are then incubated to allow the growth of ampicillin-resistant colonies. The plasmid DNA is isolated from the resistant colonies and examined by restriction analysis or by other means, in search of the presence of the fragment coding for the extracellular domain of neutrokine-alpha. For the expression of recombinant neutrocin-alpha, COS cells are transfected with an expression vector, in the manner described above, using DEAE-DEXTRAN, in the manner described for example in Sambrook et al. , Moleclar Cloning: A Laboratory Manual, Cold Spring Laboratory Press, Cold Spring Harbor, New York (1989). The cells are incubated under conditions suitable for the expression of neutrocine-alpha by the vector. The expression of the fusion protein neutrocin-alpha-HA is detected by radiolabelling and immunoprecipitation, using the methods described, for example, in Harlow et al. , Antibodies: A Laboratory Manual, 2nd Ed.; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York (1988). For this purpose, two days after transfection the cells are labeled by incubation in a culture medium containing 35 S-cysteine for 8 hours. The cells and the culture medium are collected and the cells are washed and lysed with detergent buffer containing RIPA: 150 mM NaCl, 1% NP-40, 0.1% SDS, 1% NP-40, 0.5% of DOC, 50 mM TRIS, pH 7.5, in the manner described by Wilson et al. above. The proteins are precipitated from the cell lysate and the culture medium using an HA-specific monoclonal antibody. The precipitated proteins, then, are analyzed by SDS-PAGE and by autoradiography. An expression product of the expected size is observed in the cell lysate, which is not observed in the negative controls. Example 3 (b): Cloning and Expression in CHO Cells The pC4 vector is used for the expression of the neutrocyan-alpha protein. Plasmid pC4 is a derivative of plasmid pSV2-dhfr (accession No. ATCC 37146). To produce a soluble secreted form of the neutrocin-alpha polypeptide, the portion of the deposited cDNA encoding the extracellular domain is fused with the leader sequence of the human IL-6 gene. The plasmid vector contains the murine DHFR gene under the control of the SV40 early promoter. Chinese hamster ovary cells or other cells lacking dihydrofolate activity, are transfected with these plasmids and can be selected by growing the cells in a selective medium (alpha minus MEM, Life Technologies) supplemented with the chemotherapeutic agent methotrexate. The amplification of DHFR genes in methotrexate-resistant cells (MTX) has been documented (see, eg, Alt, FW, Kellems, RM Bertino, JR and Schimke RT, 1978, J. Bioi, Chem., 253: 1357-1370 , Hamlin, JL and Ma, C. 1990, Biochem et Biophys, Acta, 1097: 101-143, Page, MJ and Sydenham, MA 1991, Biotechnology 9: 64-68). Cells that grow in increasing concentrations of MTX develop resistance to the drug by overproduction of the white enzyme, DFHR, as a result of the amplification of the DHFR gene. If a second gene is linked to the DHFR gene, it is usually co-amplified and also expressed in excess. It is known in the art that this approach can be used to develop carrier cell lines of more than 1000 copies of the amplified gene or genes. Subsequently, when methotrexate is removed, cell lines containing the amplified gene integrated to one or more chromosomes of the host cell are obtained. Plasmid pC4 contains to express the gene of interest, the potent promoter of the long terminal repeat (LTR) of the Rouse Sarcoma Virus (Vullen, et al., Molecular and Cellular Biology, March 1985: 438-447) plus a Asymmetric fragment of the intensifier of the human cytomegalovirus (CMV) immediate early gene (Boshart et al., Ceii 41: 521-530 (1985)). Downstream of the promoter, we find the following unique restriction enzyme cleavage sites, which allow the integration of the genes: BamHl, Xbal and Asp 718. Behind these cloning sites, the plasmid contains the 3 'intron and the site of polyadenylation of the rat preproinsulin gene. Other highly efficient promoters can also be used for the expression, e.g., the human beta-actin promoter, the SV40 early or late promoters or the long terminal repeats of other retroviruses, e.g., HIV and HTLVI. The gene expression systems of Clontech Tet-Off and Tet-On can be used to express neutrocin-alpha in a regulated manner in mammalian cells (Gossen, M. and Gujard, H. 1992, Proc. Nat'l Acad. Sci. USA 89: 5547-5551). For polyadenylation of the mRNA, other signals can also be used, e.g. the genes for human growth hormone or globin. Stable cell lines carrying a gene of interest integrated into the chromosome can also be selected, by cotransfection with a selectable marker such as gpt, G418 or hygromycin. It is advantageous to use more than one selectable marker at the beginning, e.g. G418 plus methotrexate. Plasmid pC4 is digested with the restriction enzyme BamHI and then dephosphorylated using calf intestinal phosphates, by methods known in the art. Then, the vector is isolated on a 1% agarose gel. The sequence of AD? coding for the extracellular domain of the neutrokine-alpha protein, is amplified using oligonucleotides PCR primers corresponding to the 5 'and 3' sequences of the gene. The 5 'primer, which contains underlined the BamHI site, a Kozak sequence, an AUG start codon, a peptide coding sequence leader the human IL-6 gene and 18 nucleotides of the 5' coding region of the extracellular domain of the protein neutrocin-alpha, has the following sequence: 5 '-GCG GGA TCC GCC ACC ATG AAC TCC TTC TCC ACA AGC GCC TTC GGT CCA GTT GCC TTC TCC CTG GGG CTG CTC CTG GTG TTG CCT GCT GCC TTC CCT GCC CCA GTT GTG AGA CA GGG GAC CTG GCC AGC-3 '(SEQ ID NO: 16). The 3 'primer contains underlined the BamHI site and 18 nucleotides complementary to the 3' coding sequence immediately before the stop codon, which has the following sequence: 5 '-GTG GGA TCC TTA CAG CAG TTT CAA TGC ACC-3' ( SEQ ID NO: 17). The amplified fragment is digested with the BamHI endonuclease and then purified again on a 1% agarose gel. The isolated fragment and the dephosphorylated vector are ligated with T4 DNA ligase. Then E. coli HB101 or XL-1 Blue cells are transformed and the bacteria containing the fragment inserted in the plasmid pC4 are identified using, for example, an analysis with restriction enzymes. Chinese hamster ovary cells lacking an active DHFR gene, are used for transfection. 5 μg of the expression plasmid pC4 is cotransfected with 0.5 μg of the plasmid pSV-neo using lipofectin (Felgner et al., Supra). Plasmid pSV2-neo contains a dominant selectable marker, the neo gene of Tn5 that codes for an enzyme that confers resistance to a group of antibiotics, including G418. The cells are seeded in alpha culture medium minus MEM supplemented with 1 mg / mL of G418. After 2 days, the cells are trypsinized and seeded in hybridoma hybridization plates (Greiner, Germany) in alpha culture medium minus MEM supplemented with 10, 25 or 50 ng / mL of methotrexate plus 1 mg / mL of G418. After about 10 to 14 days, single clones are trypsinized and then seeded in 6-well petri dishes or 10-mL flasks using different concentrations of methotrexate (50 nM, 100 nM, 200 nM, 400 nM, 800 nM) . Clones growing at the highest concentrations of methotrexate are transferred to new 6-well plates containing even higher concentrations of methotrexate (1 uM, 2 uM, 5 uM, 10 uM, 20 uM). The same procedure is repeated until clones are obtained that grow at a concentration of 100 to 200 μM. The expression of the desired gene product is analyzed, for example, by SDS-PAGE and by western blot or by reversed-phase HPLC analysis. The inventors have generated at least six expression constructs of neutrocin-alpha to facilitate the production of neutrokine-alpha and / or neutrocine-alphaSV polypeptides of various sizes and in various systems. The expression constructs are the following: (1) pNa.A71-L285 (expresses the amino acid residues of Ala-71 to Leu-285), (2) pNa.A81-L285 (expresses the amino acid residues of Ala-81 to Leu-285); (3) pNa.L112-L285 (expresses the amino acid residues of Leu-112 to Leu-285); (4) pNa.A134-L285 (expresses the amino acid residues of Ala-134 to Leu-285), (5) pNa.L147-L285 (expresses the amino acid residues of Leu-147 to Leu-285) and (6) pNa.G161-L285 (expresses the amino acid residues of Gly-161 to Leu-285). In preferred embodiments, the expression constructs are used to express several muteins of neutrocine-alpha in bacterial, baculoviral, and mammalian systems. In certain additional preferred embodiments, the constructs express a fragment of the neutrocyan-alpha polypeptide fused at the N-terminus and / or C-terminus with a heterologous polypeptide, e.g. the signal peptide of IL-6, the signal peptide of CK-beta8 (amino acid -21 to -1 of the sequence of CK-beta8 described in International Publication PCT / US95 / 09058) or the Fc region of the Human IgG Other sequences that are known to those skilled in the art can be used. Example 4: Tissue Distribution of Neutrocin-alpha mRNA Expression A Northern blot analysis was carried out to examine the expression of the neutrocine-alpha gene in human tissues, using the methods described, inter alia, by Sambrook et al. , previously mentioned. A cDNA probe containing the complete nucleotide sequence of the neutrokine-alpha protein (SEQ ID NO: 1) was labeled with 32P using the rediprime ™ DNA marking system (Amersham Life Science), in accordance with the manufacturer's instructions . After labeling, the probe was purified using a CHROMA SPIN-100 ™ column (Clontech Laboratories, Inc.), in accordance with manufacturer's protocol No. PT1200-1. The purified labeled probe was subsequently used to screen several human tissues for neutrokine-alpha and / or neutrokine-alpha mRNA. Multiple tissue Northern blots (MTN) containing several human tissues (H) or human immune system (IM) tissues were obtained in Clontech and examined with the labeled probe using ExpressHyb ™ Hybridization Solution (Clontech) in accordance with the manufacturer's protocol number PT1190-1. After hybridization and washing, the spots were mounted and exposed to a film at -70 ° C overnight, and then the films were developed in accordance with standard procedures. To determine the expression pattern of neutrokine-alpha and / or neutrocine-alpha, a Northern blot panel of multiple tissues was tested. This revealed the predominant expression of a single 2.6 kb mRNA in leukocytes from peripheral blood, spleen, lymph node and bone marrow, and detectable expression in placenta, heart, lung, fetal liver, thymus and pancreas. The analysis of a panel of cell lines demonstrated a high expression of neutrocine-alpha and / or neutrocin-alpha in HL60 cells, detectable expression in K562 cells, but no expression was found in Raji, HeLa or MOLT-4 cells. Above all it seems that the expression of neutrocine-alpha and / or mRNA of neutrocine-alpha is enriched in the immune system. Example 5: Gene Therapy Using the Neutrocytic Gene to Endogenous Lfa Another method of gene therapy according to the present invention includes the operable association of the endogenous neutrokine-alpha sequence with a promoter through a recombination homologous in the manner described, for example, in U.S. Patent No. 5,641,670, issued June 24, 1997; International Publication WO 96/29411, published September 26, 1996; International Publication WO 9412650, published August 4, 1994; Koller et al. , Proc. Nat 'l Acad. Sci. USA 86: 8932-8935 (1989); and Zijilstra et al. , Nature 342: 435-438 (1989). This method includes the activation of a gene that is present in the target cells, but which is not expressed in the cells or is expressed at a lower level than desired. Constructs of the polynucleotide containing a promoter and target sequences are prepared, which are homologous to the 5 'non-coding sequence of the endogenous neutrokine-alpha flanking the promoter. The white sequence will be sufficiently close to the 5 'end of the neutrocine-alpha, so that the promoter is operably linked to the endogenous sequence in the homologous recombination. The promoter and the target sequences can be amplified using the PCR technique. Preferably, the amplified promoter contains different restriction enzyme sites at the 5 'and 3' ends. Preferably, the 3 'end of the first target sequence contains the same restriction enzyme site as the 5' end of the amplified promoter and the 5 'end of the second target sequence contains the same restriction site as the 3' end of the amplified promoter. The amplified promoter and the amplified white sequences are digested with the appropriate restriction enzymes and subsequently treated with calf intestinal phosphatase. The digested promoter and the digested white sequences are combined in the presence of the T4 DNA ligase. The resulting mixture is maintained under conditions appropriate for the ligation of the two fragments. The construction is fractionated by size on an agarose gel and then purified by phenol extraction and ethanol precipitation. In this Example, the polynucleotide constructs are administered in the form of naked polynucleotides by electroporation. How, polynucleotide constructs can also be administered with agents that facilitate transfection, such as liposomes, viral sequences, viral particles, precipitating agents, and the like. Such distribution methods are known in the art. Once the cells are transfected, homologous recombination will be carried out which results in the promoter being operably linked with the endogenous neutrocin-alpha sequence. This results in the expression of neutrocine-alpha in the cell. The expression can be detected by immunological staining or by any other method known in the art. Fibroblasts are obtained from a subject by skin biopsy. The resulting tissue is placed in DMEM + 10% fetal calf serum. Fibroblasts in exponential growth or in an almost stationary phase are trypsinized and rinsed from the plastic surface with nutrient medium. An aliquot of the cell suspension is taken to carry out a count and the remaining cells are subjected to centrifugation. The supernatant is aspirated and the pellet is resuspended in 5 mL of electroporation buffer (20 mM HEPEs, pH 7.3, 137 mM NaCl, 5 mM KCl, 0.7 mM Na2HP04, 6 mM dextrose). The cells are recentrifuged, the supernatant is aspirated and the cells are resuspended in electroporation buffer containing 1 mg / mL of acetylated bovine serum albumin. The final cell suspension contains approximately 3 x 10 6 cells / mL. Electroporation should be carried out immediately after resuspension. Plasmid DNA is prepared according to standard techniques. For example, to construct a plasmid for targeting at the neutrokine-alpha locus, the pUCld plasmid (MBI Fermentas, Amherst, NY) is digested with J? IndIII. The CMV promoter is amplified by PCR with a Xbal site at the 5 'end and a BamHI site at the 3' end. Two non-coding sequences of neutrocine-alpha are amplified by PCR: a non-coding sequence of neutrocine-alpha (fragment 1 of neutrocine-alpha) is amplified with a HindIII site at the 5 'end and an Xba site at the 3' end; the other non-coding sequence of neutrocin-alpha (neutrokine-alpha 2 fragment) is amplified with a Ba Hl site at the 5 'end and a HindIII site at the 3' end. The CMV promoter and the neutrokine-alpha fragments are digested with the appropriate enzymes (CMV-Xbal promoter and BamH1, neutrokine-alpha-Xbal fragment 1, neutrokine-alpha -BamHl fragment 2) and ligated. The resulting ligated product is digested with HindlII and ligated with the pUCld plasmid digested with BindlII. The plasmid DNA is added to a sterile cuvette with a 0.4 cm electrode (BioRad). The final DNA concentration is generally at least 120 μg / mL. Then 0.5 mL of the cell suspension (containing approximately 1.5 x 10 6 cells) is added to the cuvette and the cell suspension and DNA solution are mixed gently. The electroporation is carried out with a Gene-Pulser device (Bio-Rad). Capacitance and voltage are set at 960 μF and 250-300 V, respectively. As the voltage increases, the survival of the cells decreases, but the percentage of surviving cells that stably incorporate the DNA introduced into their genome increases drastically. Given these parameters, a time pulse of approximately 14 to 20 msec should be observed. The electroporated cells are kept at room temperature for approximately 5 minutes and the contents of the cuvette are gently removed with a sterile transfer pipette. Cells are added directly to 10 mL of preheated nutrient medium (DMEM with 15% calf serum) in a 10 cm petri dish and incubated at 37 ° C. The next day, the medium is aspirated and 10 L of fresh culture medium are added and incubated for another 16 to 24 hours. Engineered fibroblasts are injected into the host, either alone or after being grown to confluence in cytodex 3 microacarrier beads. Fibroblasts now produce the protein product. Then, the fibroblasts can be introduced into a patient in the manner described. Example 6: Neutrocin-alpha, a New Member of the Ligand Family of Tumor Necrosis Factor that Functions as B Lymphocyte Stimulator A protein of 285 amino acids was identified in an AD? C library derived from human neutrophils / monocytes, which shared a significant homology in its extracellular ligand-receptor binding domain with APRIL (28.7%) (Hahne, M. et al., J. Exp. Med. 188, 1185-90 (1998)), T? F-alpha ( 16.2%) (Pennica, D., et al., Na t ure 312: 724-729 (1984) and LT-alpha (14.1%) (Gray, Na ture 312: 721-724 (1984)) (Figures 7A- I- 7A-II.) This cytokine was designated as neutrocin-alpha (this molecule has also been designated as B-lymphocyte Stimulator (ELiB) based on its biological activity.) Hydrophobicity analysis of the protein sequence neutrocin-alpha have revealed a potential transmembrane extension domain between amino acid residues 47 and 73, which is preceded by non-hydro amino acids phobic, suggesting that neutrocin-alpha, like other members of the TNF ligand family, is a type II membrane binding protein (Cosman, D. Stem, Cell s. 12: 440-55 (1994)). The expression of this cDNA in mammalian cells (HEK 293 and Chinese hamster ovary) and Sf9 insect cells, identified a soluble form of 152 amino acids with an N-terminal sequence beginning with the alanine residue at position 134 (the arrow in Figures 7A-I- 7A-II). The reconstruction of the mass ratio with respect to the charge, defined a mass of 17,038 daltons for neutrocine-alpha, a value that agrees with that predicted for this protein of 152 amino acids, with a single disulfide bridge (17037.5 daltons). Using human / hamster somatic cell hybrids and a hybrid-radiation mapping panel, it was found that the gene encoding neutrocin-alpha is linked to the marker SHGC-36171, which has a site on the map of human chromosome 13q34 , which is a region that was previously not associated with any member of the gene TNF superfamily (Cosman, D. Stem. Cell s.12: 440-55 (1994)).

The expression profile of neutrocin-alpha was evaluated by Northern blot (Figure 7B) and by flow cytometric analysis (Table V and Figure 8). Neutrokine-alpha is encoded by a single 2.6 kb mRNA found in high concentrations in peripheral blood leukocytes, spleen cells, lymph node cells and bone marrow cells. Low levels of expression were detected in placenta, heart, lung, fetal liver, thymus and pancreas. In a panel of cell lines, neutrokine-alpha mRNA was detected in HL-60 and K562 cells, but not in Raji, HeLa or MOLT-4 cells. These results were confirmed by flow cytometric analysis using monoclonal antibody 2E5 specific against neutrocine-alpha. As shown in Table V, the expression of neutrocine-alpha is not detected in cells of the T or B line, but is restricted to cells of myeloid origin. Additional analyzes of normal blood cell types demonstrated significant expression in resting monocytes, which were upregulated up to about 4 times after exposure to IFN-gamma cells (100 U / mL) for 3 days (see Figures 8A -8B). A concomitant increase in neutrokine-alpha specific mRNA was also detected (Figure 8C). In contrast, neutrocin-alpha is not expressed in freshly isolated peripheral blood granulocytes, in T cells, B cells or NK cells.

Purified recombinant neutrocin-alpha ("rneutrocin-alpha") was evaluated for its ability to induce the activation, proliferation, differentiation or death of numerous cells, based on assays with B cells, T cells, monocytes, NK cells, progenitors hematopoietic and a variety of cell types of endothelial and epithelial origin. In these assays, neutrokine-alpha was found to be specifically increased in B-cell proliferation, in a standard costimulatory assay in which purified B-cells of anginas were cultured in the presence of formalin-fixed Staphylococcus aureus Cowan I (SAC). in the presence of immobilized anti-human IgM antibodies as priming agents (Sieckmann, DG, et al., J. Exp. Med. 147: 814-29 (1978); Ringden, O., et al., Scand. J. Immunol 6: 1159-69 (1977)). As shown in Figure 9A, recombinant neutrokine-alpha induced a dose-dependent proliferation of amygdalin B cells. This response was similar to that of rIL2 in the dose range of 0.1 to 10,000 ng / mL. Neutrokine-alpha also induces B cell proliferation when cultured with cells co-stimulated with immobilized anti-IgM antibodies (Figure 9B). A dose-dependent response was observed as the amount of cross-linking agent increased in the presence of a fixed concentration of IL-2 or rneutrocin-alpha. In an attempt to correlate specific biological activity on B cells with receptor expression, purified neutrocin-alpha was biotinylated. The resulting biotinylated neutrocin-alpha retained the biological function in standard B cell proliferation assays. The lineage-specific analyzes of human peripheral blood cells indicated that the binding of biotinylated neutrocin-alpha was undetectable in T cells, monocytes, NK cells and granulocytes, which were evaluated by CD3, CD14, CD56 and CD66b, respectively (Figures 10A-10E). In contrast, biotinylated neutrocin-alpha bound to CD20 + peripheral B cells. Expression of the receptor was also detected in tumor cell lines REH, ARH_77, Raji, Namalwa, RPMI 8226 and MMP-9 INHIBITOR, but none of the myeloid lines tested, including THP-1, HL-60, K cells. -562 and U-937. The representative flow cytometry profiles for the myeloma cell line INHIBITOR OF MMP-9 and for the histiocytic line U-937, are shown in Figures 10F-10G. Similar results were also obtained using a biologically active FLAG-labeled neutrocyan-alpha protein., instead of chemically modified biotinylated alpha-neutrocin. Taken together, these results confirm that neutrocin-alpha shows a clear tropism for B cells both in their receptor distribution and in their biological activity. It remains to be proven whether cell activation can induce the expression of neutrokine-alpha receptors in peripheral blood cells, different from normal cell types or established cell lines. To examine the species specificity of neutrocine-alpha, splenic mouse B cells were cultured in the presence of human neutrocine-alpha and SAC. The results demonstrate that rneutrocin-alpha induced proliferation of murine splenic B cells and bound to a cell surface receptor in these cells. Interestingly, precursors of B negative cells for immature surface Ig from mouse bone marrow did not proliferate in response to neutrokine-alpha or bound the ligand. To evaluate the in vivo activity of rneutrocine-alpha, BALB / c mice (3 / group) were injected (intraperitoneally) twice daily with buffer only or with 0.8 mg / kg, 0.8 mg / kg, 2 mg / kg or 8 mg / kg of rneutrocine-alpha. The mice received this treatment for 4 consecutive days, at which time they were sacrificed and several tissues and serum were collected for analysis. In an alternative embodiment, BALB / c mice were injected (i.p.) twice daily with any amount of rneutrocin-alpha in the range of 0.01 to 10 mg / kg. In a preferred embodiment, BALB / c mice were injected (ip) twice daily with any amount of rneutrocin-alpha in the range of 0.01 to 3 mg / kg (the preferred example doses in this embodiment include, but are not are limited to, 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg and 3.0 mg / kg). In a further preferred embodiment, B7? LB / c mice were injected (ip) twice daily with any amount of rneutrocin-alpha in the range of 0.02 to 2 mg / kg (the preferred specific dose in this embodiment include , but are not limited to, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg. kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, l.lmg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg and 2.0 mg / kg). Microscopically, the effects of the administration of neutrocine-alpha were clearly evident in spleen sections stained with hematoxylin and eosin staining (H & amp; amp; amp;; E) Routine and immunohistochemically with a monoclonal antibody specific for CD45R (B220) (Figure HA). The normal splenic architecture was altered by a dramatic expansion of the marginal zone white pulp and a distinct increase in cellularity in the red pulp (Figure HA). The expansion of the marginal zone appeared to be the result of an increase in the number of lymphocytes expressing the B cell marker (CD45R (B220).) In addition, the dense areas of the periarterial lymphoid sheath (VLPA) of the T cells were also infiltrated by moderate numbers of cells positive for CD45R (B220) .This suggests that the changes in the white pulp were due to an increase in the number of B cells. The population of densely packed cells that frequently fills the spaces of the red pulp, it was not stained with CD45R (B220) Additional experiments will be required to characterize all cell types involved and to further define the mechanism by which neutrocin-alpha alters the splenic architecture Flow cytometry analysis of treated mice spleen with 2 mg / kg of neutrokine-alpha, indicated that this increased the proportion of mature B cells (CD45R (B220) du11, ThBbright) in approximately 10 times with respect to that observed in control mice (Figures 11B-11C). Other analyzes performed in which the mice were treated with buffer, with 0.08 mg / kg, 0.8 mg / kg, 2 mg / kg, or 8 mg / kg of neutrocin-alpha, indicated that the doses of 0.08 mg / kg, 0.8 mg / kg and 2 mg / kg increased the proportion of B cells (CD45R (B220) du11, ThBbrigh) mature by approximately 10-fold with respect to that observed in the control mice, while the buffer and the 8 mg / kg dose produced approximately equal proportions of mature B cells. See Table IV. TABLE IV: SCAF Analysis of the Population of Splenic B Cells in Mice.

A potential consequence of the increased number of B cells maturing in vivo is a relative increase in the serum Ig titer. Accordingly, serum IgA, IgG and IgM concentrations were compared between mice treated with buffer and treated with Neutrocin-alpha (Figures 11D-11F). Administration of Neutrocin-alpha resulted in a 2- to 5-fold increase in the serum IgA and IgM concentration, respectively. Interestingly, the concentration of circulating IgG did not increase. In addition, a dose-dependent response was observed in the serum IgA titre in mice treated with various amounts of Neutrocin-alpha, over a period of four days, whereas no apparent dose dependence was observed with administration of the same doses of Neutrocin-alfa in a two-day period. In the case of administration for four days, administration of 8, 2, 0.8, 0.08 and 0 mg / kg Neutrocin-alpha resulted in serum IgA titers of approximately 800 micrograms / ml, 700 micrograms / ml , 400 micrograms / ml, 200 micrograms / ml and 200 micrograms / ml. That is, the administration of 8, 2, 0.8 and 0.08 mg / kg of Neutrocin-alpha in a period of four days, resulted in an increase of approximately 4 times, 3.75 times, 2 times and less than once, respectively, at the serum level of IgA with respect to basal background concentrations observed when only regulatory solution was administered. In an alternative modality, these experiments can be performed with any amount of rNeutrocin-alpha in a range of 0.01 to 10 mg / kg. In a preferred embodiment, Neutrocin-alpha was administered in a range of 0.01 to 3 mg / kg (specific preferred dose doses in this embodiment, include but are not limited to, 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg and 3 mg / kg). In a further preferred embodiment, Neutrocin-alfa was administered in a range of 0.02 to 2 mg / kg (preferred example doses preferred in this embodiment, include but are not limited to 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg and 2.0 mg / kg). The data presented here defines Neutrocin-alpha as a new member of the TNF superfamily of ligands that induces, in vivo and in vi tro, the proliferation and differentiation of B cells. Neutrokine-alpha is distinguished from other growth factors and B-cell differentiation, such as IL-2 (Metzger, DW, et al., Res. Immunol., 146: 499-505 (1995)), IL-4 (Armitage, RJ, et al., Adv. Exp. Med. Biol. 292: 121-30 (1991); Yokota, T., et al., Proc. Nati, Acad. Sci. USA 83: 5894-98 (1986)), IL-5 (Takatsu, K., et al., Proc. Nati, Acad. Sci. USA 84: 4234-38 (1987); Bertolini, J. N., et al. , Eur. J. Immunol. 23: 398-402 (1993)); IL-6 (Poupart, P., et al., EMBO J. 6: 1219-24 (1987); Hirano, T., et al. , Nature 324: 73-76 (1986)); IL-7 (Goodwin, R.G., et al., Proc. Nati, Acad. Sci. U.S.A. 86: 302-06 (1989); Namen, A.E., et al., Nature 333: 571-73 (1988)); IL-13 (Punnonen, J., et al., Allergy, 49: 576-86 (1994)); IL-15 (Armitage, R. J. et al., J. Immunol., 154: 483-90 (1995)); CD40L (Armitage, rj et al., Nature 357: 80-82 (1992), Van Kooten, C. and Banchereau, J. Int. Arch. Allergy, Immunol. 113: 393-99 (1997)) or CD27L (CD70 ) (Oshima, H., et al., Int. Immunol., 10: 517-26 (1998); Lens, S.M., et al. , Semin. Immunol. 10: 491-99 (1998)) in their pattern of monocyte-specific gene / protein expression and their specific receptor distribution and their biological activity on B lymphocytes. Taken together, these data suggest that Neutrocin-alpha is probably involved in the exchange of signals between B cells and monocytes or their differentiated progeny. Although all B cells could use this mode of signaling, restricted expression patterns and Ig secretion suggest a role for Neutrokine-alpha in the activation of responses in CD5 + B cells or "unconventional". These B cells provide a critical component for the innate immune system and provide protection against environmental pathogens through the secretion of polyreactive IgM and IgA antibodies (Pennell, CA, et al., Eur. J. Immunol., 19: 1289-95. (1989) Hayakawa, K., et al., Proc. Nati, Acad. Sci. USA 81: 2494-98 (1984)). Alternatively, Neutrokine-alpha could function as a regulator of T-cell independent responses, analogously to CD40 and CD40L in the activation of T cell-dependent antigen (van den Eertwegh, AJ, et al., J. Exp. Med. 178: 1555-65 (1993); Grabstein, KH et al., J. Immunol. 150: 3141-47 (1993)). As such, Neutrokine-alpha, its receptor or its related agonists, have utility in the treatment of B cell disorders associated with autoimmunity, neoplasms and / or immunodeficient syndromes. Methods Mice. BALB / cAnNCR mice (6-8 weeks of age) were purchased from Charles River Laboratories, Inc. and were maintained in accordance with recommended standards (National Research Council, Guide for the care and use of laboratory animáis (1999)) in micro-isolating cages with paper bed recycling (Harían Sprague Dawley, Inc., Indianapolis, IN) and were given a rodent diet in pellets (Harían Sprague Dawley, Inc., Indianapolis, IN) and bottled drinking water in a base , ad libi tum. The protocols e? The animals used in this study were reviewed and approved by the Institutional Committee on the Care and Use of Animals HGS. Isolation of full-length Neutrocin-alpha cDNA. The BLAST algorithm was used to investigate the tag database (EST) of expressed sequences Human Genome Sciences Inc. in search of sequences with homology to the receptor binding domain of the TNF family. A full-length Neutrocin-alpha clone was identified, sequenced and forwarded to GenBank, (accession number AF132600). The open reading frame of Neutrokine-alpha was amplified by PCR using a 5 'primer (5' -CAG ACT GGA TCC GCC ACC ATG GAT GAC TCC ACA GAA AG-3 ') that was paired at the predicted start codon and a 3 'primer (5' -CAG ACT GGT ACC GTC CTG CGT, GCA CTA CAT GGC-3 ') designed to be paired at the predicted downstream stop codon. The resulting amplicon was queued with the restriction sites Bam Hl and Asp 718 and subcloned into a mammalian expression vector. Neutrocin-alpha was also expressed in p-CMV-1 (Sigma Chemicals). Purification of recombinant human neutrocin alfa. The full-length cDNA encoding Neutrocin-alpha was subcloned into the baculovi-rus expression vector pA2 and transfected into Sf9 insect cells (Patel, V. P., et al. , J. Exp. Med. 185: 1163-72 (1997)). Neutrokine-alpha recombinant was purified from the supernatant of the cells 92 hours after infection, using a combination of chromatography on anion exchange columns, size exclusion and hydrophobic interaction. The purified protein was formulated in a buffer solution containing 0.15 M NaCl, 50 mM NaOAc at pH 6, sterilized by filtration and stored at 4 ° C until needed. Analyzes by SDS-PAGE and CLAR-FR indicated that rNeutrocin-alpha had a purity greater than 95%. Endotoxin levels were below the limit of detection in the LAL assay (Associates of Cape Cod, Falmouth, MA). The purified final Neutrocin-alpha protein has an N-terminal sequence of Ala-Val-Gln-Gly-Pro. This corresponds identically to the soluble Neutrokine-alpha sequence derived from CHO cell lines stably transfected with the full-length Neutrocin-alpha gene. Generation of monoclonal antibodies. BALB / cAnNCR mice were immunized with 50 micrograms of His-tagged Neutrocin-alpha suspended in complete Freund's adjuvant, followed by two challenges in incomplete Freund's adjuvant. Hybridomas and monoclonal antibodies were prepared in the manner described (Gefter, M.L. et al., Somatic, Cell Genet, 3: 231-36 (1977)).; Akerstrom, B., et al. , J. Immunol. 135: 2589-92 (1985)). Cell lines All human cell lines were purchased from the ATCC (American Type Culture Collection, Manassas, Va.) SCAF Analysis Neutrocin-alpha expression was evaluated in human cell lines, in peripheral blood nucleated cells. normal freshly isolated and in cultured monocytes in vi tro, a mouse monoclonal antibody Antineutrocin-human alpha 2E5 (IgGl) followed by a goat antibody PE-conjugated F (ab ') 2 against murine IgG (CALTAG Laboratories, Buriingame, CA). Cells were analyzed using a FACScan kit (Betón Dickinson Immunocytometry Systems, San Jose, CA) with propidium iodide to exclude dead cells. Neutrocin-alpha binding was assayed using biotinylated rNeutrocin-alpha with an N-hydroxysuccinimidobiotin reagent (Pierce, Rodkfor, IL), followed by streptavidin conjugated with PE (Dako Corp, Glostrup, Denmark). Chromosome mapping To determine the chromosomal location of the Neutrokine-alpha gene, a panel of monochromosomal somatic cell hybrids (Quantum Biotechnology, Canada) that retained individual chromosomes was screened by PCR using Neutrocin-alpha specific primers (5 'primer). : 5'-TGG TGT CTT TCT ACC AGG TGG-3 'and 3' primer: 5 '-TTT CTT CTG GAC CCT GAA CGG-3 '). The predicted 233 bp PCR product was only detected in hybrids of human chromosome 13. Using a panel of 83 hybrids by radiation (Research Genetics, St. Louis, MO) and the Stanford Human Genome Center database (http: //www.shgc.stanford.edu.RH/rhserver), found that Neutrocin-alfa was linked to marker SHGC-36171 on chromosome 13. The superposition of this map with the cytogenetic map of human chromosome 13, allowed the assignment of human Neutrocin-alpha to chromosome band 13q34. B Lymphocyte Proliferation Assay Human amygdalin B cells were purified by magnetic beads (MACS) depletion of CD3-positive cells. The resulting cell population was routinely greater than 95% of B cells, which was evaluated by the expression of CD19 and CD20. Several dilutions of human rNeutrocin-alpha or the recombinant human IL-2 control protein were placed in individual wells in a 96-well plate, to which were added 10 B cells suspended in culture medium (RPMI 1640 containing 10% SFT, 2ME 5 X 10"5 M, 100 U / ml penicillin, 100 micrograms / ml streptomycin and a 10" 5 dilution of pansorbin (SAC) or anti-IgM in a total volume of 150 microliters). Proliferation was quantified by a 20 h pulse (1 microCi / well) of 3 H-thymidine (6.7 Ci / mM) starting 72 h after factor addition. Histological analysis Sodium formalin was fixed with 10% neutral buffer solution, soaked with paraffin, 5 micron slices were made, mounted on glass slides and stained with hematoxylin and eosin or stained by the enzyme-labeled indirect immunohistochemistry method for CD45R (B220) (Hilbert, DM, et al., Eur. J. Immunol., 23: 2412-18 (1993)). Table V. Neutrocin-alpha expression on the cell surface Cell Line Cell Morphology Cell surface expression of Neutrocin alfa Monocytic line U-937 Lymphoma, histiocytic / macrophage + BL-60 Leukemia, acute promyelocytic + K-562 Leukemia, chronic myelogenous + THP-1 Leukemia, acute monocytic + T cell line Jurkat Leukemia, lymphocytic T SUP-T13 Leukemia, lymphoblastic T MOLT-4 Leukemia, lymphoblastic T B cell line Daudi of Burkitt, lymphoblastic Namalwa of Burkitt, Raji lymphocytes of Burkitt, lymphocytes Reh Leukemia, lymphocytic ARH-77 Leukemia, of plasma cells IM9 Myeloma RPMI 8226 Myeloma Example 7; Tests to detect the stimulation or inhibition of B cell proliferation and differentiation The generation of functional humoral immune responses requires both soluble signaling and cognate signaling between B cell lines and their microenvironment. The signals can impart a positive stimulus that allows the cells of line B to continue with their programmed development, or a negative stimulus that instructs the cells to stop their current development path. To date, numerous stimulatory and inhibitory signals have been found to influence the response of B cells, including IL-2, IL-4, IL-5, IL-6, IL-7, IL-10., IL-13, IL-14 and IL-15. Interestingly, these signals by themselves have weak effects but in combination with several costimulatory proteins, they induce activation, proliferation, differentiation, harboring, tolerance and death in populations of B cells. One of the best studied classes of cell co-stimulatory proteins B is the TNF superfamily. In this family molecules CD40, CD27 and CD30 together with their respective ligands CD154, CD70 and CDl53, have been found to regulate a variety of immune responses. The assays that allow the detection and / or observation of the proliferation and differentiation of these populations of B cells and their precursors, are valuable tools to determine the effects that different proteins could have on these populations of B cells in terms of proliferation and differentiation. Two tests designed to allow the detection of the differentiation, proliferation or inhibition of b cell populations and their precursors are listed below. In vi tro assay - Purified Neutrokine-alpha and / or Neutrocin-alphaSV or truncated forms thereof were evaluated with respect to their ability to induce the activation, proliferation, differentiation and / or death of B cell populations and their precursors . The activity of Neutrokine-alpha and / or Neutrocin-alphaSV protein on purified human amygdalin B cells was measured quantitatively in a dose range of 0.1 to 10,000 ng / ml, evaluated in a standard B lymphocyte co-stimulation assay in the which purified amygdalin B cells were cultured in the presence of Staphylococcus aureus Cowan I (SAC) fixed in formalin or in the presence of immobilized anti-human IgM antibodies, as primers. Second, signals such as those of IL-2 and IL-5 present a synergy by forming cross-links with SAC and IgM to induce B cell proliferation, which was measured by the incorporation of tritiated thymidine. The new synergistic agents can be easily identified using this assay. The assay includes the isolation of human amygdalin B cells by depletion with magnetic beads (MACS) of CD3-positive cells. The resulting cell population is greater than 95% B cells, which was assessed by the expression of CD45R (B220). Various dilutions of each sample are placed in individual wells of a 96-well plate to which 105 B cells are added suspended in culture medium (RPMI 1640 containing 10% SFT, 2 ME 5 x 10"5 M, 100 U / ml penicillin, 10 μg / ml streptomycin and a 10"5 dilution of SAC) in a total volume of 150 μl. Proliferation or inhibition is quantified by a 20 h pulse (1 μCi / well) with ° H-thymidine (6.7 Ci / mM) starting 72 h after factor addition. The positive and negative controls are IL-2 and culture medium, respectively. Agonists (including Neutrocin-alpha and / or Neutrocin-alphaSV polypeptide fragments) demonstrated an increase in B cell proliferation when compared to that observed when the same B cell number was contacted at the same concentration of a primer agent. Antagonists according to the present invention exhibit a decrease in B-cell proliferation when compared to controls containing the same number of B-cells, the same concentration of primer and the same concentration of a soluble form of Neutrocitrogen. alpha that induces an increase in the proliferative activity of B cells (eg, 71-285, 81-285, 112-285 or 134-285 of the Neutrocin-alpha polypeptide shown in SEQ ID No. 2), in the absence of the antagonist . In vivo assay - BALB / c mice were injected (i.p.) twice daily with buffer solution alone or with 2 mg / kg Neutrocin-alpha and / or Neutrocin-alphaSV protein, or with truncated forms thereof. The mice received this treatment for 4 consecutive days, at which time they were sacrificed and several tissues were removed and serum was taken for analysis. The comparison of cuts dyed with H & amp; amp;; E of normal spleens and spleens treated with the protein Neutrocin-alpha and / or Neutrocin-alfaSV, identify the results of the activity of the protein Neutrocin-alpha and / or Neutrocin-alphaSV on the splenic cells, such as the diffusion of the periarterial lymphatic sheaths and / or significant increases in nucleated cellularity in the red pulp regions, which may indicate the activation of the differentiation and proliferation of B cell populations. Immunohistochemical studies using a B-cell marker, anti-CD45R ( B220), are used to determine whether any physiological change of splenic cells, such as splenic disorganization, is due to an increase in the representation of B cells in the areas of poorly defined B cells that infiltrate established T cell regions. . Flow cytometry analysis of the spleens of mice treated with Neutrocin-alpha and / or Neutrocin-alphaSV, are used to indicate whether the protein Neutrocin-alpha and / or Neutrocin-alphaSV specifically increases the proportion of B-cells ThB +, CD45R ( B220) dull with respect to the proportion observed in the control mice.

Similarly, a predicted consequence of increasing the representation of mature B cells in vivo is a relative increase in the Ig titer in the serum. Accordingly, IgM and IgA concentrations in serum were compared between mice treated with buffer and mice treated with the protein Neutrocin-alpha and / or Neutrocin-alphaSV. Example 8: Effect of Neutrocin-alpha and its agonists in the treatment of atrophy and lymphoid hypoplasia associated with graft versus host disease in mice An analysis of the use of Neutrocin-alpha for the treatment, prevention and / or diagnosis of Hypoplasia / lymphoid atrophy associated with graft versus host disease (EIVH) was performed using a murine model of C57BL / 6 progenitor mice in (BALB / c mice X C57BL / 6) Fl (CBF1). This mouse progenitor mouse model Fl is a well characterized and reproducible animal model of EIVH in patients with bone marrow transplants, which is known to those skilled in the art (see, Gleichemann, et al., Immunol. Today 5 : 324, 1984). Soluble Neutrokine-alpha is expected to induce B lymphocyte proliferation and differentiation and correct the hypoplasia and lymphoid atrophy observed in this EIVH animal model (Piguet et al., J. Exp. Med. 166: 1280 (1987); , et al., Blood 90: 542 (1997)). The onset of EIVH is induced by intravenous injection of approximately 1-5 x 108 spleen cells from C57BL / 6 mice in mice (BALB / c X C57BL / 6) F1 (both available from Jackson Lab, Bar Harbor, Maine) . groups of 6 to 8 mice received daily a dose of 0.1 to 5.0 mg / kg of Neutrocin-alpha or a dose of control buffer solution, intraperitoneally, intramuscularly or intradermally, initiating the day when hypoplasia and lymphoid atrophy are mild (~ days 5), moderate (~ day 12) or severe (- day 20) after the injection of progenitor cells. The effect of Neutrocin-alpha on hypoplasia and lymphoid atrophy in the spleen was analyzed by SCAF and by histopathology at different points in time (3-4) between days 10 and 30. Briefly, splenocytes were prepared from normal CBF1 mice, EIVH mice or mice treated with Neutrocin-alpha and stained with biotin-conjugated anti-H-2Kb antibodies, fluorescein-phycoerythrin-conjugated anti-H-2Kb antibodies and FITC-conjugated anti-CD4 antibodies, anti-CD8 antibodies or anti-B220 antibodies, followed by avidin conjugated with CyChrome. All of these conjugated antibodies can be purchased at PharMingen (San Diego, CA). The cells are then analyzed in a FACScan device (Becton Dickinson, San José, CA). The recipient and donor lymphocytes are identified as H-2Kb + Kd + and H-2Kb + Kd- cells, respectively. The number of CD4 + T, CD8 + T and B220 + B cells of recipient or donor origin was calculated from the total number of splenocytes recovered and the percentages of each subpopulation were determined by the three-color analysis. Histological evaluation of the relative degree of tissue damage in other organs associated with EIVH (liver, skin and intestines) can be carried out after the animals have been sacrificed. Finally, animals treated with Neutrocin-alpha or with a regulatory solution are subjected to a clinical evaluation every third day to evaluate cachexia, body weight and lethality. Neutrocin-alpha agonists and antagonists can also be examined in this model of murine EIVH. Example 9. Isolation of antibody fragments directed against Neutrocin-alpha polypeptides from a library of scFvs. Genes V of natural origin isolated from human peripheral blood leukocytes (LSPs), were constructed in a large library of antibody fragments with activity against Neutrocin-alpha and / or Neutrocin-alphaSV to which the donor could be or could not be exposed (see, eg, U.S. Patent No. 5,885,793 which is hereby incorporated by reference in its entirety).

Rescue of the library. A library of RNA scFvs from human LSPs was constructed in the manner described in International Publication WO 92/01047 (which is incorporated herein by reference in its entirety). To rescue the fragments of antibody displayed on phage, approximately 109 E. coli cells carrying fagemid were used to inoculate 50 ml of 2 x TY containing 1% glucose and 100 microgram / ml ampicillin (2 x TY-AMP). -GLU) and were grown to an OD of 0.8 in agitation. From this culture, 5 ml were used to inoculate 50 ml of 2xTY-AMP-GLU, 2 x 108 TU of the delta 3 cooperating gene (gen III delta M13, see International Publication WO 92/01047) were added and the culture was incubated 37 ° C for 45 minutes without agitation and then at 37 ° C for 45 minutes with shaking. The culture was centrifuged at 4000 rpm for 10 minutes and the pellet was resuspended in 2 liters of 2x TY containing 100 microgram / ml ampicillin and 50 microgram / ml kanamycin, and grown overnight. The phages were prepared in the manner described in International Publication WO 92/01047. The gene III delta M13 was prepared in the following manner: the helper phage gen III delta M13 does not code for the protein of gene III, therefore the fage (mid) that displays fragments of antibody has a higher avidity for binding to the antigen. Infectious particles of gene III delta M13 were prepared by growing the helper phage in helper cells of a pUC19 derivative that supplied the wild type gene III protein during phage morphogenesis. The culture was incubated for 1 hour at 37 ° C without agitation and then for an additional hour at 37 ° C with shaking. The cells were centrifuged (IEC-Centra 8, 4000 revs / min for 10 minutes), resuspended in 300 ml of 2x TY broth containing 100 micrograms of ampicillin / ml and 25 micrograms of kanamycin / ml (2x TY-AMP-KAN ) and were grown overnight with 37 ° C agitation. The phage particles were purified and concentrated in the culture medium by means of two PEG precipitations (Sambrook et al., 1990), resuspended in 2 ml of PBS and passed through a 0.45 micron filter (Minisart NML; Sartorius) to obtain a final concentration of approximately 1013 transduction units / ml (clones resistant to ampicillin). Washing and Purification of the Library. Immunotubes (Nunc) were coated overnight with 4 ml of 100 micrograms / ml or 10 micrograms / ml of a polypeptide of the present invention in PBS. The tubes were blocked with Marvel 2% PBS for 2 hours at 37 ° C and then washed 3 times with PBS. Approximately 10i3 TU of the phage were applied to the tubes and incubated for 30 minutes at room temperature on a rotating top-down tray and then allowed to stand for another 1.5 hours. The tubes were washed 10 times with PBS with 0.1% Tween 20 and 10 times with PBS alone. The phage was eluted by adding 1 ml of 100 mM triethylamine and rotating for 15 minutes on a rotating tray from top to bottom, after which the solution was immediately neutralized with 0.5 ml of Tris-HCl, 1.0 M, pH 7.4 . Then, the phage were used to infect 10 ml of E. coli TGl cells in logarithmic growth phase, incubating the phage eluted with the bacteria for 30 minutes at 37 ° C. The E. coli cells were then inoculated onto TYE plates containing 1% glucose and 100 micrograms / ml ampicillin. The resulting bacterial library was rescued with the delta 3 gene helper phage in the manner described above to prepare the phage for a subsequent round of selection. Subsequently, this process was repeated for a total of 4 rounds of affinity purification, increasing the tube washes to 20 times with PBS containing 0.1% of Tween 20 and 20 times with PBS alone, for rounds 3 and 4. Characterization of the United Fagos.

Phage eluted from the third and fourth rounds of selection were used to infect E. coli HB 2151 cells and soluble scFv was produced (Marks et al., 1991) from isolated colonies, to perform the test. ELISA tests were performed with microplates coated with 10 picograms / ml of the polypeptide of the present invention in 50 mM bicarbonate pH 9.6. Positive clones by ELISA were further characterized by PCR fingerprint (see e.g., International Publication WO 92/01047) and then by sequencing. Example 10. Neutralization of the Neutrokine-alpha / Neutrokine-alpha Receptor Interaction with a Monoclonal Antineutrocin-alpha Antibody. Monoclonal antibodies against Neutrocin-alpha protein were generated according to the following method.

Briefly, mice were injected subcutaneously (in the front of the back) with 50 micrograms of the protein Alpha-labeled neutrokine-alpha produced by the method of Example 2 in 100 microliters of PBS emulsified with 100 microliters of Freund's complete adjuvant. Three additional subcutaneous injections of micrograms of Neutrocin-alfa in incomplete Freund's adjuvant at 2-week intervals. The animals were tested again one month before they received the final intraperitoneal reinforcement of 25 micrograms of Neutrocin-alpha in PBS. Four days, the mice were sacrificed and the splenocytes were taken for fusion. The "fusion" process was carried out by fusing splenocytes from a single spleen with Plasmacytoma cells 2x 10E7 P3X63Ag8.653 using PEG 1500 (Boehringer Mannheim), according to the manufacturer's modifications of a previous method (see Gefter, ML, et al., Somatic Cell Genet 3: 231-36 (1977), Boehringer Mannheim, product description: PEG 1500 (Catalog No.783641)). After fusion, the cells were resuspended in 400 ml of HAT medium supplemented with 20% SFT and 4% hybridoma supplement (Boehringer Mannheim) and distributed in 96 well plates at a density of 200 microliters per well. Seven days after the fusion, 100 microliters of the medium were aspirated and placed in other plates with 100 microliters of fresh medium. Fourteen days after the fusion, the hybridomas were selected with respect to their antibody production. The supernatants of the hybridomas were selected by ELISA with reference to their binding to the protein Neutrocin-alpha immobilized on plates. Plates were coated with Neutrocin-alpha by overnight incubation with 100 microliters per well of Neutrocin-alpha in PBS, at a concentration of 2 micrograms per milliliter. The supernatants of the hybridomas were diluted 1:10 with PBS and placed in individual wells of plates coated with Neutrocin-alpha and incubated overnight at 4 ° C. The next day, the plates were washed 3 times with PBS containing 0.1% Tween 20 and developed using the anti-murine IgG ABC system (Vector Laboratories). The color development of the reaction was stopped with the addition of 25 ml / well of HS04 2 M. Then the plates were read at 450 nm. The supernatants of the hybridomas were verified by Ig isotype using reactive strips. The cloning was carried out by the method of limiting dilutions in HT medium. Approximately 3 x 10 6 cells were injected into 0.9 ml of HBSS in mice primed with pristane. - After 7 to 9 days, ascitic fluid was collected using a 19 gauge needle. All antibodies were purified by affinity chromatography with protein G, using the Acta FPLC system (Pharmacia). After the primary injection and two consecutive subcutaneous injections, the three mice developed a strong immune response. The serum titre was 10"7, tested by ELISA on plates coated with Neutrocin-alpha In one experiment, using splenocytes from the positive mice, more than 1000 primary hybridomas were generated, and nine hundred and seventeen of them were selected with respect to the production of antibodies Antineutrocin-alpha The selection was carried out using diluted supernatants 1: 1 in order to detect all the positive clones of the 917 selected hybridomas, it was found that 76 were positive and 17 of which were IgG producers. After testing the affinity and performing a cloning, 9 of them were selected for further expansion and purification. All purified monoclonal antibodies were able to bind to different forms of Neutrokine-alpha (including the His-tagged protein and the protein produced from a baculoviral system (see Example 2)) by Western blot analysis and by ELISA Six of nine clones were also able to bind to Neutrokine-alpha on the cell surface THP-1. However, none of the antibodies tested was able to capture the Neutrocin-alpha in solution. High-affinity monoclonal antibodies Antineutrocin-alpha were generated that recognized Neutrocin-alpha expressed on the cell surface, but not in solution, which can be used for neutralization studies in vivo and in assays of monocytes and B cells in vi tro. These antibodies are also useful for a sensitive detection of Neutrocin-alpha in western blot tests. In an independent experiment, using splenocytes from the positive mice, more than 1000 primary hybridomas were generated. Then, 729 of the primary hybridomas were selected with respect to the production of an Antineutrocin-alpha antibody. The selection was made under strict conditions using 1:10 diluted supernatants in order to collect only the highest affinity clones. Of the 729 selected hybridomas, 23 were positive, including 16 IgM producers and 7 IgG producers (among these, 4 gave a strong IgM background). In this experiment, the distribution of IgG antibody isotypes was shifted towards subclass IgG2. Three of seven IgG hybridomas produced antibodies of subclass IgG2a and two produced an antibody of subclass IgG2b, while the remaining two were IgGl producers. The supernatants of all the positive hybridomas generated in the second experiment were tested for their ability to inhibit the proliferation of B cells mediated by Neutrocin-alpha. In the first screening experiment, two hybridomas producing IgG neutralizing antibodies were detected (these are antibodies 16C9 and 12C5). In further experiments, the IgG-neutralizing activity of the hybridomas (i.e., 16C9 and 12C5) was confirmed and two additional strongly neutralizing supernatants were identified, coming from hybridomas 15C10 and 4A6. Subsequently, three clones were expanded in vivo (a single clone i. E., 15C10 was also expanded in a hollow fiber system) and the antibodies were purified by affinity chromatography. The three clones were able to bind to Neutrocin-alpha on the surface of THP-1 cells and were also able to bind (i.e., "capture") to Neutrocin-alpha in solution. Specifically, experiments were performed using the Antineutrocin-alpha monoclonal antibodies described in the second experiment above, to determine if the antibodies neutralized the Neutrokine-alpha / Neutrocin-alpha receptor binding. Briefly, the protein Neutrocin-alpha was biotinylated using the EZ-link T reagent NHS-biotin (Pierce, Rockford, IL). The biotinylated neutrokine-alpha, subsequently, was used to identify cell surface proteins that bound Neutrocin-alpha. Preliminary experiments showed that Neutrokine-alpha binds to a receptor on B lymphoid cells.

The inclusion of Antineutrocin-alpha antibodies generated in the second experiment described above, neutralized the binding of Neutrocin-alpha with a Neutrocin-alpha receptor. In a specific embodiment, the antibody Antineutrocin-alpha 15C10 neutralithe binding of Neutrocin-alpha with a Neutrocin-alpha receptor. Thus, the Antineutrocin-alpha monoclonal antibodies generated in the second experiment described above (in particular the 15C10 antibody) recognize and bind both the Neutrokine-alpha protein bound to the membrane and the one in solution and neutralize the binding Neutrokine-alpha / Neutrocin receptor-alpha in vi tro. It will be clear that the present invention can be practiced in other ways than those particularly described in the foregoing description and Examples. It is possible to make numerous modifications and variations of the present invention in light of the above teachings and, therefore, these fall within the scope of the appended claims. The description of all publications (including patents, patent applications, articles of scientific journals, laboratory manuals, books or other documents) cited herein, are incorporated herein by reference.

- - In addition, the Sequence Listing sent with this, and the Sequence Listing sent with the Copending Applications Serial No. 09 / 005,874 filed on January 12, 1998; US 60 / 036,100 filed January 14, 1997 and PCT / US 96/17957 filed October 25, 1996, both in computer readable form and on paper, in each case, are hereby incorporated in their entirety as a reference . It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

- - LIST OF SEQUENCES < 110 > Human Genome Sciences, Inc. < 120 > Neutrokine-alpha and Variants by Neutrocin-alpha splicing < 130 > PF343PCT2 < 140 > Not assigned < 141 > 2000-02-22 < 150 > 60 / 122,388 < 151 > 1999-03-02 < 150 > 60 / 124,097 < 151 > 1999-03-12 < 150 > 60 / 126,599 < 151 > 1999-03-26 < 150 > 60 / 127,598 < 151 > 1999-04-02 < 150 > 60 / 130,412 < 151 > 1999-04-16 < 150 > 60 / 130,696 < 151 > 1999-04-23 < 150 > 60 / 131,278 < 151 > 1999-04-27 < 150 > 09 / 255,794 < 151 > 1999-02-23 < 150 > 60 / 131,673 < 151 > 1999-04-29 - - < 150 > 60 / 136,784 < 151 > 1999-05-28 < 150 > 60 / 142,659 < 151 > 1999-07-06 < 150 > 60 / 145,824 < 151 > 1999-07-27 < 150 > 60 / 167,239 < 151 > 1999-11-24 < 150 > 70 / 168,624 < 151 > 1999-12-03 < 150 > 60 / 171,108 < 151 > 1999-12-16 < 150 > 60 / 171,626 < 151 > 1999-12-23 < 150 > 60 / 176,015 < 151 > 2000-01-14 < 160 > 38 < 170 > Patentln Ver. 2.1 < 210 > 141 < 211 > 1100 < 212 > DNA < 213 > Homosapiens < 221 > CDS < 222 > (147) .. (1001) - - < 400 > 1 aa "" cag to taactctcct gaggggtgag ccaagecct ^ ce-ítgtag g cac cagga £ 3 atcaacaaac aeagataaca g aa & tgat catccectgt ggteaettat tccaí GGCC ceaßccts lio;:. 'Agi-to g.-ca-s.?* gt atg g' t gac tcc here gaa agg gag cag 1? 2 Mee Aap As Ser Tr.r Gl- Arg Glu Gln 1 5 ta ecc cr; ac; tet tgc c; c a-ag aa aga gas ca a at a g aaa ctg aag 2 -1 Ser Arg Leu Thr S * r Cys Leu Lys Ly = Arg Glu Glu Met Lys Leu Lys 10 15 20 25 ga ^ tgt gtc tc atctc cea cgg aag gaa age cc tet gcc cga ::; 269 Glu Cys a Ser Leu Pro Arg __ lie ys Ber Glu Pro Arg Ser Val Ser 30 3S 40 aka AAG CTG gga aa gac "cg GCT CTG CTG CTG GCA GCA acc CTG CTG Lys Asp 317 Gly -.ya be eu Le. * - Thr Ala Ala" -and? Leu Leu Leu Ala and 45 cct tgc tgc 50 55 acg gtg gg etc ttc tet tac cag ctg gtg gcc gc cea cys Cys Ser 3¿5 Le- Tnr val tyr Val Ser Phe Ala Leu Ala val Cln C »60 65 70 crgg lr_ gac ctg gcc ag ctc «gg gca gag ctg cag ggc cac cac gcg gag 413 Gly Asp leu Ala E.« * r Leu Arg Ala Glu Leu Glr. Gly Kis His Wing Glu T5 EO B5 aag ctg cca cea gga gca ga gcc cc aag gcc ggc c g gag gaa gct 451 Lyd Leu Pro Wing Gly Wing Gly Wing Pro Lys Wing Gly Leu Glu Wing Glu 90 95 cca gct 1GC -.CS gts gga acc geg etg aaa ttt cca ate gaa gga gct cca 509 Pro Ala Val cea Thr Lys Ala Gly Leu Glu Pro lie Ph *? Ro Ala Pro Gly 120 110 US gaa agt cag aka gí aac aac age aga aat aag cgt gcc gtt cag ggt 55"Glu Gly Asr 'Ser Ser Gln Asn Ser Arg YES. Lys Arg Ala Val Gln Gly 125 130 135 gaa cca drop ac gtc act caa gac tgc ctg caa ctg att gca gac« gt é05 - - Pro Cl_; Glu Thr Val Thr Gln Asp Cys eu Glr- eu ie Ala As? S * r Í4 1 5 15 caca here cca act ata caa aaa gga tct tac ac-- tf.c gt cea tgS ctt 65-. Glu Thr Pro Thr lie Glp Lys Gly Ser Tyr Thr £ he Val Pr: - r & Le 15 * 160 65 ctc age ttt aaa sg-? ga agt gcc cta gaa gaa aaa gag aat aaa ata "Ol Leu Ser Phe ys Are Gly Ser Ala L« u Glu G y ¿Glu = n Lys ¿170 i "-S ISO 1S5 ttg stc aa gaa act ggt tac ttt ttt ata tat ggt cag gtt tta tac "" 13 eu Val Lys Glu r Gly Tyr P fi P e > ls Tyr Gly Gir. Val Leu Tyr 19C &5 20 act gat a g acc tac gcc atg # a cat eta att cag agg < ? ag aag gt? * - "Thx Asp Lys Thr Tyr?" To Jtet Gly His Leu IJ. © Glr. Arg Lys Lys val 205 - 21C -15 cac gtc ttt cg sat g «a ttg & g ctg etc act ttg ttt cga tgt att S45 H __ = al Phe Gly Asp Glu Leu S * r Leu Val Thr Le-_? b Arg Üys "lie 220 125 230 ca atat cct gea aea cta ecc aat? - tc tgc tac to gct ggc e9 Gln Asft M «t Pro Glu Thr Leu Pro Asn Asn Ser Cys Tyr Se Al * Gi I35 240 2í? att. gca aaa ctg gaa &gga gat gaa etc ceta ct gca ata cca aga 941 lie Ala Lys eu Glu Glu Giy Asp Glu L * '~ Cln Leu Ais lie. Arg 250 255 2 2 € S gaa aat gca ca ta tea ctg gac gga ga; gtc ac «ttt ttt 53c ga 999 Giu Asr. Ala Oin : le_ Ser Lej Asp Gly ASO at Tr.r P < = Fhe Giy Al? 270 2'f5 260 ttg aaa ctg CZQ tgacstactt acaccatgtc tgtagctatt ttcctccctt tctccgtacc tetaagaaga aagaatctaa ctgaaaatac caaaaaaaaa aaaaaaaaa _- «. l < 210 > 2 < 211 > 285 < 212 > PRT < 213 > Homosapiens - < 400 > 2 Met Asp Asp Ser Thr Clu Arg Glu Gis Se Arg Leu Thr Ser Cys Leu I 5 10 15 Lys Lve Arg Glu Slu Met Lys La *. Lys GU Cys Vai See lie eu? Ro 2C 2S 3¡ Arg Lya Glu Ser Pro Ser Val Arg Ser Ser Lys Asp Gly Lys «Leu 25 4C 45 Ala Ala Tcr Leu Leu Leu Ala Leu Leu Ser Cys Cys e Thr Val Val 50 55 60 S Ala Glu e »Gin Gly His His Ala Giu Lys Leu Pro? La Gly Ala Gly 85 90 95 Ala? Ro Lys Ala Gly L = u Gl Glu Ala? Ro Ala Val Thr Ala Gly Leu LO 105 113 Lys Ie Pne Gl Pro Pro Ala Pro Gly sl Gly Asn Ser Ser Gin Asn 115 120 125 Ser Arg A = n Lys Arg Ala Val Glr. Gl / Pro Gi? Giu Thr Val Thr Gir. 130 135 140 As cys leu Gin Leu II © Wing Asp Ser Gl .: Thr P or Thr lie Gin Lvs 145 150 1SS 160 Gly Ser Tyr Thr Phe Val Pro Trp I read Leu Ser? Ne Lys Arg Gly Ser l 170 i * »! Ala e GLu Glu y = Glu Asn Lye He Leu Val Lys Glu Thr G2y Tyr 180 Ies! 9C Phe Phe lie Tyr Gly Glr. Val Leu Tyr Thr Asp v5 Thr Tyr Ala Kec 195 200"205 Gly His Leu lie Gln Arg Lys Lys val His Val Pn Gly Asp Glu Le- 210 215 22 Z be Leu Val Thr Leu Phe Arg Cys He Gln Asn Ha? Ro Glu hr Leu 21- 230 235 240 Pro A = n Ace? Being Cys Tyt Being Wing Giy He Wing Lys Leu Giu Giu Glv 243 250 255 Asp Sl Leu Gla Leu Wing He Pro Arg Giu Asr. Ala Gln lie Ser Le_ 263 2 = 5 270 Asp Gly Asp Vai Thr? He Phe Gly Ala Leu Lvs Leu Leu 275 ß0"265 - - < 210 > 3 < 211 > 233 < 212 > PRT < 213 > Homosapiens < 400 > 3 e-t Ser Thr Giu Ser Hat He Arg Asp Vai Glu Leu Wing Gli- Glu Wing 1 5 lü 15 eu Pro and $ Lys Thr Gly Gly P or Glr. Gly Ser Are Arg Cys Leu? Hß 20 25 30 Leu Ser Leu Phe Ser Phe eu He Val Val Ala Gly Aia Thr Thr Leu Phe 40 45 Cys Leu Leu His Phe Gly ai He Gly Pro Glr- Arg Glu Glu Phe? R- 50 55 € 0 Ara AS Leu Ss e lie Eer £ ro Le Ala Glp Ala Val Arg Being Being Ó5. 73 75? Z S $ Arg Thr Pro Ser Asp Lys Pro Vai Ala His val Val Ala Asr. Pro 85 9 95 Gln Ala C-lu Gly Gln Le Gln Trp Leu Ase. Arg Ar? R Ala Asr. Ala Leu 100 1D5 11J Leu Ala se. Gly v ^ l Gl-_ ^ Arg Asp A3r. Gl-i Leu Val v «l? R = Ser 115 123 125 Giu Gly Leu Tyr Leu He Tyr Ser Gln Val Leu Phe L s Gly Gln Gly 1 3 125 14. Cys Pro Ser Thr Kis Vai s Leu Thr YES Thr 5le Ser? Rg lie Wing 1? 150 155 150 Goes-. Ser Tyr Gin Thr Lys Val ASR Leu Leu Ser Wing He Lys Ser P o 165 17ü 175 Cys Gln Arg Glu T r Pro Glu Gly Wing Glu Ala Lys? or Trp Tyr Giu 1B0 1B5 150 Prc Tie Tyr Leu Cly Gly Val Phe Glt? Leu Glu Lys Gly Asp Arg Le? 195 2C0 2J5 Ser Wing Glu lie Asn Arg Pro Asp Tyr Leu Asp Phe Wing Glu Ser Gly 210 215 220 Gln Val Tyr Phe Gly He Z e Wing Leu 225 230 - - < 210 > 4 < 211 > 205 < 212 > PRT < 213 > Ho osapiens < 400 > 4 Met Thr Pro Pro Glu Arg Leu Phe Leu Pro Arg Val Arg Giy Thr Thr i 5 1 15 Leu rtis Leu Leu Leu Leu Gly Leu Leu Leu Val Leu Leu Pro Gly Aia 2C 25 30 Glr; Gly Leu Pro Gly Val Gly Leu Thr Pro be Ala Ala Gin *? R Ala 35 40 45 Arg Glr < HLS Pro Lys > 2et Hia Leu Wing HIS Ser Thr Leu Lys P or Wing 53 55 60 Wing His Leu l e Gly Asp Pro Ser Lys Glr. Aso Ser Leu Leu Trp Arg € 5 70 75 80 Aia Asp Tnr Asp Arg Wing Phe Leu Gip A = p Gly Phe Ser Leu Ser Asn 85 90 93 Asn be Leu Leu Val ??? > Ti? R Ser Gly lie Tyr Phe Val Tyr Ser Glr. 100 105 110 Val Val Pr_e Ser Gly Lys Aia Tyr be Pro L / s Ala Thr be Pro 115 120 12S EÜU Tyr Leu Ala is Giu al Gln Leu P.ie Ser Ser Glr. Tyr Pro Phe 130 135 140 His Val? Ra I_eu Leu Ser Ser Gln Lys Mer to Tyr Pro Giy e Gln 145 150 155 163 Giu? Rs Trp Leu Kis Ser Xe- Tyr Kis G and Ala Ala? He Gir. Leu Thr 165 170 175 Gln Cly Asp Gln Leu Ser Thr H15 Thr Asp Giy íe pro His Leu "at 180 1B5 190 Leu Ser? Ra Ser Thr Val P e Phe Gly Wing Phe Ala Leu 135 200 235 - - < 210 > 5 < 211 > 244 < 212 > PRT < 213 > Homo sapiens < 400 > 5 Mee Gly Ala Leu Gly Leu Glu Gly Arg Giy Gly Arg Leu Clr. Gly Arg 1 5 10 15 Giy Ser Leu Leu Leu Ala Wing Ala Gly Wing Thr Ser Leu Val Thr Leu 20 25 3 Leu Leu Wing Val Pro lie Tpr Val Leu Wing Vai Leu Wing Leu Pro-JS 40 45 Gln Aep Gln Gly Gly Leu Vai Thr Glu Thr Wing Asp Pro Gly Ala Gln 50 55 63 Wing Glp Glp Gly Leu Gly P e Gin Lys Leu Pro Glu Glu Glu Pro Glu 65 70 75 80 Thr A3p Leu Ser Pro Gly Leu Pro Wing Aia Kis Leu lie Gly Aia Pro 8S 90 95 Leu Lys Gly Gln Gly Leu Giy Trp Gili Thr Thr Lys Glu Gln Ala? H ^ 100 105 110 Leu Thr Ser Gly Thr Gln P'ne be Asp Wing Glu Gly Leu Wing Leu Pro 115 120 125 Gln Asp Giy Leu Tyr Tyr Leu Tyr Cys Leu val Gly Tyr Arg Cly Arg 130 135 140 - - Wing Pro Pro Gly Giy Gly Asp Pro Gin Gly Arg Ser Vai Tr Leu Arg 142 150 155 1 * 3 Be Ser Leu Tvr Arg Wing Giy Gly Wing Tyr Giy Pro Gly Thr Pro Glu S 170 175 Leu ee Giu Gly Wing ßl Thr Vai Thr Pro Val Leu Asp? Ro Ala 150 idS isc Ara xs Gir. Gly Iryr Giy Pro Leu Trp Tyr Thr Ser val Giy Phß Giy iSS 200 20 Gly Leu Val Gin Leu Arg A g Gly Glu. Arg Val Tyr al Asr. lie Ser 210 215 220 ü s Pío Aap Kec Val Asp Phe Wing Arg Gly Lys Thr Phe Phe Gly Aia 225 230 135 ¿43 Vai «« e Val Gly < 210 > 6 < 211 > 281 < 212 > PRT < 213 > Homo sapiens < 223 > Description of the DNA / RNA Combined Molecule: n equal to, t, g, or c - - < 400 > 6 Kec Gir- Gln? R & P e Asn Tyr Pro Tyr Pro Gln - a Tyr Trp to s 5 10 15 Be Ser Wing S «Pro Tro Wing Po Pro Gly Thr Val Leu Pro Cy 20 2 3C Pro Thr S r Val? Ro Ar_j Arg Pro Gly Glr. Arg Arg Pro Pro Pro Pro 40 45 Pro Pro Pro P © Pr £ > Leu Pro Pro Pro Pro Pro Prs Pro eu? _ • - • 50 55 60 Pro Leu P or Leu Pro Pro Leu Lys Lys Arg Gly Asn HIS Be Thr C.y «5 70 75 80 Leu Cys Leu Leu Val Het Phe Phe Met. Val Leu Val Ala Leu Val Gly 85 90 95 L * »u Giy Le Gly Met Phe Gln Leu Phe '? ÍS Leu Glr- Lys Glu Leu Alo 1DC 105 110 Glu ßíi Arg 31-- Be Tiir Be Without He- K;, Thr Al * Ser Ser Leu Glu 115 12í > 12i Lys Gln lie Giy Kis Pro Pro Pro Pro Giu Lys Lye Glu Leu Arg ii & 135 140 Lys Val Ala His e__ Thr Giy Lys Ser Asn S «? Arg Sar t? Ro Leu 145 150 1S5 1S0 Glu Trp Glu Asp Thr Tyr Gly li © Val Leu Leu Se Gly Val Lys Tyr 165 170 LTS Lvs vs. Giy Val Tyr S * r Lys Val Tyr Phe Arg Giy Gla Se Cys Asn Asr. Ls- Pro Leu Ser 155 200 2C5 Kis Lys Val Tyr K < = t Arg Asn Ser Lys Tyr Pro G_n A- Leu Val Met 210 21S 220 Met Gl- Gly Lys Me ~ Ket Ser Tyr Cys T? T r Gly Gin «et Trp Ala 221; "230 235 2 0 A.ra S ^ r Ser Tyr Law Gly Ala Val? He Asn L * ~ Thr Ser Wing Asp H? «245 250 '255" eu Tyr W. Asr_ Vai be Glsa Le Ser Leu Vai AS?? Ne Glu di Ser 260 65 270 Gln Thr P .-. (? Phe Gly Leu Tyr Lys La'-? 7", 235.}. - - < 210 > 7 < 211 > 337 < 212 > DNA < 213 > Homo sapiens < 223 > Description of the Combined DNA / RNA Molecule: n equal to, t, g or c < 221 > misc_feature < 222 > (3) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (58) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (67) ... (71) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (212) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (255) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (297) < 223 > n equal to, t, g or c < 221 > mise feature - - < 222 > (300) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (320) < 223 > n equal to, t, g or c < 221 > m? sc_f eature < 222 > (335) < 223 > n equal to, t, g or c < 400 > 7 ggr.taactcr c tgaggg t gagccaagcc tg catgía gtgcsscgcag gacarrs-nca 6 $ á_ü ac. = ¿? N? R. í-casga-sata atccattccc tg ggtcact -att taaay? crccaacct 1I.C agc¡j.gt.sat.a tggafcgactc cacagaaagg gagcagceae 190 tcgccrt-taag aaaagagaag aaatgaaac: gr. & A $$ a tg Cgí ^ tscat £. ccccccga 240 aggaaagc;:!: cacintccga ccícaaag cg aaa ^ c gc? .ggcr.g? ac accttgi-tigr. 200 tggase stg ttcttgctgp c ^ caagg-tgg-gttncc 337 < 210 > 8 < 211 > 509 < 212 > DNA < 213 > Homo sapiens < 223 > Description of the Combined DNA / RNA Molecule: n equal to, t, g or c < 221 > misc_feature < 222 > (10) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (13) < 223 > n equal to, t, g or c < 221 > mise feature - - < 222 > (209) < 223 > n equal to, t, g or c < 221 >; misc_feature < 222 > (315) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (322) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (325) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (334) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (343) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (347) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (351) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (356) - - < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (409) ... (410) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (416) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (422) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (424) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (426) ... (427) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (429) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (431) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (433) < 223 > n equal to, t, g or c - - < 221 > misc_feature < 222 > (438) ... (439) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (443) ... (444) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (446) ... (447) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (449) ... (450) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (452) ... (453) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (458) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (461) ... (462) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (466) < 223 > n equal to, t, g or c < 221 > mise feature - - < 222 > (469) < 223 > -n equal to, t, g or c < 221 > misc_feature < 222 > (471) ... (472) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (474) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (478) ... (481) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (496) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (498) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (504) < 223 > n equal to, t, g or c - - < 400 > 8 aa ^ cggcap a p-aas e g? Tacít? -í ar.scacsgcc sggttrtata tactgataag acctacgcca tgggacstct. agtecagagg aagaaggtcc acgtct ^ egg ggatgaatcg 1? C agtctgg-ga t ^ g? n c? ßtg'a.tcaa aata? c cg aascac acc caat &attcc 180 sgctastcß ct.ggc._t. tac aaaßccggna ggaaggagat gaaccc; aac t gcaatacc 40 aggggaaaat gcacaattat cactgggavg gaga ^ gtc a c-1-.ttcc-.ss tgecat-ga 300 as-ctg cg ace.twc: -t * c ancangtgc "gttp ^ tatt ttpcctncc. nt c ntggc 36C aacctcctag gaagg &agga C? cttaaetg ggaaa aacc caaaaaaati? tcaaangggt C angngniana ns ?? gggmng i imncnngr.pg r.?ct ncg nntatr.ttnt r.nir.gggr.n- *. 430 pg aaaaa.g gggccti- mgg gggnc ttt S59 < 210 > 9 < 211 > 497 < 212 > DNA < 213 > Homo sapiens < 221 > misc_feature < 222 > (168) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (213) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (288) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (325) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (346) < 223 > n equal to, t, g or c - - < 221 > misc_feature < 222 > (406) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (415) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (419) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (437) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (442) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (467) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (473) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (476) < 223 > n equal to, t, g or c < 221 > mise feature - - < 222 > (481) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (483) ... (484) < 223 > n equal to, t, g or c < 221 > misc_feature < 222 > (494) < 223 > n equal to, t, g or c < 400 > 9 aat-tcggcac ga? Caaggcc ggcct agg aagctccagc tgcca-rcg g ccaergaaaa i t_ ?? accagctcca gg-sgaaggrca a ccag-ca gsa.ca rada aat --- sgc? "g 12" cc? cr ~ aggg cccsgsagaa ßcagrcac c aagactgctt gcaacLgr-t "gcagacagtg lac aaaca c iic t aca aaaa? gcrcccttc tgn gccae-t -: -ogg; cs ggaat? cd Zi gatt ^ cttc tctgg? take tM - gcs - ßa «t" - «*? at a: cctt;: ccc.gggaat. JOO aaaggíia.aa t.crd_rt: a cca gattriacací t £ tg ^ - c: ca tgggtí ??: t £ aag tHt aa 3SC aggggagtgr- í "- ggag? r aaaag gg ^ aa.: ar.r-.ggc? aacct.? ctg gtta-tt_ ^ ¿2C aü-itatg c aggcttntat anctggeagg cct- ^ gccacg ggcattnatt canggngagg ¿, »nn tC-tt gggprga < iS " < 210 > 10 < 211 > 27 < 212 > DNA < 213 > Homo sapiens < 223 > Description of the DNA / RNA Combined Molecule: x deoxyinosine < 400 > 10 g-gggst .rea g ctcc ggc «gag? G ZX < 210 > 11 < 211 > 33 < 212 > DNA - - < 213 > Homo sapiens < 400 > 11 gtg = agctcz tatcacagca gtttcaatgc acc 33 < 210 > 12 < 211 > 26 < 212 > DNA < 213 > Homo sapiens < 400 > 12 gtgt acgag cctccgggca. gagc ~ g 2 $ < 210 > 13 < 211 > 33 < 212 > DNA < 213 > Homo sapiens < 400 > 13 gcgaagcttí. attacagca g ttc aat ge acc 2 < 210 > 14 < 211 > 28 < 212 > DNA < 213 > Homo sapiens < 400 > 14 gpggga-cc-; cgg cagßgi tgcagggc? < 210 > 15 < 211 > 33 < 212 > DNA < 213 > Homo sapiens - - < 400 > 15 gtgggar ct a acagca. g tt aatgc ac 33 < 210 > 16 < 211 > 129 < 212 > DNA < 213 > Homo sapiens < 400 > 16 gcgggc.r.ctg c- * c: atgaa ctccttctc acaagcgcct ecggcccagt tgccttctcc &? - ctggs? Rctgc eerc-cggtgtt gcírtect.gec ttccctgccr cagttgegag acaaggggac 120 c; ggcc? Gc 12 $ < 210 > 17 < 211 > 30 < 212 > DNA < 213 > Homo sapiens < 400 > 17 gtggqatcct, tacagcagt tcsatgcacc 20 < 210 > 18 < 211 > 903 < 212 > DNA < 213 > Homo sapiens < 221 > CDS < 222 > (1) .. (798) < 400 > 18 ag? Ist gac tcc here gaa agg? Ag cag tea cgc ctt act tet tere ctt 43 Met Asp Asp Ser Thr Gl'J Arg Glíi Gln Ser Arg Leu Thr Ser Cys Leu 1 S 10 15 - - aag aaa ags cea gaa atg aaa ctg aag gas tgt gtt tcc acc ctc ees Lys Lvs Arg Giu. Glu Ket Lys Leu Lys Glu Cys Vai Ser lie Lev Pr-. 20 25 30 Cgg a g gaa age ecc tet s cga tcc tcc aaa cae gga - ag cte e s 14-; Arg Lys Giv. HE? Pro Ser Vai Arg Ser 3e?. $ Asp Gly Lys Lev. Leu 35 40 4? gct gcß acr ttg ets ct? j 9Ca etg ctg c tac tcc ecc acg gcg gtg 19- Wing Aia Thr Leu Leu Leu Wing Leu Leu S «r Cys Cys Leu Thr val Val 55 55 60 ttt tcc tac cag gtg gcc gcc cc ggg gac ctg gcc ag ctc cgg 24 Be Phe -Ty Glr. Val Ala Ala Leu Gin Gly Asp Leu Ala s. ~ L «Arg 65 70 7 «, 80 gca cag ctg c«, g egc tac cac gcg gag aag ceg cca gca gga gca ss- - = s Wing Glu Leu Gin Giy K? S His Wing Glu Lys Leu Pro Aia Gly Wing Gly 3S -? (J 55 gcc ecc aag gcc ggc ctg eag gaa gct cca qz z ote a:; gcg gga 'ctg 36 Wing Pro Lye Wing Giy Leu Glu Glu Aia Pro Wing Wing Thr Wing Gly Leu 100 105 110 aaa ate ttt gaa CA cca gct cca gga gaa ggc aac tcc agt cag ace 3 £ 4 Lys He? He Glu Pro Pr »Aia Pre Gly Glu Giy Asn Ser 3er GIn As :: 115 1 0 125 age aga aa cgt gc gr.t cag ggt c a gaa gaa here gca tcc tac -? l l Being Arg Asn Lys Axg Aia Vai Gln Gly Pro Glu Glu Thr Giy Being Tyr 135 135 140 here ttt gtt cea tgg cct ctc age ttt aaa sg? gga agt gcc cta? aa 430 Thr Phe Vai Peo Trp Leu Leu Ser Phe 'lys Arg Gly Se: r Aia L «u Glu 145 150 15 * IdC gaa ASA gag aat sa a a ttg gtc aaa gaa act ggt tac ttt ttt ata 525 Giu lys Glu ksr. Lye lie Leu al Lys Clu r Giy Tyr Pr. E P e lie 165 170 175 tat Í? SI cag gtt tta at act gat aag acc acc gcc atg gga cat cta 5".

Tyr Giy Gin Val e Tyr Thr Asp Lys Thr Tyr Wing Mst Giy HIS Leu 180 185 130 att cag agg aag aag gtc cat gcc ttt ggg gat gaa; g agt ctg gtg 5i4 lie Gin Arg Lya Lys VAI HIS Val phe Gly Asp Glu Leu Ser Leu Vs.1 1? 5 200 2ÜS act ttg ttr cga tgt att ca aat a'.g cct gaa here cta ec aat aat 672 Thr Leu Phe Arg Cys lie Gir. Asn Me? Pro Giu Thr Leu Pro ASp Asp 21 Í 21 220 tcc tgc tat tea g: ggc att g a aaa ctg gaa gaa gga gat gaa ctc 720 Ser Cys Tyr Ser Ala Gly lie Aia Lys Leu Glu Glu Gly Asp Glu Leu 22S 210 235- 240 ca ctt gca ata cca aga gaß aac gca ca ata ata a ctg gat gga gat 768 Glr. 1- Ala lie Pro Arg Glu A = n Ala Gin lie Ser L & Asp Gly Ase 245 250 255 - - gcc - .. u t "ttt ggt oca ttg aaa ctg czg tgs. ctü tt acaccat? -t oíd Vel Thr £ > he ne Gly Ala L «u Lys Leu Leu 26C • 2S5 tgtagctatt ttcctcccttctctctacc rc aagaaga aag = tc aa ctcaaaacat S7S c? aisa aaa a a.aaaaa a aaa a a a < 210 > 19 < 211 > 266 <; 212 > PRT < 213 > Homo sapiens < 400 > 19 Mst Asp Asp Ser r GI; Arg Glu Gln Ser Arg Leu Thr Se Cys Les 1 5 10 15 I.ys Lys «r < j Giu «the Ket Lys Leu Lys Glu Cy = Vai 3eí lie e Pro 20 25 3" Arg Ly = 3iu S = r Pro Ser v «? l rg ser Ser s Asp Giy Lys Le;. Le1 .: JS 40 45 Wing Aia Thr Leu Leu Leu Ala Leu read Ser Cys Cys Leu Thr Val Val &C 55 cC 3e Phe Tvr Gin Val Allah Ala L Glr, G_y Asp L «Aia be Leu Arg 65 7» 75 80 Aia Sin 'u & Glp Ciy KiS Kis Ala Clu Ls'5 Leu Pro Wing Gly Wing Gly 9B 90 35 Ais Pro Lys Wing Gly Leu Giu Glu Wing Aia Val Thr Wing Gly Leu 100 10 = 11C Lys rie? 'He Glu Pra Pro Aia Pro Cly Glu Gly Asr. Ser Se Gln Aen 115 120 125 S r Arg Asr. Lys Ring Wing Val Gir. Gly Peo Giu Glt; hr Giy Ser Tyr 130 135 140 ~ h Phe val Pro Trp Leu Leu Ssr Pie Lys Ring Gly Ser Ala Leu Glu 145 150 1SS 150 í? Lu Lys Giu Asr. L s Tlft Leu al Lys Giu Thr Gly Tyr nß P s = lie 165 i? O 1? S T-yr Giy Slr. Val Leu Tyr Thr Asp Lys Thr Tyr Aia Xßt Gly His Leu lsC 185 193 lie Gln Arg Lys Lys Val His Val Phe Giy Asp Giu Leu Ser Leu Vai 195 tO 20S Thr Leu Pfce Arg Cys? I «Cln Asn ee? Ro Gl Thr Leu P or AS? AS? 210 215 220 Ser Cye Tyr Se? Wing Giy lie Aia Lys Lau Glu Giu Gly Asp Giu Leu - - 225 230 22 5 ^ 4 C Slr. ? sp Val Thr Phe P.ife Gly Ala Ley ys Le '. Leu < 210 > 20 < 211 > 136 < 212 > PRT < 213 > Homo sapiens < 400 > 20 r-is Ser Val Leu His Asp i 5? Er Asp Val Thr Gl'j Val Met Trp Without Pro? Leu Arg Arg Gly Arg 20 2S 20 Gly Lau Glr, Al * Gln Gly Tyr Gly v &Arg He Gln A = p Ala Gly Vdl 3;. 40 4S Tyr Leu Leu Tyr Ser Clft Val L * u? He Glt? Asp Val *? Hr? He Th.r Mee 50 55 60 Gly Without Val to Being Arg Giu GXy Gin Gly Arg Gl «Gly? Hr eu he $ 5 70 75 80 Arg Cys He A ^ Ser Met? Ro Ser His Pro Asp Arg Ala Tyr Asn Se 85 SO 35 Cys Tyr Ser Leu be Val He He Pro Arg Arg Ala Lys Leu Asn Le Ser? Ro His Gly 115 -20 12 < »Thr P» Leu 3ly P-va Val Lys Lau 130 135 < 210 > 21 < 211 > 462 < 212 > DNA < 213 > Homo sapiens - - < 400 > 21 a ^ gct ^ cs-- agggtcegga agaaaccget aetcaggace gccttcagc gatagcagac 60 t.ct.gaaa- ~ egaccaccca gaaaggttct tacacsttts ctccttggc g tttc. tt¿- 12'J «« acg? g it c? ccíresrga gaga agaß aacaaaaccc cgg taí-aga aactggttae 1SC c ^ a? ct acggtcagg tvtttacac gataa ^ acc ?: acgcca-ggg rcacccgatt 40: &g g; aag_i aag t acg? t * íríggtgac gagctgtcti; tg ttaet-t. atticgctgc 3Qü as E cagase * t.3c.t: g§aaa3 -ctctcct &c aaeeectgec aet-rtgeegc caccgcaaag í £ 0 r.6.ga -, and s! ig7 gtgaigaact: gc-? g < .tggca artccccgrg aaaacgcaca aattt ccg 420 graegge_M_t: j taßccctctc cggtgcactg aa.act c ^ g & aa 462 < 210 > 22 < 211 > 1040 < 212 > DNA < 213 > Homo sapiens < 221 > CDS < 222 > (1) .. (468) - - < 400 > 22 cgc gtg gta gac ecc cca gcc ecc c = e gr a -c. 5c ctg cct coa cgc 43 Arg Val Val Asp Le Set Pro Pro Wing Pro Cys Pro Le * a Pro GLy Cys i 5 10 1S cgc falls on the g aga g aga g ac ac aac c a a g aa: aga act Arg K s Ser 5 r. H-.S Asp Asp Asp Sly Met. > 5r_ e Arg Asn Axg t? tac here ttt gtt that "g ctt ctc ag ttt aad ja 53a aa; g'-C t? 144 Tyr Thr Phe '.ai Pro Trp Leu Leu Ser Phe ys Aig 31and Asn "Ala" ^. 35 43 45 gag gag aaa gag aac sa & ta gtg gtg a? G ac ac ggc tat tc ttc 19 Glu Glu Lys Giu Asn Lys lie Val Val Arg Gin Thr Gly Tyr P? E Ph «50 55 6C at tac age cag gtt .cta tac acg ga-: ecc ate ttt gct acg ggc cat • 40 Tyr S #, r Glp Val _eu Tyr Thr Asp Pro Jle Ph «Ale Me1: Gly H¿Í ß 70 75 6. gcc at cag ag aag aaa gca cac g * c ttt ggg gac aag ctg age eg 2S3 Val lie Gln Arg Lys Lys V & l His Val Pne Gly Asp Glu Leu Be Law 85 3-3 95 gtg acc ctg ttc cga tgt att cag aa arg cc aaa ceg ecc aac 336 Val Thr Leí. Pne Arg Cys le Gin hsn ee rc Lys Thr eu Pro Asn ICO 105 110 aac cc tac teg gct gec acc gcg agg ctg gaa gaa gga gat gac 334 SO. Ser Cye Tyr Ser Aia Gly lie Wing Arg Leu Giu Glu Gly Asp Gl ^ 1 120 125 at ao "gca at: ecc cgg gag aa ga cag att a cgc aac gg < a 432 lie Gin ß? Aia IJ * Pro Arg Glu Asn Ala Gln lie Ser Arg Asp Gly 130 135 143 gac gac acc ctc ttt ggt gcc cca aaa ctg ctg cacticact gct 47R A »p Asp Thr Pliß Pi. * Giy Ala Leu Lys Leu Leu 14;. 150 1: 5 ggagt- rcg g atcccc? ec ctcgt ctct ccgtacctcc gagggagaaa cagaegactg S3S gaaaaac aa aagatgggaß aagccgtcag cgaaagtttt c cg gac c gttgaacctg 5 '- 8 «Tcc? Aaeia ggaaatacaa cagacagcc» caaccgaa.it gtgcca & gtg agttatgaga 558 aacggagccc gcgctcagaa agac ggatg aggaagaeeg tttüctccag tcctctgcca 713 - - acacgcactg caaecttgcc ttttgc cg ggcgacacac ctteagaatg; sgggagat "" i tccttgt -c gcgacttg c atgagaagag gscrcacaac tgcaggtca gisagcac e 83 »aegctaagcc tcaggattta eccteecttc tcatgctda? tacacacacg ct tect; *. 855 «Gtaaeae a tgg ^ atacca tggaaaggtt gctcjt ttt saat cagaa. gtcttgaac-, 3SS ggca &eagac aaaa = ccccc ataaac caa gcgcaaaatí. aa ctaacca aas soguea? o? e agtgc.5aa.-3 aaaaaa a a a 13 O < 210 > 23 < 211 > 155 < 212 > PRT < 213 > Homo sapiens < 400 > 23 A g Val Val s Lex »S * r Ala P or Pro Ala Tro T s Leu Pro Gly C a 1 5 i: 15 Arg rfi = yßr Gir- His Asp A = Asn Gly Me Asr, _- < =? Ar? Asn Arg Thr 25 30 Tyr T.-tr Pr-e Val rc p Lau eu Ser Pne L * Arg Gly Asn Ala ev 3? 40 4 *. QX Glu Lys Gi "Asp Lys lie V-al Val Arg Gin Thr Gly Tyr? R? E Phe 50 55 60 li * z-? er clr. -Jal i »eu Tyr hr A $? Pre Ha Phe A ^ a Met Cly His 5 5 T i "5 8C Val Xle Gir. Arg Lys Lys Val Eis Val Pke Gly Asp Glu L «u Ser 1« 'J 35 9C 95 Val Th-r au Phe Arg Cys lie Gln Asr. Met Pro Lys Tí-r Lea Pro Asn 130 1C5 11 * ¡.n £ > er Cys Tyr Ser Ai Gly lid Wing Arg eu Glu Glü Giy ASp G1J 115 120 125 I ~ s. Glp L *? Í Aj.a lie Pro Arg Glu Asn Aia Gln lie Ser Arg Asn Gly 13: 13 = üO As Asp Tr-r PLe Pr.e Gly Ala «U Lys Leu Leu 14 = 150 155 < 210 > 24 < 211 > 26 < 212 > DNA < 213 > Homo sapiens - - < 400 > 24 CCAccagetc caggagaagg caactc Z6 < 210 > 25 < 211 > 19 < 212 > DNA < 213 > Homo sapiens < 400 > 25 accgcgggac cgaaaatct 9 < 210 > 26 < 211 > 23 < 212 > DNA < 213 > Homo sapiens < 400 > 26 cacg ttatt t tgctsttc tga 22 < 210 > 27 < 211 > 657 < 212 > DNA < 213 > Homo sapiens < 400 > ? 27 taccasgtgg cggccgtgca aggggacctg gccagcctc ggg agagct gcagssccsc 60 cacgcggaga agctgccagc aagagcaaga gcccccaagg ccc-gt ttggg ggaagcccca 110 gctgtcaccg caggactgaa aa ctttuaa ccu c ^ GCTC caggagaagg caactc agt 1 &0 shits gaaa cagca aa.gg tgctacccag ggtgcagaag aaacagceac t aagaccgc 240 ctgcaaccga ctgcagac & g tgaaacacca ctaeacaaa aaggAf.ct a caca tt tc 300 ccatggctcc ccagctttaa aaggggaa t gccctagasg aaaaagagaa taaaatattg 360 gtcaaagaaa ecegttacct ttttatacac ggtcaggett tacacacsiga caagacctac 4¡.D gccac ggac atctaactca gaggaaaaaa gcccarg ^ ct ttggggatga at. sg «agtctg 480 gcgascctgc c cgacgtat -caaaatatg estgaaae & c tacccaataa ttcetgeta 540 tcagctggca tgeaaaact ggaagaagga gatgaacttc aacttgcaac acca gagaa 60 aa gcacaaa? .atcactgga cgcagatgcc acattttteg gtgcccccaa ßctgccg 657 < 210 > 28 - - < 211 > 219 < 212 > PRT < 213 > Homo sapiens < 400 > 28 Tyr Glr- V l Ala Ala Val 31:?. Gly Asp Leu Aia Ser Leu Arg Ala Glu 1 5 10 15 Leu Ciln Gly His His Wing Giu Lys Leu Pro Aia Arg Wing Arg Wing Pro 20 25 30 Lys Wing Gly Leu Gly Glu Wing Pro Wing Va ^ Thr Ais Giy Leu Lys lie 40 45? He Gi Pro Prc Wing Pro Gly Giu Gly Asp Ser Se SIl Ser Ser Arg SS 55 GZ Asn Lys Arg Ala lie Glr; Gly Ala Glu Glu Thr Val lie Gin Aap Cys 55 70 75 30 Leu G n Leu lie Ala Asp £ «t Glu ftx Prc Thr lie Cin Lye Giy Ser a $ 90 95 Tyr Thr Phß Val Pro Trp Leu Leu Ser Phe Lys Are Gly Ser Aia Leu ICO 105 11C Giu Gl.-. Lys í? I Asn ys 11 * Leu Val Lys Clu Thr Giy Tyr Phß Phe 115 120 125 lys Tyr GX 3lr. Val Lß? Tyr Thr Asp s Thr Tyr Aia Mer. Giy His 1J0 13 S 14C eu lie G .. 'n Arg s lys Val His Val Pha Gly Asp Giu Leu Ser leu 145 150 15? 150 Val hr Le? He Arg Cys lie Gin Asa Hez Pro G u Thr eu? ß A-.n 16S 17C 175 kst? er Cys Tyr Ser Ala Gly He? the Lys Leu Cl Giu Gly Asp Giu 130 195 190 Leu Glr. ß'j Aia lie Pro Arg G iu Asr. Ala Glr. Z i «Ser l« t¡ S & Cly 19-20C 205 Asp Val Thr Pnß? He Gly Ala Leu Lys leu Leu 210 215 < 210 > 29 < 211 > 657 - - < 212 > DNA < 213 > Homo sapiens < 400 > 29 ^ ac agg-gg cggc; cf * gca aggggacctg gccagcctcr gggcagagct gcagagccac cacgcggaga agttgccagc aagagcaaga gcccccaagg ggr ~ ?. gg ggaagctcca gccg caccg cgggaet to aatc-ccgaa cc c agct ^ c g ag &agg caactccagt I8S eagagcagca gaaataagcg tgctacccag aaacagtcat teaa ^ actgc 24C? gcaa? f? ttgcagacag tgaaacaeca actacacaaa aaggatc ta acatrtgic ccatggc? _. t.c tca tttaa aaggggasgt? rccc? agaag aaaaagagaa raaaataitc 160 gcca acjaaa cug tacc *? ctar.acat ggtcag ctt tatacaccga taagacczae -____ 9 ''. caeggí.a? r at ^^ aa s.ca §ag $ aa ** aa gtcrß cgtct, et ggg * cga atcgagLccs 48C gcgactttgt ttcgatgtat tcaßaasatg cct.gaa --- .ac tacccaar.aa cc gcta S v tcagctggca cacaaaact ggaagaaggg ga ^ gaacccc aaccc caat accaegagaa 60 E? aa.g acdaa ai t-iCtgga tggagatgt-c ac & t-r ctig g gccc caa accgctg 657 < 210 > 30 < 211 > 219 < 212 > PRT < 213 > Homo sapiens < 400 > 30 Tyr Glr. Val Aia Ala Val Glr. Gly Asp e «j Ala £ er Leu Arg la Glu 1 5 10 15 Leu Gln Ser His His Wing Giu Lys Leu Pro Wing Arg Ala Ar? Ala Pro lys Wing Gly Leu Gly Giu Wing Pro Wing Vai Thr Aia Gly Leu Lys I ._. e 35 40 4 £ Phe Glu Pr Pro Wing Pro Gly Gl Gly AS.T Ser Ser Gln Ser Sar A s 50 S5 60 Aar Lys Arg Ala He Gln Gly Ala Glu Glu Thr Val lie Glr. Asp Cys - - fS 78 73 S L & Gl-i is: lie Wing Asp Ser Glu Thr Pro? go le GÍ? Lys Gly be 65 SO 9S and Thr Phe Val Pro Trp Leu Leu Ser Phe Lys Axg Gly S ^ Ala e 130 IS5 110 Glu Glu Lys Glu Asn Lys? Le Le Val Lys Gly Thr Gly Tyr Ph? Phe 15 120 ?: "He Tyr Glv Glp Val Leu Tyt Thr Asp Lys Thr Tyr Wing «at Gly His 13C 135 14-) Leu lie < Sl-- Arg Lys ys Val K¿ «Val Phe Gly Asp Giu e« Ser e 145 150 155 150 Val Tht e'J Pne Arg Cys. lie Gln Asn Ms Prs 31u Thr Leu Pro As 155 i? d X Asn er Cys Tyr Ser Wing Gly Ilß Aia Ly * - * e ~ Cl 3lu Gly Asp C * u 1BC 1S5 2.30 eu Gln Leu Ala lie Pro Arg Glu Asr . Ala Gln ie Sar Lau Asp Gly 195 200 2C5 Asp Val thr? and í * he Gly * the Le Lys Leu «u 210 215 < 210 > 31 < 211 > 38 < 212 > DNA < 213 > Homo sapiens < 400 > 31 sgtcgccgue tccaaegegg cegttcaggg t_cca © a &s 38 < 210 > 32 < 211 > 49 < 212 > DNA < 213 > Homo sapiens < 400 > 32 t.g5-tc.cg c ccaaeortacc Aagett-gcac e? Cagatctt ttccagatc 49 - - < 210 > 33 < 211 > 21 < 212 > DNA < 213 > Homo sapiens < 400 > 33 tggta ^ t.c -tc < ? gagt.gt. 1 < 210 > 34 < 211 > 19 < 212 > DNA < 213 > Homo sapiens < 400 > 34 cgcß "-agaa acggegacc 19 < 210 > 35 < 211 > 22 < 212 > DNA < 213 > Homo sapiens < 221 > misc_f eature < 222 > (7) < 223 > n equal to deoxyinosine < 221 > misc_feature < 222 > (12) < 223 > n equal to deoxyinosine < 221 > misc_feature < 222 > (16) - - < 223 > n equal to deoxyinosine < 400 > 35 tac agr.rgg cngccntgea ag 22 < 210 > 36 < 211 > 22 < 212 > DNA < 213 > Homo sapiens < 221 > misc_feature < 222 > (3) < 223 > n equal to deoxyinosine < 221 > misc_feature < 222 > (14) < 223 > n equal to deoxyinosine < 221 > misc_f eature < 222 > (16) ... (17) < 223 > n equal to deoxyinosine < 400 > 36? Jtnacagcag ittn «r.neca ce 22 < 210 > 37 < 211 > 866 < 212 > DNA < 213 > Mus musculus - - < 400 > 37 atggatSAgt c.gcaaagac cctgceacca cratc ctct ctcct-t ctc cragaaasga SO gaaga-aegs aagtggg & ca tgatcecatc ac cgcaga ¿gg tgcc-ggr "gggar t ca gggatgaaaf gccgc-ggcc gccacccí- -c tgctggccci: gtcgccca c IsD ag ttcacag ctgtcct gtac? agttg gctgcctegc aagcagac t ga gaasctg 240 cgcarggagc tgca ^ agcta ccgag $ t.tca gcaacaccag ccgccgcegg gc cc.aga._ Did you hear? / accgc- gagccaaact cct-gacaccc gcagetcctc gacíccacaa ct.-í-gc 3í ,? ggecacagg * ac &aaegegc ct? .ccaggga ccagaggaaa cagaacaaga tg-agacctc 42 C c gcü t cc caccat? r cccgce-gga cgcccccat ,: ctcaaca a agates ..gga í3C atgaaccita g < -aacacca. tcaagactgc ctgca ctga ttgcagacag gacacgr 5 * 0 gccttg? Agg agaaagagaa caa -u-agtg g-.gaggcjtaa caggcca rt ec a tc ~ ac 6 6 agcca gttc tacacacgga ccccatctt t; gctatgggtc atgtcstc a gaggaagaaa? = Gzacacgtct ttggggacga gctgag cg gtgaccctgt c gracgci-; tcag aa-r. cccaaaacac igc-cc a c aac tcctt ta g.cggct-ggca c C? j gc ggaagaagsa "JPO ga-gagatcc agctt caaí: ccrcgggag aacgcacaga rztcacgcsa cggagacgac 8 C acctrccttg g gccctaaa acrgc ?, Yes < 210 > 38 < 211 > 177 < 212 > DNA < 213 > Mus musculus < 400 > 38 m? Sakteces kg_? Mkvgyc.t kgaw c rdg r s a? R? Rts syrgsacaaa sü gatagv caa r nssrghm rrastdvdsa acgcrhs d? sdtaknkwr 120 tgyysvytda üig. '. vrkkvhv gás rcnrik tJ-n = cysßga rg? arnasrr. gd = cgak 1 ~ 7

Claims (25)

1. - CLAIMS Having described the invention as an antecedent, the content of the following claims is claimed as property: 1. An isolated nucleic acid molecule characterized in that it comprises a polynucleotide having a nucleotide sequence with at least 95% identity to a sequence that is selected from the group consisting of: (a) a nucleotide sequence coding for the neutrocin-alpha polypeptide, having the complete amino acid sequence of Figures IA and IB (SEQ ID NO: 2); (b) a nucleotide sequence encoding the neutrocin-alpha polypeptide, which has the complete amino acid sequence encoded by the cDNA clone contained in the deposit with accession number ATCC 97768; (c) a nucleotide sequence encoding the extracellular domain of the neutrocyan-alpha polypeptide; (d) a nucleotide sequence encoding the transmembrane domain of the neutrocyan-alpha polypeptide; - - (e) a nucleotide sequence encoding the intracellular domain of the neutrocyan-alpha polypeptide; (f) a nucleotide sequence encoding a neutrocin-alpha polypeptide comprising the extracellular and intracellular domains, but lacking the transmembrane domain; and (g) a nucleotide sequence complementary to any nucleotide sequence of parts (a), (b), (c), (d), (e) or (f) above.
2. 2. The nucleic acid molecule according to claim 1, characterized in that the polynucleotide has the complete nucleotide sequence of Figures IA and IB (SEQ ID NO: 1).
3. 3. The nucleic acid molecule according to claim 1, characterized in that the polynucleotide has the nucleotide sequence of Figures IA and IB (SEQ ID NO: 1) encoding the neutrocin-alpha polypeptide having the amino acid sequence complete of Figures IA and IB (SEQ ID NO: 2).
4. 4. The nucleic acid molecule according to claim 1, characterized in that the polynucleotide has the nucleotide sequence encoding a soluble neutrocin-alpha polypeptide, which comprises the extracellular domain shown in Figures IA and IB (SEQ ID NO. NO: 2).
5. 5. An isolated nucleic acid molecule characterized in that a polynucleotide having a nucleotide sequence with at least 95% identity to a sequence that is selected from the group consisting of: (a) a nucleotide sequence encoding a polypeptide having the amino acid sequence consisting of residues n-285 of SEQ ID NO: 2, wherein n is an integer in the range of 2 to 190; (b) a nucleotide sequence encoding a polypeptide having the amino acid sequence consisting of residues 1-m of SEQ ID NO: 2, wherein m is an integer in the range of 274 to 284; (c) a nucleotide sequence encoding a polypeptide having the amino acid sequence consisting of the nm residues of SEQ ID NO: 2, where n and m are integers as defined respectively in subparagraphs (a) and ( b) previous; and (d) a nucleotide sequence encoding a polypeptide consisting of a portion of the amino acid sequence of complete neutrokine-alpha encoded by the cDNA clone contained in the deposit having accession number ATCC 97768, wherein said - - portion excludes from 1 to 190 amino acids of the amino terminus and from 1 to 11 amino acids of the C-terminal end of the complete amino acid sequence.
6. 6. The nucleic acid molecule according to claim 1, characterized in that the polynucleotide has the complete nucleotide sequence of the cDNA clone contained in the deposit having the accession number ATCC 97768.
7. 7. The nucleic acid molecule of according to claim 1, characterized in that the polynucleotide has the nucleotide sequence coding for the neutrocin-alpha polypeptide having the complete amino acid sequence encoded by the cDNA clone contained in the deposit having the accession number ATCC 97768.
8. 8 The nucleic acid molecule according to claim 1, characterized in that the polynucleotide has the nucleotide sequence encoding a soluble neutrokine-alpha polypeptide comprising the extracellular domain encoded by the cDNA clone contained in the deposit having the accession number ATCC 97768.
9. 9. An acid molecule isolated nucleic acid characterized in that it comprises a polynucleotide that hybridizes, under stringent hybridization conditions, with - a polynucleotide having a nucleotide sequence identical to a nucleotide sequence of parts (a), (b), (c), ( d), (e) or (f) of claim 1, wherein said hybridizing polynucleotide does not hybridize under stringent hybridization conditions to a polynucleotide having a nucleotide sequence consisting only of A residues or only of T residues.
10. 10. An isolated nucleic acid molecule characterized in that it comprises a polynucleotide that encodes the amino acid sequence of a portion n epitope carrier of a neutrokine-alpha polypeptide having the amino acid sequence of parts (a), (b), (c), '(d), (e) or (f) of claim 1.
11. 11 The isolated nucleic acid molecule according to claim 10, characterized in that it encodes for an epitope-bearing portion of a neutrocin-alpha polypeptide that is selected from the group consisting of: a polypeptide comprising the amino acid residues of about Phe- 115 to about Leu-147 (SEQ ID NO: 2); a polypeptide comprising amino acid residues from about Ile-150 to about Tyr-163 (SEQ ID NO: 2); a polypeptide comprising the amino acid residues of about Ser-171 to about Phe-194 (SEQ ID NO: 2); a polypeptide comprising the - amino acid residues from about Glu-223 to about Tyr-24-6 (SEQ ID NO: 2); and a polypeptide comprising the amino acid residues of about Ser-271 to about Phe-278 (SEQ ID NO: 2).
12. 12- A method for preparing a recombinant vector, characterized in that it comprises inserting an isolated nucleic acid molecule according to claim 1 into a vector.
13. 13. A recombinant vector characterized in that it is produced by the method according to claim 12.
14. 14. A method for preparing a recombinant host cell, characterized in that it comprises introducing the recombinant vector according to claim 13 into a host cell.
15. 15. A recombinant host cell, characterized in that it is produced by the method according to claim 14.
16. 16. A recombinant method for producing a neutrocine-alpha polypeptide, characterized in that it comprises culturing the recombinant host cell according to claim 15, under conditions such that the polypeptide is expressed and said polypeptide is recovered. -
17. 17. An isolated neutrocin-alpha polypeptide, characterized in that it 'comprises an amino acid sequence having at least 95% identity to a sequence that is selected from the group consisting of: (a) the amino acid sequence of the neutrocin-alpha polypeptide having the complete amino acid sequence of Figures IA and IB (SEQ ID NO: 2); (b) the amino acid sequence of the neutrocin-alpha polypeptide having the complete amino acid sequence encoded by the cDNA clone contained in the deposit having accession number ATCC 97768; (c) the amino acid sequence of the extracellular domain of the neutrocine-alpha polypeptide; (d) the amino acid sequence of the transmembrane domain of the neutrocin-alpha polypeptide; (e) the amino acid sequence of the intracellular domain of the neutrocine-alpha polypeptide; (f) the amino acid sequence of a soluble neutrocin-alpha polypeptide comprising the domain; and (g) the amino acid sequence of an epitope-bearing portion of any of the polypeptides of part (a), (b), (c), (d), (e) or (f).
18. 18. An isolated polypeptide according to claim 17, characterized in that it comprises an epitope-bearing portion of the neutrocyan-alpha protein, wherein said portion is selected from the group consisting of: a polypeptide comprising the amino acid residues of about Phe-115 to about Leu-147 (SEQ ID NO: 2); a polypeptide comprising amino acid residues from about Ile-150 to about Tyr-163 (SEQ ID NO: 2); a polypeptide comprising the amino acid residues of about Ser-171 to about Phe-194 (SEQ ID NO: 2); a polypeptide comprising the amino acid residues from about Glu-223 to about Tyr-246 (SEQ ID NO: 2); a polypeptide comprising the amino acid residues of about Ser-271 to about Phe-278 (SEQ ID NO: 2).
19. 19. An isolated antibody characterized in that it specifically binds to a neutrocin-alpha polypeptide according to claim 17.
20. 20. A pharmaceutical composition characterized in that it comprises a polypeptide according to claim 17 and a pharmaceutically acceptable carrier.
21. 21. An isolated polynucleotide characterized in that it encodes a modified neutrocin-alpha protein, wherein, except for at least one conservative amino acid substitution, said modified polypeptide has an amino acid sequence that is identical to a member that is selected from the group consisting of of: (a) amino acids 1 to 285 of SEQ ID NO: 2; (b) amino acids 2 to 285 of SEQ ID NO: 2; (c) amino acids 1 to 46 of SEQ ID NO: 2; (d) amino acids 47 to 72 of SEQ ID NO: 2; and (e) amino acids 73 to 286 of SEQ ID NO: 2.
22. 22. A modified neutrocin-alpha polypeptide molecule, characterized in that, except for at least one conservative amino acid substitution, said modified peptide has an amino acid sequence that is identical to a member that is selected from the group consisting of : (a) amino acids from 1 to 85 of SEQ ID NO: 2; (b) amino acids 2 to 285 of SEQ ID NO: 2; (c) amino acids 1 to 46 of SEQ ID NO: 2; - - (d) amino acids 47 to 72 of SEQ ID NO: 2; and (e) amino acids 73 to 286 of SEQ ID NO: 2.
23. 23. An isolated nucleic acid molecule, characterized in that it comprises a polynucleotide having a sequence with at least 95% identity to a sequence that is selected from group consisting of: (a) the nucleotide sequence of SEQ ID NO: the nucleotide sequence of SEQ ID NO: (c) the nucleotide sequence of SEQ ID NO: 9; (d) the nucleotide sequence of a portion of the sequence shown in Figures IA and IB (SEQ ID NO: 1), wherein said portion comprises at least 30 contiguous nucleotides from nucleotide 1 to nucleotide 2442, excluding the nucleotide sequence 1387 to nucleotide 1421, the sequence of nucleotide 9 to 382, the sequence of nucleotide 1674 to 1996, the sequence of nucleotide 1401 to 1784, the sequence of nucleotide 900 to 1237, and any fragment located within these sequences; Y - - (e) a nucleotide sequence complementary to any of the nucleotide sequences of parts (a), (b), (c) or (d) above.
24. 24. An isolated nucleic acid molecule, characterized in that it comprises a polynucleotide having a nucleotide sequence with at least 95% identity to a sequence that is selected from the group consisting of: (a) a nucleotide sequence encoding the Neutrocin-alphaSV polypeptide having the complete amino acid sequence of Figures 5A and 5B (SEQ ID NO: 19); (b) a nucleotide sequence encoding the neutrocin-alphaSV polypeptide having the complete amino acid sequence encoded by the cDNA clone contained in the deposit with accession number ATCC 203518; (c) a nucleotide sequence coding for the extracellular domain of the neutrocine-alphaSV polypeptide; (d) a nucleotide sequence encoding the transmembrane domain of the neutrocine-alphaSV polypeptide; - - (e) a nucleotide sequence coding for the intracellular domain of the neutrocine-alphaSV polypeptide; (f) a nucleotide sequence encoding a soluble neutrocyla-alphaSV polypeptide comprising the extracellular and intracellular domains, but lacking the transmembrane domain; and (g) a nucleotide sequence complementary to any of the nucleotide sequences of subsections (a), (b), (c), (d), (e) or (f) above.
25. 25. The isolated antibody according to claim 19, characterized in that it inhibits the binding of the protein of SEQ ID NO: 2 to a neutrocine-alpha receptor.