TW200533369A - Applications of treatment using interferon-tau - Google Patents

Abstract

Methods of modulating cytokine levels in human subject by administering interferon-tau(IFNτ)are described. More specifically, a method of up-regulating the interleukin 10 (IL-10) level in patients afflicted with a condition that responds to treatment by having an increased blood IL-10 level, such as an autoimmune condition, a viral infection, or a condition of cellular proliferation by administering IFNτ is described. Also described are methods of modulating blood levels of interleukin-12 (IL-12) and interferon-gamma (IFN-γ) by administering IFNτ. In various embodiments, IFNτ is administered alone or in combination with a second therapeutic agent.

Description

20053323i & Qc IX. Description of the invention: [Technical field to which the invention belongs]

The present invention relates to a pharmaceutical composition containing interferon tau (IFN0) and a method of using the same. More particularly, the present invention is to alleviate disease or to interleukin 10 (IL-10) by administering interferon tau (IFNI) to mammals. As a method of symptomatic response, interferon tau (IFNt) can be administered to a subject alone or in combination with one or more agents. The present invention further stimulates the production of interleukin 10 (IL-10) and / or affects interleukin The concentration of 12 (IL-12) is reduced in order to adjust the blood concentrations of interleukin 10 (IL-10) and interleukin 12 (IL-12) simultaneously or separately. The present invention also prevents interferon-gamma (IFN- γ) concentration increased. The present invention also relates to the use of interferon tau (IFNO or a combination of one or more agents). [Prior art] Interferon tan (IFN :) (hereinafter referred to as "IFNt" or The "interferon-τ" table) is a pregnancy-identifying hormone produced by the nourishing ectoderm of a pregnant body during ruminant development (published by Imakawa, K. et al., Nature, 330: 377-379 in 1987; and Bazer, FW and Johnson, H. Am. J. Repro. Immunol., 26_: 19-2 Published by Order 2 in 1991. Interferon tau (IFN0 gene distribution is restricted to ruminants, including cattle, sheep, and goats (by Alexenko, A. P, et al. In Interferon and Cytokine Res., 19: 1335-1341 (Published in 1999), but has shown activity on cells of other species including humans and mice (published in 1991 by Pontzer, C.H. et al. In Cwcer 5: 5304_5307; Alexenko, A.P. et al. In / Wer / erow and 2005332 ^ 6® Welcome: 817-822 published in 2000. For example, ifNt has been shown to be antiviral (by Pontzer, C.H. et al. In Biophys. Res. Commun., 152: 801- 807, published in 1988), can inhibit the proliferation phenomenon (published by Pontzer, CH et al. In 1991) and have immunomodulatory activity (by Assal-Meliani, A., Am. J. Repro. Immunol., 33: Order 267-275 was published in 1995).

IFNt exhibits a variety of activities traditionally associated with type 1 interferons such as interferon-alpha (IFN-α) and interferon-beta (IFN-β), but IFNt interferon tau (IFN0 and other type 1 interferences) There are also quite different aspects of the hormones. The biggest difference is the role of interferon tau (IFNt) in pregnant ruminants. Other interferons do not have similar functions in pregnancy recognition. They are also different for virus induction. All Except for interferon tan (IFNt), the first type of interferon is easily induced by viruses and dsRNA (published by Roberts et al. At 1_3_: 432 in 1992). The induction of interferon-alpha (IFN-α) and The performance of interferon-beta (IFN-β) is transient and lasts for several hours. On the contrary, once induced, the synthesis of IFNt can continue for several days (by Godkin ^ A ^^ Reprod. Fert.f 65: 141 was published in 1982). On a single cell basis, compared to the production of other interferons, interferon tau (IFN0 can be produced more than 300 times (by Cross J. C. and Roberts R. . M. et al in Proc. Natl, Ac ad, Sci. USA 8_8_: 38 17-3821 published in 1991). Other differences include that the amino acid sequence of interferon tau (IFNt) is different from the amino acid sequence of other type 1 interferons. Interferon tau ( The similarity percentages of amino acid sequences between IFN〇 and 200533 class c other interferons a2b, βΐ, ωΐ, γ and τ are summarized in the following table: rHuIFNa2b rHuIFNP 1 RHuIFNicol rHuIFNy rOvIFNx RhuIFNa2b 33.1 60.8 11.6 48.8 RhuIFNpi 33.1 33.1 12.2 33.8 RhuIFNo) 1 60.8 33.1 10.2 54.9 RhuIFNy 11.6 12.2 10.2 10.2 rovIFNx 48.8 33.8 54.9 10.2 The comparison of sequence composition is based on the following references:

Taniguchi et al., Gwe, 1 £ (1): 1 1 (1980) Αάο \ ϊ et al., Biochim. Biophys, acta, 1089 (2): 167 (1991) Streuli et al. 209: 13430980)

Imakawa et al., 330: 377 (1987) Interferon tau (IFNT) (rOvIFNi) of recombinant sheep has 48.8% homology to IFNa2b and 38.8% homology to IFNpl. Due to the limited homology between interferon tail (IFN〇 and interferon-alpha (IFN-a)) and interferon tau (IFN〇 and interferon-beta (IFN-β)), it is impossible to predict whether or not to interfere with the oral route. The response behavior of interferon tau (IFNt) will be the same as interferon-alpha (IFN-α) and interferon-beta (IFN-β). At the same time, interferon tau (IFNt) has been reported to be more effective on human cell type 1 receiving devices. Low receptor binding affinity (Brod, S., J.

Cytokine Res., J_8 .: 84 1 was published in 1999; and Alexenko, A. Temple, J. Interferon and Cytokine Res., J_7_ · 769 issued in 1997). In addition, since interferon tau (IFNt) is actually a non-endogenous human protein, when interferon tan (IFNt) is introduced into the human body, it can lead to the formation of systemic neutralizing antibodies (Brod, S., in * /. / wkr / erc ^ (2 in cyohk acupoints, 11: 841 published in 1999). Interferon tau (These differences between IFN0 and other interferons, which makes interferon tau (IFNt) administered by the human body produce It is difficult to predict the relative positive effects of the treatment and the therapeutic benefits it can provide.

As with other proteins and peptides, the limiting factor in the use of interferon tan (IFN0) is related to biodistribution. When administered by injection, it will be affected by interactions with blood cells and protoplasts. It is more complicated when administered by the oral route. It also needs to consider the proteolytic effect in the stomach. The molecule may be destroyed by the acidic environment before reaching the preset destination. For example, the fragments of protein and polypeptide are generated because of the stomach. With the action of pancreatic enzymes, the exo- and endogenous enzymes are broken at the intestinal mucosa brush border to produce double peptides or triple peptides. If the hydrolysis of pancreatic enzymes can be avoided, the polypeptide will only be brushed by the marginal peptide Enzyme cleavage, polypeptide or protein may survive through the stomach and be metabolized in the small intestine mucosa and there is a barrier to penetration to prevent direct access to the cells. For this reason, many studies have focused on how to use lozenges or solutions in the mouth Maintains a period of time and uses the oropharyngeal area to deliver proteins. Cytochrome's role is between various diseases and cytochrome blood levels and disease occurrence Interrelationship and severity are issues of concern to the medical community. For example, treatment with interleukin-10 (IL-10) has been shown or suggested to be beneficial for the diseases mentioned below. Or other related interleukin-10 (IL-10) and specific Disease or physiological condition. For example: liver fibrosis (Nelson, DR et al., Hepatology, 38 (4): 859-868 (2003); Louis, H.? Acta Gastr. 20053i ^ 3i69

& / g ·, M (l): 7-14 (2003)); pulmonary fibrosis (Aral, T. et al., dm. J. Physiol. Lung. Cell. Mol. Physiol., 278: L914- L922 (2000)); Alzheimer's disease (De Luigi, A. et al ·, Mα /; ······ Dev., 16: 1985-1995 (2001); Remarzue, EJ et al.? Exp. Gerontol. , 36 (1): 171-176 (2001); Town, T. et al. 5 J. Neuroimmunol 132 (1-2): 49-59 (2002)); Stroke (Frenkel, D. et al ·, J Immunol., 171 (12): 6549-6555 (2003)); anti-phospholipid syndrome (Krause, I. et al.? Eur. J. Immunol., 32 (12): 3414-3424 (2002)); Atherosclerosis (Ohashi R. et al., Med. Sc / · Mom '/ ·, 10 (11): RA255-60 (2004); Zimmerman MA, et al. 5 J. Surg. Res., 121 ( 2): 206-13 (2004); Fichtlscherer S. et al.? J, Am, Coll · Cardiol ·, 44 (1): 44-9 (2004); Potteauz S. et al ·, ⑽ckr. Price 〇 / ·, M (8): 1474-8 (2004)); Organ transplant rejection (Zheng HX et al., //. // μ " Z⑽g ⑽ /, 23: 541-6 (2004); Fischer S. et al. J. Thora. Cardiovas. Surg., 126: 1174-80 (2003); Sembeil R. et al. 5 TranspL Immunol., 13 (1): 1-8 (2004)); autism (Jyonouchi, HL et al., J. Neuroimmun., 120: 170-179 (2001)); chronic pulmonary embolism (Takanashi, S. et al. 5 Eur. Respir J., 14: 309-314 (1999)); various autoimmune syndromes, including type 1 diabetes (Slavin AL, et al., Int. Immunol., 13 (6): 825-33 (20010) Zhang ZL ·, et al ·, Acta Pharmacol. Sin "24 (8): 75 1-6 (2003)); arthritis, including rheumatoid arthritis (Tanaka Υ · et al ·, Λα ·, 45 (6 ): 283-8 (1996); Detanico T. et al.? Clin. Exp. Immunol., 20053iS3i6 9c 135⑵: 336-42 (2004); Driessler F. et al.? Clin. Exp. Immunol., 13 5 (1): 64-73 (2004)) '' Cowskin (Asadullah K. et al., Pharmacol. Rev., 55 (2): 241-69 (2003) »Asadullah K. et al., Curr. Drug Targets Inflamm. Allergy., 3 (2): 185-92 (2004)), multiple sclerosis (Soos et al ·, J. ⑽ / ·, 75: 43-50 (1997)); uveitis (Kezuka, T. et al., "/. / Mm 关 (9 /., 173 (2): 1454-1462 (2004), Sun, B. et al.? Exp. Eye Res.,

21: 493-502 (2000)); allergies (Zuany-Amorim, C. et al., Clin. Invest., 95: 2644-2651 (1995), Borish, L. et al., // d // er magic; C / zi / mm㈣〇 /., £ 2: 1288-1296 (1996)); inflammatory bowel disease (Li MC · et al ·, fFor / d J · 10 (5): 620- 5 (2004), Braat H. et al.? Expert Opin. BioL Ther., 1 (5): 725-3 1 (2003)); Optic neuritis (Navikas, V. et al., ScaW. /. Health) ^ (2): 171-178 (1995)) and other diseases. Downstream feedback regulation of interleukin-12 (interleukin-12) reportedly Oral treatment of multiple sclerosis is beneficial (Tuohy, V. w W '/ mm noodles /., ^ 2): 55 (2000)). The association between interferon gamma (ΙρΝ γ) and multiple sclerosis has also been reported in the literature (Moldovan, IR et ^ j] ^ [eur〇immun〇i ^ J_4J_ (l-2): 55 (2000 )) 〇 ~ Although many diseases can either be improved or treated with various methods and ingredients. With many copies, the solution should be safer and more detailed. The solution to this need. From 20053i ^ 9c [Abstract] Interleukin 10 has been found to be associated with a variety of disease states. Accordingly, the present invention provides methods or conditions for improving the response of mammals to Interleukin 10 treatment. The object of the present invention is to provide a method or condition for improving the response of mammals due to the treatment of Interleukin 10, including administering a daily dose of interferon-tan (IFNt) greater than about 5 X 108 units. ) To mammals.

A secondary object of the present invention is to provide a method for improving the autoimmune state of a subject, which comprises adjusting the cytochrome concentration in the subject's serum to reduce the symptoms, prevent the symptoms from worsening, and / or accelerate the relief of the symptoms. It is a further object of the present invention to provide a method for improving viral infection other than hepatitis infection. More specifically, in addition to the hepatitis C virus, the cytochrome concentration in the serum of the subject is adjusted to reduce symptoms, prevent the symptoms from worsening, and / or accelerate the relief of symptoms. It is a further object of the present invention to provide a method for improving cell proliferation in a subject, which includes adjusting the cytochrome concentration in the serum of the subject to reduce symptoms, prevent the symptoms from worsening, and / or accelerate the relief of symptoms. Compared with the baseline serum cytochrome concentration of the patient population module before treatment, when the patient is suffering from or is experiencing a deteriorating disease or condition reflecting the upstream feedback of interleukin 1 0 (IL_10), it provides sufficient interference. -Tau (IFNt) to selectively regulate cytochrome concentration in serum. Another object of the present invention is to provide a method for preparing a pharmaceutical composition for improving the concentration of interleukin 10 (IL-10) in blood. It also selectively lowers the concentration of interleukin 12 (IL-12) in blood in 200533, and the composition of this agent includes oral interferon-tau (IFNt). And the dosage of the medicament should be greater than about 5 X 108 units per day.

It is a further object of the present invention to provide a method for upstream feedback of interleukin 10 (IL-10) concentration in the blood of a human subject, comprising orally administered interferon-tau (IFNt) at a daily dose greater than about 5 X 108 units, which allows subjects to produce an increase in initial interleukin 10 (IL-10) concentration that can be measured relative to subjects who have not received interferon-tan (IFNt). Subjects administered interferon-tan (IFNt) orally for at least several times a week. Subjects individually altered interleukin 10 (IL-10) concentrations until the desired clinical endpoint was reached. It is a new object of the present invention to provide an increased interleukin 10 (IL-10) / interferon-gamma pseudo (IFN-γ) ratio in subjects suffering from autoimmune conditions or viral infections but not hepatitis C virus infections. A method comprising orally administering interferon tan (IFNt) treatment to a subject at a daily dose of greater than about 5 X 108 Units, which causes the subject to produce a receptor relative to those not receiving interferon-tau (IFNt). The tester's measurable initial interleukin 10 (IL-10) concentration increased, and the status was divided into: The concentration of interferon-gamma (IFN-γ) in the blood of the subject relative to the level of unreceived interferon-tau (IFNt) Subjects without substantial changes; or (Π) Subjects' blood levels of interferon-gamma (IFN-γ) decreased relative to subjects who did not receive interferon-tau (IFNt) for several times a week Interferon-tau (IFNt) agents were given regularly, and the interleukin 10 (IL-10) concentration in the blood of the subject was changed individually until the expected clinical endpoint was reached. An object of the present invention is to provide a method for preventing an increase in the concentration of interferon-gamma 20053d ^ 3 > ^ 9 (IFN-γ) in a patient who is at risk of controlling a subject due to an increase in interferon-gamma pseudo (IFN-γ). Among them, the increase of interferon-gamma pseudo (IFN_y) is due to the administration of therapeutic agents or (ii) the occurrence of disease states. Methods include administering oral interferon-tau (IFNt) to a subject at a daily dose of greater than about 5 X 10 units (Units) 'relative to a test that does not receive interferon-tau (IFNt).

It is used to reduce the blood concentration of interferon-gamma (IFN_Y) in the subject. This method is used to increase the concentration of interferon-gamma (IFN-γ) in the body due to the autoimmune status of the subject. Oral administration of interferon-tau (IFNt) during the onset of the disease. The method is also used to treat interferons caused by the treatment of interferon-alpha (IFN-α) and interferon-beta (IPN-β) in subjects. The local (IFN-γ) concentration increased and oral interferon-tau (IFNt) was administered during the onset of symptoms. It is still another object of the present invention to provide a method for increasing the interleukin 10 (IL-10) / interleukin 12 (IL-12) ratio in a subject with autoimmune abnormalities, which comprises administering to the subject oral interferon-tau (IFNt) At a daily dose greater than about 5 X 108 units (Units) to produce a measurable increase in initial interleukin 10 (IL-10) concentration relative to subjects who have not received interferon-tau (IFNt), while allowing interleukin The concentration of 12 (IL-12) decreased, and the interferon-tau (IFNi) agent was regularly administered several times a week, and the interleukin 10 (IL-10) concentration in the blood of the subject was individually changed until the expected clinical endpoint was reached. In an embodiment of the invention, interferon-tau (IFNt) is interferon-tau (IFNt) in sheep or bovine interferon-tau (IFNt). Exemplary sheep interferon-tau (IFNt) sequences are The identification record is, for example, a sequence code SEQ ID NO ·· 2 or a sequence code SEQ ID NO: 3. In other embodiments of the invention, interferon-tau (IFNt) is administered orally to a subject's intestine.

When the subject's autoimmune physiological condition is abnormal, the experimental endpoint in the examples is to alleviate the subject's symptoms. Exemplary autoimmune physiological conditions include multiple sclerosis, type 1 diabetes, rheumatoid arthritis, lupus erythematosus, psoriasis, myasthenia gravis, and Graves' disease ), Hashimoto's thyroiditis, Sjogren's syndrome, Ankylosing spondylitis, and inflammatory bowel disease (IBD). In other embodiments, interferon-tau (IFNt) is administered orally to a subject infected with a virus but does not include a hepatitis C infection. Interferon-tan (IFNt) is administered until a clinical midpoint is reached, such as a decrease in symptoms of viral infection or a decrease in blood virus titration. Viral infections include either a DNA infection or an RNA infection. Exemplary viral infections include, for example, Epstein-Barr Virus, HIV infection, herpes virus infection (EB, CML, and herpes simplex), papilloma, and malignant Stomatitis virus (poxvirus), foot-and-mouth disease virus (picorna virus), adenovirus (adeno virus), rhino virus (hinovirus), HTLVI, HTLVII and human rotavirus (human rotavirus) in other embodiments of the present invention, interfere -Tau (IFNt) is administered orally to a subject with a condition characterized by abnormal cell proliferation. Interferon-tan (IFNt) is administered until a clinical endpoint is reached, such as reducing abnormal symptoms. Exemplary conditions such as: human lung large cell carcinoma, human colon adenocarcinoma, human malignant melanoma, human renal adenocarcinoma , Human acute myeloid leukemia type 3 (human promyelocytic leukemia), human T cell lymphoma, human cutaneous T cell lymphoma, human breast adenocarcinoma , And steroid sensitive tumors (steroid sensitive tumors) °

In other embodiments, the administration of interferon-tan (IFNt) can be taken simultaneously or sequentially with other second therapeutic agents. Exemplary second agents include antiviral agents, anticancer agents, and other diseases suitable for treating autoimmune diseases. On the other hand, the present invention further proposes a method for slowing the progression of multiple sclerosis, which comprises orally administering interferon-tan (IFNt) at a daily dose of greater than about 5 X 108 units (Units), as compared to uninterferon receiving -tau (IFNt) subjects can produce measurable changes in the concentration of interleukin 10 (IL-10) in the blood. Interferon-tan (IFNt) agents are given regularly several times a week, which alone changes the subject's blood Interleukin 10 (IL-10) concentration. In another aspect, the present invention also provides a method for reducing relapse in a patient with multiple sclerosis, which comprises administering to a subject oral interferon-tau (IFNt) at a daily dose greater than about 5 X 108 Units to increase the measurable initial interleukin 10 (IL-10) concentration relative to subjects who did not receive interferon-tan (IFNt), while reducing the interleukin 12 (IL-12) concentration and continuing Interferon-tan (IFNt) agents were regularly administered several times a week, which alone changed the interleukin-10 (IL-10) concentration in the blood of the subjects. In yet another aspect, another object of the present invention is to provide a method for improving the symptoms of psoriasis 20053iS3i69c ', comprising regularly administering orally interferon_tau (IFNt) to a subject to produce a dose relative to unreceived interferon_tau (IFNt). Subject can

The measured interleukin-10 (IL-10) concentration increased. Treatment continues until the symptoms have subsided to the appropriate endpoint for clinical evaluation. The degree of improvement is expected to be at least about 50%, preferably at least about 70%, and more preferably at least about 80%. For example, it is based on the global assessment of physician statistics, which is at least about 70%; and the quantification index, plaque index, and erythema index are reduced by at least about 50%. It is prudent to consider reducing or exacerbating psoriasis in this direction. In a further aspect, another object of the present invention is to provide a method for improving autoimmune conditions, including administering oral interferon-tan (IFNt) to a subject to produce relative The measurable initial interleukin 10 (IL-10) concentration increased in subjects who did not receive interferon-tan (IFNt); when the administration of interferon-tau (IFNt) was stopped, the interleukin 10 ( IL-10) concentration relative to those who do not receive interferon-tan (IFNt) will continue to be administered when the interferon-tau (IFNI) agent is given. The purpose and features of the present invention will be described in detail with the legend below, but it is not To limit the present invention, without departing from the spirit and scope of the present invention, some modifications and retouching can be made. Therefore, the protection scope of the present invention shall be determined by the scope of the attached patent application. [Embodiment] Details of the present invention I. Definition Interferon tau is referred to as IFNt or interferon-τ, including any interference 20053i3zS | 69c

Protein has at least one of the following two sets of properties: (i) (a) anti-lutein disintegration (b) antiviral (c) anti-cell proliferation; and (ii) about 45-68% amino acids and interferon-alpha (IFNa) homology, and more than 70% of the amino acids are homologous to known IFNt (for example: Ott et al., J. Interferon Res., 1 1: 357, 1991; Helmer et al., J. Reprod Fert. , 79: 83 in 1987; Imakawa et al. In Mol. Endocrinol, 3: 127 in 1989; Whaley et al. In J. Biol. Chem, 269: 10846 in 1994; Bazer et al. WO 94 (/ 10313 published in 1994). Amino acid homology can be identified using, for example, the LALIGN program and debugging parameters. The program is in FASTA version 1.7 sequence alignment program (Pearson and Lipman, PNAS, 85: 2444 published in 1988; Pearson in Methods in Enzymology, 183: 63 published in 1990; the program can be used from William R. Parson is in the Department of Biochemistry, Box 440, Jordan Hall, Charlottesville, VA. IFNt sequences have been parsed in different back dances, including but not limited to cows (Bovine sp "Helmer SD, in J. Reprod. Fert ·, 79:83 published in 1987; Imakawa, K ·, Mol, Endocrinol ·, 119: 532 published in 1987), sheep (Ovine sp ·), sweet cattle (Ovibos sp ·), giraffe (Giraffa .sp, Gene Bank Accession No. U55050), Horse (Equus caballus), Zebra (Equus Burchelli, Gene Bank Accession No .: NC005027), Hippo (Hippopotamus sp.), Elephant (Loxodota sp.), Americas Horse (Llama glama), goat (Capra sp., Gene bank registration numbers Nos: AY357336, AY357335, AY347334, AY357333, AY3 57332, AY35733, AY357330, AY357329, AY357328, 17 20053S3i6 9〇AY357327) Deer (Cervidae sp.). Interferon tau (IFNt) nucleotide sequences of many species can be compared in published databases or literature (eg, Roberts, RM ·, et al., I Interferone and Cytokine Res., 18 : 805 published in 1998; Leaman D.W. et al. In I Interferone Res ·, 12: 1 in 1993; Ryan, A · M · et al. In Anim. Genet., 34: 9 Res., 12: 1 published in 1996). Interferon tau includes all anti-invasion species of various animal interferon tau (IFNt) proteins, such as the aforementioned animal species, and at least one of the aforementioned two sets of characteristics.

Sheep's interferon tau (IFN〇 was confirmed to be related to a protein containing the amino acid sequence SEQ ID NO: 2 and the amino acid of the protein was replaced with a neutral amino acid without affecting its activity, such as interferon tau (IFN The protein was identified as SEQ ID NO: 3. More often, a sheep's interferon tau (IFNt) protein has as much as 80% or even 90% of the systemic homology to the confirmed sequence SEQ ID NO: 2. Treating a condition is by administering an effective therapeutic substance to reduce the condition and / or reduce the severity. For oral drugs, the route of administration involves direct contact from the mouth to the stomach or small intestine; including direct administration of the stomach. Gut-related digestive tract The part extends from the lower opening of the stomach to the anus; the composition includes the small intestine (duodenum, jejunum, ileum) and large intestine (ascending, transverse, descending, sigmoid, rectum). "Measureable blood interleukin 10 (IL-10) `` Concentration '' reflects a statistically significant increase in the concentration of interleukin 10 (IL-10) in blood (serum and / or blood cells) relative to the measurement of the same condition before treatment, an increase of at least 20% 200533 ^ a The best condition is to produce a 25% increase. The method for measuring the blood concentration of interleukin 10 (IL-10) is to use a commercial enzyme-linked immunosorbent assay (ELISA). The fold increase is determined at individual time points. Divide by screening 値 or benchmark 値. The percentage increase is determined to find the difference between the individual time point and screening 値 or benchmark 値, then divide by screening 以 or benchmark 値, and then multiply by 100.

The π measurable amount of interleukin 12 (IL-12) reflects a statistically significant increase in the concentration of interleukin 12 (IL-10) in blood (serum and / or blood cells) relative to the measurement of the same condition before treatment At least 20% increase, and a better condition is to produce a 25% increase. The method for measuring the blood concentration of interleukin I2 (IL-12) is to use a commercial enzyme-linked immunosorbent assay (ELISA). Determine the fold increase Is the individual time point 値 divided by the screening 値 or benchmark 値. The increase in the percentage is determined to find the difference between the individual time point and the screening 値 or benchmark 値, and then divided by the screening 値 or benchmark 値, and then multiplied Take 100. "Measureable amount of interferon-gamma (IFN-γ) in blood" or "non-substantial decrease in amount of interferon-gamma (IFN-γ) in blood" reflects no statistically significant The concentration of interferon-gamma (IFN-γ) in blood changes. The method for measuring the concentration of interferon-gamma (IFN-γ) in blood is to use a commercial enzyme-node immunosorbent assay (ELISA). Daily doses greater than 5 X 108 units ”are sufficient to provide sufficient interferon tau (IFN〇 to provide The antiviral activity of protein in 5 X 108 antiviral units (such as ...), where the antiviral activity of interferon tau (IFNt) is measured using a standard cytopathic inhibition test as described in subsequent sections. 鲛 Appropriate 19 20053δ3 69 Protein mass (eg milligrams) to provide daily doses greater than 5 x 10 08 units (Units) and vary depending on the antiviral activity of the specific protein. II. IFNt composition and treatment methods A. Interferon τ First identified IFNt is sheep's IFNt, an 18-19kDa protein. Various isoforms were found in the homogenate of the embryo body (embryo and its surrounding envelope) (Martal, J. et al. In J. Feri // ·· , 5_6_:

63-73 published in 1979). Subsequently, it was found that a low molecular weight protein was released into the embryo body medium, and after purification, it showed heat resistance and sensitivity to proteases (Godkin, JD et al., J. Fer " ···, 65: 141-150, published in 1982) . Interferon-tau (iFNt) was originally called ovine germ layer protein 1 (o-TP-1), which is the key period of sheep's maternal identification, and the main secreted protein in the outer layer of germ layer of sheep embryo. Subsequent research has determined that interferon-tau (IPNτ) is a pregnancy recognition hormone that establishes the physiological response of pregnancy in ruminants such as sheep and cows. (Bazer, FW, and Johnson. Η.Μ. et al. rod. / wm㈣〇 / ·, Cong: 19-22 published in 1991). An interferon-tau (IFNt) cDNA was found in the sheep's embryo sac gene library. A synthetic oligonucleotide representing an N-terminal amino acid sequence (Imakawa et al., 1987) has a predicted amino acid The sequence, 45-55% homologous to human, mouse, rat and pig interferon-alpha (IFN_a) and 70% homologous to bovine interferon-alpha (IFN--all), was named IFN-Ω. Several cDNA sequences have also been reported to represent non-serving isomers (Stewart, HJ et al., Mo /. Xinru cr / ⑽ /., B 65, 1989; Klemann, SW, et al. A ^ c · Dc / A · 7 ?, J_8: 6724 20 200533¾ ^ ¾ published in 1990; and Charlier, M. et al. In Mo / · CW / · 5/7 and ~ 0 /., 21: 161-171 (Published in 1989). All sequences are approximately 11 ^ in size with an open reading frame of 585 bp, and this frame encodes a leader sequence with 23 amino acids and a mature protein with 172 amino acids. The predicted structure of interferon-tan (ΚΝτ) is a four-stranded helix that combines the amino and carboxyl ends side by side, which further supports its classification as a type 1 interferon (IFN) (Jarpe, M · A · et al. In Pro such as > 2 · ⑺ · π ·, 2: 863-867 published in 1994). Describe interferon type 1 type 1 type 2 type α & ω β τ γ production source leukocyte fibroblasts germ layer lymphocytes antiviral + + + + antiproliferative + + + + pregnancy message — — + —

Although interferon-tan (IFNt) exhibits some activities related to traditional type 1 interferon (IFNs) (see table above for details), interferon-tau (IFNi :) and other type 1 interferons are also quite different The place. The biggest difference is the role of interferon-tan (IFNt) in pregnant ruminants. Other interferons have no similar function in pregnancy recognition. It is also different for virus induction. All type 1 interferons, except for interferon-tan (IFNt), are easily induced by viruses and dsRNA (published in 1992 by Roberts et al. In jEWocr / Science and Development, 432). The induction of interferon-alpha (IFN-α) and interferon-beta (IPN-β) is transient and lasts only about a few hours. In contrast, once induced, the resulting synthesis of interferon-tau (IFNt) can last for several days (published by Godkin et al., 1982 20053 & 369c). On a single-cell basis, relative to the production of other interferons, interferon-tau (IFNt) can produce more than three hundred times the amount (as defined by Cross JC and Roberts R. M. et al. 3817-3821 in (Published in 1991).

Other differences may exist in the regulatory site of the interferon-tau (IFNt) gene. For example, transfection of human trophoblast cell lines with human IFNt gene in cattle will produce antiviral properties, but transfection of cattle with IFN-Ω gene will not produce antiviral properties. This suggests that interferon-tau (IFNt) gene expression involves a unique switching factor. Consistent with this observation, the proximal promoter region of interferon-tau (IFNt) (from position 126 to the start of transcription), interferon-alpha (IFN-α), and interferon-beta (IFN-β) is highly homogeneous in the same region; the region from positions 126 to 450 is not homogeneous with the same regions of interferon-alpha (IFN-α) and interferon-beta (IFN-β) And only enhance the expression of interferon-tau (IFNt) (Cross, JC and Roberts, R.M., published in # 1991 / .dc to · Sc / · t / U 2M: 3817-3821 ). Therefore, compared to other types of IFNs, the expression of IFNt involves different regulators. The 172 amino acid sequences of sheep IFNt were proposed and applied for in US Patent No. 5,958,402, and the homologous bovine IFNt sequence was published in Helmer et al. In J. fvm, 83-91 in 1987 and 111 ^ 1 ^ \ ¥ & 1 <: et al in the literature from 〇 /. 心 ^ (9 6 ^ / 7〇 /., 1,127 in 1989. The interferon-tau (IFNt) sequence of sheep and The bovine interferon-tan (IFNt) sequence is incorporated herein for reference. The sheep interferon-tau (IFNt) amino acid sequence is represented by SEQ ID NO: 2. 22 200532¾ ^ 1. Isolation of interferon- tau (IFNt) interferon-tan (IFNt) can be collected from pregnant sheep embryos and then cultured in test tubes in an adjusted basal medium, as Godkin, L D. et al. in "Fer " / •, pull : 141-150, published in 1982 with Vallet, JL, et al. Valence 0 / · 11: 1307, published in 1987. Stem

Interferon-tan (IFNt) can be used to purify embryo cultures by ion exchange chromatography and colloidal filtration. Homogeneity of isolated interferon-tau (IFNt) can be assessed using sodium lauryl sulfate polyacrylamide gel electrophoresis (Maniatis, T. et al. In MOLECULAR COLONING: a LABORATORY MANUAL, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 1982; and Ausubel, F. M., et al. In CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wieley & Son Press Media, PA 1988), and the protein concentration of the purified IFNt sample can use BCA (bicibchoninic Assay) Inspection decisions (Pierce Chemical Company, Rockford, IL; and Smith, PK, et al., Published in Anal. Biochem. 150: 76, 1985). 2. Genetic recombination produces interferon-tau (IFNt). Genetic recombination of interferon-tan (IFNt) proteins can be produced using any interferon-tau (IFNt) polynucleotide fragment and using a suitable expression system such as bacteria Or yeast. A method for isolating interferon-tau (IFNt) nucleotides and peptide sequences is published in PCT Publication No. WO / 94/10313, which is incorporated herein by reference. To create a vector for the expression of interferon-tan (IFNt), the interferon-tau (IFNt) coding sequence 比如 (J (for example, SEQ ID NOS: 1 or 4)) is placed in an expression set 20053ι23 ^ 90. For example, a bacterial expression vector is expressed in accordance with standard methods. Examples of suitable vectors include lambda gtll (Promega, Madison WI), pGEX (Smith, P.K. et al. 150: 76 published in 1985), pGEMEX (Promega) and pBS (Strategen, LA Jolla CA) and other vectors. Other bacterial expression vectors include suitable promoters, such as the T7 RNA polymerase promoter and the tac promoter can also be used. The materials and methods described in this case Interferon-tau (IFNt) synthesizes a polynucleotide to an adjusted piN III omp-A expression vector.

As described herein, the IFNt coding sequence presented in SEQ ID NO: 4 is selected into a vector, and is suitable for transforming yeast cells, including a methanol-regulated alcohol oxidase promoter and a Phol signal sequence. . Vectors Transgenic yeast host cells and transfected cells were used to express proteins according to the manufacturer's instructions (Invetrogen, San Diego, CA). Other yeast vectors suitable for expressing interferon-tau (IFNt) in conjunction with the method of the present invention include 2 micron plastid vectors (published by Ludwig. LP et al. At m: 33 in 1933), enzyme-integrated plastids (Shaw, KL See D, 4, published in 2: 117 in 1988), YEP vectors (Shen, LP et al. 5W. 21: 856 in 1986), yeast mitochondria (YCps), and other regulators Performance vectors (see Hitzeman, RA et al., U.S. Patent No. 4,775,622, approved on October 4, 1988; Rutter, W. J. et al., U.S. Patent No. 4,769,238, approved on September 6, 1988; Oeda, K et al., U.S. Patent No. 4,766,068, issued August 23, 1988). Preferred vectors include an expression cassette containing a potent yeast promoter, such as the MFal promoter 24 2005333 ^ 6flc

(Bayne ·, M · L. Et al. In Gene .. 235-2 «published in / 9⑽ Mou), glycerol awakening a 3-phosphate dehydrogenase (GADPH) promoter (Wu, DA et al. In DNA , 10; 201 published in 1991) or galactose-induced GAL 10 promoter (Ludwig. L.P. et al., Gene, 132: 33, 1993; Feher, Z., et al., Curr. Genet ·, J_6: 461 published in 1989; Shen, LP · et al. 5W · 67 &, M: 856 published in 1986). The yeast transformant is mainly a traditional beer brewer cerevisiae 5 but as mentioned above, other yeasts suitable for transfection can also be used (such as fission yeast yeast and the like). Furthermore, DNA encoding one of the interferon-tau (IFNt) peptides can be cloned into any commercially available vector to produce a peptide expression on a suitable host system. These systems include the bacterial and yeast expression systems described above, but also include the expression systems described below: Baculovirus Expression System (Remy, P.R. et al., BACULOVIRUS EXPRESSION VECTORS: A LABORATORY MANUAL, 1992; Beames Et al., Published in biotechniques, 1: 378 in 1991; Clontech, Palo Alto CA), plant cell expression system, transgenic plant expression system and mammalian cell expression system (Clontech, Palo Alto CA; Gibco-BRL, Gaithersburge MD). Recombinant peptides can be expressed as nuclear fusion proteins or native (original) proteins. Genetic engineering can be used to design features into expression vectors, such as leader sequences that promote the secretion of expression sequences in the culture medium. Polypeptides produced by genetic recombination are mostly isolated from hydrolyzed cells or culture media. Methods of purification can be known, including salting out, ion exchange 25 200532 secret delta chromatography, affinity chromatography. It is also possible to use immunoaffinity chromatography as described above, and use antibodies produced by interferon-tau (IFNt). In addition to genetic recombination methods, IFNt proteins or peptides can be separated from selected cells by affinity-related methods, such as using IFNt peptides to produce appropriate antibodies. Furthermore, the interferon-tau (IFNt) polypeptide (such as SEQ ID NO: 2 or 3) can be chemically synthesized using conventional techniques. B. administration of interferon tau (IFNi :)

In support of the investigations performed in the present invention, interferon tan (IFN0) was administered to patients who responded to treatment with interleukin-10. Particularly in a study, treatment with interferon tau (IFNt) was diagnosed as multiple Patients with sclerosis. In another study, patients diagnosed with a viral infection were treated with interferon tau (IFNt). During the treatment period, 'monitoring of each patient's serum interleukin-10 (IL-10), interferon tan (IFNt), and interleukin (IL-12) concentrations. These studies are detailed below. 1. Administration of 1E interferon tau (IFNt) to patients with multiple sclerosis. Patients with multiple sclerosis receive income from interferon. Clinical trial of tau (IFNt) treatment. As described in Example 1, fifteen patients were randomized into three study groups and summarized in Table 1. 26 20053iS3t69c Table group I _ (n = 5) group π ( π = 5) group π (n = 5) interferon tau (IFN〇 oral dose 1 0.2 mg / mg / day (2 x 107 U) 0.6 mg / day (mg / day) (6 x 107 U ) 1.8 mg / day (1.8 x 108 U) Average weight 67.2 kg (kg) 58.9 kg (kg) 90.0 kg (kg) Average age 30 34.5 47 4 mg interferon tau (IFN〇 = 1 x 108 Units)

Before treatment, a blood sample was taken from each subject to measure the cytokine concentration in the basic serum. On the first day after blood drawing, each subject began to receive an appropriate dose of oral interferon tau (IFN0) treatment. The treatment lasted 28 days and blood was collected on the first 1, 4, 8, 15, 29, and 57 days of investigation Blood samples were analyzed for interferon-gamma (IFN-γ) and interleukin 10 (IL-10) concentrations. Patient groups I, II, and interleukin 10 (IL-10) concentrations were shown in Figure 1A. -1C. Figure 1A shows the concentration of serum interleukin 10 (IL-10) in pm / mL. Five patients were included in group I. Three patients were numbered 103, 104, and 105. The concentration of interleukin 10 (IL-10) increased on the day. However, the concentration of interleukin 10 (IL-10) was found to decrease on the eighth day. It was also found that from the fourth day, the interleukins of patients 103 and 104 The concentration of 10 (IL-10) did not change significantly on the eighth and fifteenth days. Figures 1B and 1C show the relative results of patient group II and group III. It was found that the concentration of serum interleukin 10 (IL_10) was between Patients slightly increased after administration of interferon tau (IFNt) ', especially those included in group III. 27 2005333 ^

Figure ID shows the mean serum concentration of interleukin 10 (IL-10). Results are shown in groups I, II, and III in Pg / mL. During the treatment with interferon tau (IFNt), there was a slight upstream feedback of interleukin 10 (IL-10) concentration in the test group on days 2 to 28. However, a statistical analysis of Example 1 found that a slight upstream feedback Interleukin 10 (IL-10) concentration is not statistically significant. After stopping the administration of interferon tau (IFNt) on day 28, a slight rise in blood interleukin-10 (IL-10) concentrations continued to be observed in groups I and II. The serum concentration of interleukin-10 (IL-10) remained above the baseline level on day 57 or 34 days after discontinuation. The present invention is expected to treat the subject's autoimmune condition. Interferon tau (IFNi) treatment is administered in sufficient amounts to produce an initial interleukin 10 (IL- 10) Increased concentration. After interferon tau (IFNT) treatment is stopped for a period of time, compared to subjects who have not received treatment with interferon tau (IFNt), the blood's interleukin 10 (IL-10) Concentrations continue to increase. So it is necessary to confirm that the administration of interferon tau (IFNt) is necessary. The concentration of interferon-gamma pseudo (IFN-γ) in blood was also monitored during the study. Interferon-gamma pseudo (IFN-γ) γ) is an inflammatory cytochrome's rising interferon-gamma (IFN-γ) concentration also reflects patients' autoimmune conditions such as multiple sclerosis and arthritis. Interferon-beta (IPN_β ) In the treatment of multiple sclerosis, there have been studies showing an increase in interferon-gamma pseudo (IFN-γ) secreting cells during the first two months of the treatment period, and increased serum levels of interferon-gamma (IFN-γ) may be Because the patient experienced during interferon-beta (IFN-β) treatment Obviously similar to a cold condition. So treating patients with autologous conditions 28 20053 ^ ft〇 Immune status When the concentration of interleukin 10 (IL-10) rises, it is more beneficial to patients if there is no accompanying increase in interferon-gamma (IFN-γ).

Figures 2A-2D show the concentration of interferon-gamma (IFN-γ) in pg / mL. Patient groups I, II, and III suffer from multiple sclerosis and are administered oral interferon tail (IFNt). Figure 2A shows the serum concentration of patient group I treated with 0.2 mg of interferon tau (IFN0. Interferon-gamma pseudo- (IFN-γ) of each of patient numbers 101, 102, 104, 105 during treatment. ) Blood levels were all decreased. The increase in serum concentration was discontinued when treatment was stopped on the 28th day. The serum interferon-gamma (IFN-γ) concentration of patient number 103 did not increase and remained essentially unchanged Figure 2B shows the interferon-gamma (IFN-γ) concentration in the blood of patient group II, in pg / mL, 0.6 mg of interferon tau per day (IFNO treatment. Figure 2C shows the patient group II. Interferon-gamma (IFN-γ) concentration in blood, in pg / mL, treated with 1.8 mg of interferon tau (IFNt) per day. As mentioned earlier, the first dose of interferon tau (IFNt) It is given on the first day after the blood is taken without medication, and the final dose is given on the twenty-eighth day. Therefore, the data points on the first day can be regarded as the basis for the screening of patients. After receiving interferon-gamma bureau (IFN_Y ) During treatment, all patients in group 11 and group 111 experienced interferon-gamma IFN-γ) decreased serum concentrations or insignificant changes in interferon-gamma pseudo (IFN-Y). Figure 2D summarizes the average concentration of interferon-gamma (IFN_Y) in blood in units of Pg / mL. Groups 1, 11, and 111. The trend for reduced interferon-gamma (IFN-γ) is particularly pronounced in group III, which receives high doses of interferon-tau (IFNt). 29 200533fcSi69c

Figures 3A-3E show the serum concentrations of interleukin 10 (IL-10) (diamond graphics) and interferon-tau (IFNt) (square), both in pg / mL, and the individual patient is selected from the group I, Π , And III. Fig. 3A shows the kinetics of cytochrome production by group I of patient number 101 in the treatment group. There was no statistically significant increase in interleukin 10 (IL-10) (diamond pattern) in blood during treatment. Interferon-gamma (IFN-γ) blood levels decreased during oral interferon-tan (IFNt) administration. ◦ Interleukin 10 (IL-10) concentration benchmark 値 and interferon-gamma (IFN-γ) The concentration benchmarks were 15.8 pg / mL and 14.5 Pg / mL, respectively, and the initial interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration ratio was 1.1. During interferon-tan (IFNt) treatment, the interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration ratio increased to 2.2 because of interferon-gamma (IFN-γ) blood The concentration decreases. On day 57, approximately one month after the termination of administration, the interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration ratio) returned to 1.1. During interferon-tau (IFNt) treatment, the interleukin 10 (IL-10) / interferon-gamma pseudo (IFN-γ) concentration increased by about 100% over radon. FIG. 3B shows the cytochrome production kinetics of group I patient No. 105 in the treatment group. Interleukin 10 (IL-10) concentration reference and interferon-gamma (IFN-γ) concentration reference average 6.6 pg / mL and 49.2 pg / mL, respectively, and the initial interleukin 10 (IL-10) / interferon- The gamma (IFN-γ) concentration ratio 値 was 0.13. During oral interferon-tau (IFNt) administration, the interleukin 10 (IL-10) / interferon-gamma pseudo (IFN-γ) concentration ratio was reduced to about 0.2-0.3, because interferon-gamma (IFN- γ) The blood concentration decreases. On the 57th day, approximately one month after discontinuation of the administration, the interleukin 10 (IL-10) / dry 30 20053i3z3 > i & 9) c interferon-gamma (IFN-γ) concentration ratio returned to 0. 12. Therefore, interferon-tau (IFNt) treatment is effective for adjusting the concentration of interleukin 10 (IL-10) / interferon-gamma (IFN-γ), and the increase is more than 50%, and the better condition is more than 80%. Variety.

FIG. 3C shows the cytochrome production kinetics of group III patient number 302 in the treatment group. Interleukin 10 (IL-10) concentration reference and interferon-gamma (IFN-γ) concentration reference (data obtained on screen day and the first day and averaged) were 5.8 pg / mL and 4.0 pg / mL, respectively The initial interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration ratio 値 is 1.45. During interferon-tan (IFNt) treatment, the mean interleukin 10 (IL-10) blood concentration (mean interleukin 10 (IL-10) blood concentration was obtained on days 4, 8, and 15) was 7.7 pg / mL, compared with the baseline blood concentration of interleukin 10 (IL-10) (data obtained and averaged on the screening day and the first day), there is no statistical difference. Interferon-gamma (IFN-γ) concentrations remained constant during treatment. Figure 3D shows the cytochrome production kinetics of group III patient No. 303 in the treatment group. Interleukin 10 (IL-10) concentration baseline and interferon-gamma (IFN-γ) concentration baseline (data obtained on average and averaged on the day of screening) are 4.4 pg / mL and 3.6 pg / mL, respectively. And the initial interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration ratio 値 was 1.2. During oral interferon-tan (IFNt) administration, the interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration ratio decreased to approximately 11 on day eight because interferon-gamma ( The blood concentration of IFN-γ) decreased; it did not return to baseline 値 until day 29. Figure 3E shows the cytochrome production kinetics of group I patient number 305 in the treatment group. Interleukin 10 (IL-10) concentration benchmark, and interferon-gamma bureau 20053 3569) c (IFN-γ) concentration benchmark, average (data obtained on screen day and first day and averaged) were 4.3 pg / mL And 34.8 pg / mL, and the initial interleukin 10 (IL-10) / interferon-gamma (IFN-y) concentration ratio was 11. During the administration of oral interferon-tan (IFNt), the interleukin 10 (tljo) blood concentration remained substantially unchanged. Due to a slight decrease in the blood concentration of interferon-gamma pseudo (IFN_y), the interleukin 10 (IL-10) / interferon-gamma pseudo (IFN-Y) concentration ratio 値 increased by 14% on the eighth day to 0.14.

So 'in a way, the method of increasing the interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration ratio in subjects with autoimmune disorders or viral infections, including administering effective A dose of oral interferon-tau (IFNt) to produce an initially measurable blood concentration of interleukin 10 (IL-10) relative to a subject who has not been administered oral interferon-tan (IFNt). There were no significant changes in interferon-gamma (IFN- [gamma]) blood concentrations in subjects who were not administered oral interferon-tan (IFNt). Or (ii) a decrease in interferon-gamma (IFN-γ) blood levels in subjects administered interferon-tau (IFNt) relative to subjects not administered oral interferon-tan (IFNt) . Interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration increased by at least about 10% compared to 値, more suitable condition is about 25%, and better condition is about 40%, until the best condition is about 50% . In one embodiment, the interferon-tau (IFNt) is sheep or bovine interferon-tau (IFNt). In other embodiments, the interferon-tau (IFNt) is administered at a dose greater than about 5 X 108 antiviral unit (U), preferably at a dose of 0.5 X 109 U or more until better Dose 1 X 109 U or more. 2. Administration to human subjects infected with the virus 20053 ^ 9〇

Another study was to screen patients infected with hepatitis C virus. Patients were divided into four groups and treated with oral interferon-tau (IFNt) (sequence code SEq id NO ·· 3). As described in Example 2, the subjects in the experimental group self-treated with a fixed amount of a 1 mg / mL interferon-tau (IFNt) solution three times daily. Experimental groups I, II, and III were administered at a total dose of 1 milligram (mg) of interferon-tau (IFNt), 3 milligrams (mg) of interferon-tan (IFNt), or 9 milligrams (mg) of interferon-tan ( IFNt), (1 milligram (mg) interferon tau (iFNT) is approximately 1 x 108 antiviral units). The treatment period was up to 84 days. Patients returned to the clinic periodically and provided a blood test to analyze interleukin 10 (IL-10) and interferon-gamma (IFN-γ) concentrations. Monitoring continued for 169 days, that is, 85 days after the administration of interferon-tau (IFNx) was stopped. Figures 4A-4C show the serum concentrations of interleukin 10 (IL-10) in pg / mL. Six patients were divided into three study groups ρ Π, and ΙΠ. Figure 4A shows the serum concentrations of interleukin 10 (IL_10) in six patients in group I. Interferon-tau (IFNi)-0.33 milligrams (mg) three times a day. U). Data from all patients showed, but were not statistically significant, an increase in interleukin-10 (IL-10) concentrations. FIG. 4B shows six patients in the study group II who were administered 1 mg of interferon-tau (IFNt) (3 X 108 U / day) three times daily until day 84. During the treatment period, patient data showed a clearer but not statistically significant increase in the concentration of interleukin 10 (IL-10) (Days 1-84). After stopping the administration of interferon-tau (IFNt), the serum concentration of interleukin 10 (IL-10) was continuously monitored, and from day 85-169, it gradually returned to the baseline level. Figure 4C shows the serum concentrations of interleukin 10 (IL-10) 33 200533396Soc in six patients in group III, 3 milligrams (mg) of interferon-tan (IFNt) three times daily (9 x 108 U / day) Continue to give until the 84th day. During treatment, all patient data showed statistically significant concentrations of interleukin 10 (IL-10) due to the increase in the administration of interferon-tau (IFNt). After stopping the administration of interferon-tan (IFNt), the serum concentration of interleukin 10 (IL-10) remained at an elevated state for about three months.

Fig. 4D conclusion chart compares the results of serum concentrations of interleukin 10 (IL-10) in experimental groups I, II, and III in Figs. 4A-4C. Figure 4D shows the percentage increase in serum concentration of interleukin 10 (IL-10) over time in the experimental group I (diamond pattern, 0.33 milligrams (mg) three times a day), and group II (square, three times a day 1) Milligrams (mg)), and group III (triangle, 3 milligrams (mg) three times a day). Plot the percentage increase in serum concentration of interleukin 10 (IL-10) against dose. The highest dose is 9 milligrams (mg) (0.33 milligrams (mg) per day; (9 X 108 units (U) / day) triggers interleukin. (IL-10) produces greater than 100% upstream feedback within I5 days. Daily doses of 3 milligrams (mg) (Research Group II, square) stimulate Interleukin 10 (IL-10) within 15 days Generated greater than 150% upstream feedback. During the 84-day study period, a daily dose of 3 milligrams (mg) was sufficient to maintain an increase of more than 150%. Figure 4D also shows the relative to the 85-169 days after discontinuation The pre-treatment condition showed a continuously rising concentration of interleukin 10 (IL-10). On day 169, experimental group III (interferon IFN (IFNt) at a daily dose of 3 milligrams (mg)) Interleukin 10 (IL-10) concentration did not fall back to baseline. Therefore, the treatment of physiological conditions of autoimmune abnormalities, especially multiple sclerosis, psoriasis, rheumatoid arthritis and allergies. 34 20053 ^ ¾ Relative to subjects not administered with interferon-tau (IFNt), a sufficient amount of interferon-tau (ΙΡΝτ) is administered to produce an initially measurable amount Increased blood levels of interleukin 10 (IL-10); discontinue administration of interferon-tan (IFNt) —

After a period of time, relative to subjects who have not been administered interferon-tau (IFNt), the blood concentration of interleukin 10 (IL-10) remains elevated; treatment can be resumed when needed, such as when symptoms worsen . A sufficient amount of interferon-tau (IFNt) to produce an initially measurable increase in the concentration of interleukin 10 (IL-10) means greater than about 5 X 108 units (U) per day, preferably 0.5 X 109 Units (U) / day or more, preferably 1 X 109 units (U) / day or more. Stopping the administration of interferon-tan (IFNt) may change during the course of the disease, but it is actually based on the disease status of the subject in the study. By monitoring the period of treatment with interferon-tau (IFNt) and stopping the interferon -Results of interleukin 10 (IL-10) blood concentration during tau (IFNt) administration. The results of the study can be applied to the general patient to provide a dose recommendation model. In addition, during the treatment of interferon-tau (IFNt), individual disease conditions can be tracked by regularly monitoring the concentration of interleukin 10 (IL-10) during the treatment period, such as weekly or twice a week during non-treatment period, or according to the subjective awareness of patients The recognition of symptoms determines when treatment needs to be resumed. Treatment response is when the blood level of interleukin 10 (IL-10) in a particular patient approaches the pre-treatment concentration, or the symptoms of a certain type of patient, or a particular patient being treated, worsen. Figures 5A-5C show the interferon-gamma (IFN-γ) concentration ' in the patients participating in the study in pg / mL. Figure 5A shows the interferon-gamma (IFN-γ) concentration of six patients receiving Interferon-tau (IFNt)-0.33 milligrams (mg) three times a day in experimental group I. The interferon-gamma (IFN-γ) concentration tended to remain at the baseline level, and the tendency for the interferon-gamma pseudo (IFN-γ) concentration to decrease slightly was quite obvious. FIG. 5B shows the interferon-gamma (IFN-γ) serum concentrations of six patients receiving Interferon-tan (IFNt) 1 mg three times a day in experimental group II. The decrease in interferon-gamma (IFN-γ) concentration is apparent in early treatment, i.e., about 3 to 15 days. Concentration returned to baseline and was maintained at the pre-dose concentration during subsequent treatments.

FIG. 5C shows interferon-gamma (IFN-γ) serum concentrations of six patients who received interferon-tau (IFNt) 3 mg / mg three times in experimental group III. Some patients experienced a definite decrease in interferon-gamma (IFN-γ) concentrations, and the overall treatment population showed some changes during the experiment. From day 85 to 169, an increase in interferon-gamma (IFN-γ) concentration was observed after discontinuation. It has been shown that interferon-tau (IFNt) affects the decrease in concentration to some extent. Fig. 5D is a conclusion chart comparing the results of interferon-gamma (IFN-γ) serum concentrations in experimental groups I, II, and III in Figs. 5A-5C. The interferon in experimental group I is plotted over time. -Gamma Bureau (IFN-γ) serum concentration average 値 (diamond pattern, 0.33 milligrams (mg) three times a day), group II (round, 1 milligram (mg) three times a day), and group III (triangle, 3 milligrams (mg) three times daily). It is clear that the administration of interferon-tau (IFNt) (1) produces insignificant changes in blood concentration of interferon-gamma (IFN-γ), which is maintained at the baseline level at the time of screening or the concentration before administration 'or (2) Cause the blood concentration of interferon-gamma pseudo (IFN-γ) to decrease from the standard radon or pre-dose concentration. 36 20053S3 seriesa

Therefore, from another point of view, methods for reducing the concentration of interferon-gamma (IFN-γ) in the blood of a subject include: administering an effective dose of IFN-γ to a subject not receiving oral interferon-tau (IFNt). Interferon-gamma (IFN-γ) is administered to the subject to reduce the concentration of interferon-gamma pseudo (IFN_Y). This method is particularly useful for patients who have an increase in interferon-gamma (IFN-γ) or have diseases that can increase the level of interferon-gamma (IFN-γ). So 'think about how to prevent a patient at risk of rising interferon-gamma (IFN-γ) from interfering with the interferon-gamma (IFN-γ) in his blood by administering a therapeutic agent or (Π) having a disease Condition, but the subject is administered an effective dose of interferon-tau (IFNt) to reduce the amount of interferon-gamma (IFN-y) in the blood relative to the subject without interferon-tau (IFNt) concentration. As previously noted, the treatment of multiple sclerosis with interferon-beta (IFN-β) can cause patients to have increased interferon-gamma (IFN-γ) concentrations. Co-administration (simultaneous or sequential) of interferon-tau (IFNt) helps to maintain the concentration of interferon-gamma (IFN-γ) before treatment. Traditionally, a sufficient amount of interferon-tan (IFNx) can cause the subject's interferon-gamma pseudo (IFN-γ) blood and liquid production to decline by more than about 5 X 108 units (U) per day, compared with It is preferably 0.5 χ units (U) per day or more, and even more preferably 1 x 109 units (U) per day or more. Figures 6A-6F show the serum concentrations of interleukin 10 (IL-10) (diamond type) and interferon-gamma pseudo (IFN-γ) (square) in pg / mL. The patient is selected from treatment groups I, II, and III corresponds to Figure 4-5 for discussion. FIG. 6A shows the serum concentrations of interleukin i 0 (diamond pattern) and interferon-tau (IFNt) (square) in patient 101 of treatment group I, receiving interferon-tau (IFNt) —0.3 3 mg three times a day (Mg) Daily dose ^ 37 200533ά6τ9 > Milligram (mg). Interleukin 10 (IL-10) concentration benchmark and interferon-gamma (IFN-γ) concentration benchmark (data obtained on screening day and the first day And averaged) were 5.2 pg / mL and 3.9 pg / mL, respectively, and the initial interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration ratio was 1.3. Interferon-tau (IFNt) treatment During this period, the interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration ratio increased to 1.6 on the 22nd day, and then returned to the baseline value until the 84th day when the drug was stopped.

Figure 6B. Serum concentrations of interleukin 10 (IL-10) (diamond pattern) and interferon-tau (IFNt) (square) in patient 205 of treatment group II, receiving interferon-tau (IFNt)-1.0 mg three times a day (Mg) Daily dose is 3 milligrams (mg). Interleukin 10 (IL-10) concentration reference and interferon-gamma (IFN-γ) concentration reference (data obtained on the first day of screening and averaged) are 3.8 pg / mL and 5.2 pg / mL, respectively. The initial interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration ratio was 0.73. During interferon-tau (IFNt) treatment, the interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration ratio increased to 1 on day 15 and then returned to baseline until 84 Days until the drug is stopped. Therefore, the treatment with interferon-tan (IFNt) resulted in an increase in the concentration of interleukin 10 (IL-10) / interferon-gamma (IFN-γ) by about 25% compared to the 値 adjustment. FIG. 6C shows the serum concentrations of interleukin 10 (IL-10) (diamond pattern) and interferon-tan (IFNt) (square) of patients 301 in treatment group III, receiving interferon-tau (IFNt) —three times a day 3 milligrams (mg) 9 milligrams (mg) per day. Interleukin 10 (IL-10) concentration benchmark and interferon-gamma (IFN-γ) concentration benchmark (data obtained and averaged on the screening day and the first day) are 4.4 pg / mL and 3.9 pg / mL, respectively. The initial interleukin 10 38 200531¾½¾ (IL-10) / interferon-gamma (IFN-γ) concentration ratio 値 was 1.0. During interferon-tan (IFNt) treatment, interleukin 10 (IL-10) concentration increased by 4 to

5 times, increasing continuously, while the concentration of interferon-gamma (IFN-γ) was maintained at the initial concentration of 4-5 pg / mL. Therefore, the interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration ratio was increased from 1.0 to 4.0, a four-fold increase. Figure 6D-6F shows the serum concentrations of interleukin 10 (IL-10) (diamond pattern) and interferon-gamma (IFN-γ) (square) in patients in treatment group III, receiving interference -Tan (IFNt)-3.0 milligrams (mg) three times a day at a dose of 9 milligrams (mg). The analysis of the interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration ratio was similar to that of patient 301 discussed in Figure 6C. In particular, FIG. 6D shows the data of the patient 303. In this patient, the concentration of interleukin-10 (IL-10) increased approximately four-fold from the baseline on day 43 and approximately six-fold from the baseline by day 71. The blood levels of IFN-γ remained constant. Therefore, the interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration ratio 値 is increased from 0.6 liters to more than 3, which is about a five-fold increase from the baseline 値. FIG. 6E shows 304 patients in treatment group III. The patient's blood levels of interleukin 10 (IL-10) increased by about four to five times the baseline. The blood levels of interferon-gamma (IFN-γ) remained essentially unchanged. So by the 71st day, the interleukin 10 (IL-10) / interferon-gamma (IFN-γ) concentration ratio was increased from 0.6 to 2.6, which was about four times the baseline. Figure 6F shows 305 patients in treatment group III. Evidence shows that the patient's interleukin-10 (IL-10) blood concentration continued to increase during treatment, rising from 0.7 to greater than 9 on day 43. The concentration of interferon-gamma (IFN-γ) in blood 39 20053i ^ 3i6.9c remained essentially unchanged. The interleukin 10 (ILe 10) / interferon-gamma pseudo (IFN-γ) concentration ratio increased by more than 10 times.

In summary, data show that the use of interferon etau (IFNt) in patients in group 111 can effectively increase the concentration of interleukin 10 (K-10) / interferon-gamma (IFNγ). In particular, the increase in the blood concentration of interleukin 10 (IL-10) due to oral interferon-tau (IFNt) can be confirmed by the statistically significant increase in the blood concentration of interleukin 丨 0 (IL-10). The blood concentration of interleukin 10 (IL_10) increased by more than 25%, and the blood concentration of interleukin 10 (IL-10) increased relatively more in this group of patients. In another study, five patients with viral infection, hepatitis C were enrolled in study Interferon-tau (IFNt). In the study, the patient described in Example 3 received interferon-tau (IFNt) 7.5 mg twice a day, a total daily dose of 15 mg of interferon-tau (IFNt) (1.5 X 109 antiviral unit (antiviral units). The first dose was taken before breakfast in the morning and the second dose was taken three hours after dinner in the evening. Blood samples were taken regularly during 113 days of testing. Interferon-tau (IFNt) administration was discontinued on day 84. Samples The serum concentrations of interleukin 10 (IL-10), interleukin i2 (il-12), and interferon-gamma pseudo (IFN_y) were analyzed using commercial methods. Figures 7A and 7B show the serum concentrations of interleukin 10 (jl-10) ( Fig. 7A) The serum concentration of interferon-gamma (IFN-γ) (Fig. 7B) is taken as the unit, and the data of five patients are plotted on the horizontal axis of time and the unit of day. As shown in Fig. 7A, three Patients have interleukin 10 (IL-10) (Patients are represented by triangles, diamonds, and numbers (x's). During the period of treatment with interferon tau (IFNt), that is, the first day to the 84th day shows interleukin 丨 〇 (IL _ 丨 〇) concentration increased. 20053¾ ^ During treatment, Figure 7B shows that all five patients had interferon-gamma pseudo- (IFN- γ) The concentration of blood decreased. After stopping the dose, the concentration of interferon-gamma (IFN-γ) increased, as shown on the 85th day to the 113th day.

Blood samples were taken from the patients in this study and analyzed for interleukin-12 (IL-12) concentrations. Interleukin 12 (IL-12) is an inflammatory cytochrome and is pathologically related to multiple sclerosis. Documents (1) Increase of interleukin 12 (IL-12) is the main mechanism of the pathogenesis of multiple sclerosis (Filson W α /., Clin. Immunol ·, 106 (2): 127 (2003); (2) Multiple The standard symptoms of patients with sexual sclerosis (MS) are a decrease in interleukin 10 (IL-10) and an increase in interleukin 12 (IL-12), and these cytochrome concentrations are related to the disease stage (van Boxel_Dezaire a /., TV ^ wro / ·, 45: 695 (1999)). As for virus infection, high concentrations of interleukin 12 (IL-12) have also been shown to be sufficient to worsen pertussis (5. Bacterial reproduction (Carter e / a / ·, C / / "·

Exp. Immunol., 135 (2): 233 (2004)). Therefore, monitoring of interleukin 12 (IL-12) in patients under investigation is needed. Figures 8A-8D show the interleukin 10 (IL-10) (diamond pattern) and interferon-gamma (IFN-γ) (square) and interleukin 12 (IL-12) (triangle) of six patients in Example 3. Serum concentration in pg / mL ◦ The true interleukin 12 (IL-12) concentration is ten times higher than that shown in Figures 8A to 8D (the real radon is divided by 10 to allow all data to be displayed in a single graph (Inside.) Figure 8A shows the data of patient 401. As shown in the figure, the concentration of interleukin 10 (IL-10) increased during the treatment with interferon-tan (IFNt), and the concentration of interferon-gamma OFN-γ remained unchanged or slightly decreased 'and interleukin 41 2〇 The concentration of 〇5mm 10 (IL-10) fluctuated until the 29th day when downstream feedback was generated. The initial interleukin 10 (IL-10) concentration was 53.1 pg / mL, and the initial interleukin 12 (IL-12) baseline was 696 pg / mL. The concentration ratio of interleukin 10 (IL-10) to interleukin 12 (IL-12) It is 0.08. During the treatment period, the proportion change rose from 0.12 to 0.18, with an increase of 570 to 100%. This patient's increase in interleukin 10 (IL-10) concentration increased from a baseline of 53.1 pg / mL to greater than 140 pg / mL, resulting in a greater than 160% increase (2.6 times).

FIG. 8B shows the data of the patient 402, and FIG. 8C shows the data of the patient 403. The initial interleukin 10 (IL-10) baseline for patient 402 was 42.7 pg / mL (data were obtained and averaged on screening day and first day). Interleukin 10 (IL-10) reached its maximum concentration at the 43rd level, at which time the concentration was 67 pg / mL with a 56% increase. Interferon-tau (IFNT) blood levels fluctuate around the baseline. The baseline of interleukin 12 (IL-12) is 934 pg / mL, and the concentration ratio of interleukin 10 (IL-10) to interleukin 12 (IL-12) is 0 · (M6. On day 43, interleukin 10 (IL-10) ) And interleukin I2 (IL-12) concentration ratio reached 0.088, a 90% increase from the baseline 値. In Figure 8C, the initial concentration ratio of interleukin 10 (IL-10) and interleukin 1¾ IL-12) was 0.10. (IL-10 = 118.5 pg / mL; IL-12 = 1227 pg / mL). The ratio increased during the treatment period, with a ratio of 0.22 on day 43 and a 2.2-fold increase in the concentration ratio of interleukin 10 (IL-10) to interleukin 12 (IL-12). The patient's interleukin 10 (IL-10) blood concentration reached a maximum at day 43 (63% above baseline). FIG. 8D shows the data of the patient 404. The patient's initial interleukin 10 (IL-10) concentration was 69 · 6 pg / mL and the initial interleukin 12 (IL-12) concentration was 42 2005332 ¾ ^ 1552 pg / mL, so the initial interleukin 10 (IL-10) and interleukin 12 The concentration ratio of (IL-12) was 0.045. During treatment with a daily dose of 1.5 x 109 units (U) of interferon-tau (IFNt), the concentration of interleukin 10 (lL-10) increased by about 60% on day 43. Interleukin 12 (IL-12) concentration decreased to 900 pg / mL on the 43rd day, so the concentration ratio of interleukin 10 (IL-10) to interleukin 12 (IL-12) was 0.12 on the 43rd day.

Patient 405 had an initial interleukin 10 (IL-10) blood concentration of 34.9 pg / mL and an initial interleukin 12 (IL- 丨 2) blood concentration of 976 pg / mL interleukin 10 (IL-10) and interleukin in this study. The concentration ratio of Π (IL-12) is 0.036) (data not shown). During the administration of interferon-tan (IFNt) at a daily dose of 1.5 X 109 units (U), the concentration ratio of interleukin 10 (IL-10) to interleukin 12 (IL-12) can be effectively increased. In 71 days, the ratio reached 0.058, with a 60% increase. Interleukin 10 (IL-10) blood levels increased by 20% from pre-treatment to day 71. Therefore, an effective dose of interferon-tau (IFNt) is administered to a subject suffering from an autoimmune disease to increase the concentration ratio of interleukin 10 (IL-10) to interleukin I2 (IL-12), and to obtain For subjects treated with interferon-tan (IFNt), the measurable subject's measurable method for increasing the initial interleukin (IL-10) concentration is relative to that of patients not receiving interferon-tau (IFNt) treatment. The subject reduced the subject's interleukin-12 (IL-12) concentration. At the same time, consider the method of administering an effective dose of interferon-tau (IFNt) to suppress the deterioration of patients with autoimmune diseases. Compared with subjects who have not been treated with interferon-tau (IFNt), we have received interferon-tau in this study. (IFNt) -treated subjects produced measurable increases in initial interleukin 10 (IL-10) blood levels, compared to 20053S3 ^ 90 ° c subjects who did not receive interferon-tan (IFNt) treatment. The concentration of interleukin 12 (IL-12) in the subject. In particular, patients treated with interferon-tau (IFNi :) greater than about 5 X 108 units (U) can increase interleukin 10 (IL-10) blood concentrations by more than 25% and in many cases by more than 50%. In the same patients, the blood levels of interferon-gamma pseudo- (IFN-γ) remained essentially unchanged or decreased, and the concentration of interleukin-12 (IL-12) was generally reduced. In summary, the present invention administers oral interferon-tau (IFNt) to patients in need of treatment. The initial dose of interferon-tau (IFNt) is selected to achieve an increase in the concentration of interleukin 10 (IL-10) in the blood of a specific patient, and / or to reduce or not change the concentration of interferon-gamma pseudo (IFN-γ), and And / or reduce the concentration of interleukin-12 (IL-12). A suitable form of administration of interferon-tau (IFNt) is through the intestine rather than the oral cavity. The dose can be selected, for example, by monitoring the concentration of interleukin 10 (IL-10) ' such as before and after the first treatment. In addition, the effective dose can be determined according to the response of the patient module under different disease states. For example, patients with specific conditions in a specific age range, such as viral infection or autoimmune abnormalities, can monitor the concentration of interleukin 10 (IL-10) to respond differently. The initial interferon-tau (IFNt) dose is used to determine the appropriate patient's annual radon / disease dose, and dosage specifications can be provided by the treating physician. In one aspect, the present invention includes an interferon-tau (IFNt) treatment group that delivers the target protein to the intestine in an oral form, such as an interferon-tau (IFNt) in the form of an enteric coating, and is reported in the product literature or as a single copy The effective dosage specifications provided are administered according to different patient conditions, that is, to provide a measurable increase in interleukin 10 (IL-10) concentration. A better situation is to provide a dose range and to predict an increase in the concentration of interleukin 10 44 20053S3 ^ 810c (IL-10).

Track the initial administered dose, or the dose reaches a measurable amount (effective dose) sufficient to increase the concentration of interleukin 10 (IL-IO) in the blood, and the effective dose of interferon tau (IFNt) is continued. It is recommended that it be administered daily or for a week. Several times, for a long time. Effective dose administration for a period of time is effective to provide an initially measurable increase in interleukin 10 (IL-10) concentration, independent behavior of true interleukin 10 (IL-10) concentration over a longer treatment period, whether or not the same or different persists Effective dose. Therefore, during treatment, the concentration of interleukin 10 (IL-10) in the blood may be maintained in an increasing state, continuously increasing or decreasing (for example, in response to reducing the concentration of viral infection), and even receiving interferon tau (IFN 〇In order to effectively produce the initial measurable concentration of interleukin-10 (IL-10) in the blood, the effective dose may be maintained at an increase. The effective dose is substantially greater than about 5 X 108 units per day, and may even be as high as about 1012 units per day. Yes, the dosage is substantially greater than about 5 X 108 units per day, preferably about 0.5 X 109 units per day or more, and even more preferably about 1 X 109 units or more per day. It can be adjusted to obtain the desired initial interleukin 10 (IL-10) concentration, for example between 1.5 and 4 times greater than the normal radon for treatment. Interferon tau (IFNt) is administered in some patients and under some conditions in combination with others Agents are also used. Details are described below, for example, the combination of interferon tau (IFN0 and an antiviral agent may be beneficial for some patients. Similarly, the combination of interferon tau (IFNt) with agents for treating autoimmunity in some cases situation Beneficial to the city. Combining interferon tan (IFNt) with agents for the treatment of abnormal cell proliferation is beneficial in certain conditions at night markets. More general use of interferon tau 45 20053 ^ 2¾ ^ ¾ (IFNO combines with any known agent to complete Treatment and demonstration of the combination of agents in the subsequent examples. The combination of agents of the interferon tau (IFNt) referred to here can be taken sequentially or simultaneously, and can be taken immediately or non-immediately. III. Method of use

As described in the above information, the administration of interferon-tan (IFNt) provides treatment for patients suffering from diseases or conditions that cause upstream feedback of interleukin 10 (IL-10) concentrations. Disease or condition π response to interleukin 10 (IL-10) treatment "refers to the presence, exacerbation, or change in symptoms due to the administration of interleukin 10 (IL-10) or a medicament resulting in an increase in interleukin 10 (IL-10) concentration The above information describes that the administration of interferon-tan (IFNt) can treat the response to interferon treatment. Responding to interferon-tau (IFNt) treatment refers to the presence, deterioration, or symptoms of the disease due to the administration of interferon agents Changes, especially type 1 interferon, and more specifically interferon-tau (IFNt). Symptoms that respond to interferon-alpha (IFNa) or interferon-beta (IFNP) also affect interferon tau ( Response to IFN0 treatment. Methods include the provision of interferon-tau (IFNt), which is suitable for delivery to the stomach or intestine as an oral administration form. As evidence shows, for example, specific patients or the same conditions as those investigated Of patients treated with increased interleukin 10 (D-10) concentration. A sufficient amount of interferon tau (IFN〇 to increase the concentration of interleukin 10 (IL-10) in the blood can also effectively reduce the level of interleukin 12 (Π-Π) in the blood Concentration, while reducing or not changing the interferon-gamma pseudo (IFN ^). Quasi-treatable disease or condition is responsive to cytochrome treatment. Interleukin 10 (IL-10) responsive to the disease or symptoms of a very wide range 'of 46 2005333ρ6 (9〇

Interferon-tau (IFNt) treatment can be used alone or in combination with other therapeutic agents. For example, the method of the present invention can effectively treat neuropathy, including Alzheimer's disease, autism, and fibrotic diseases, including pulmonary fibrosis, liver fibrosis, and autoimmune disorders. , Including anti-phospholipid syndrome (anti-phospholipid syndrome), arthritis, allergies, diabetes (diabetes), such as type 1 diabetes (type I diabetes mellitus); inflammatory bowel disease ( inflammatory bowel disease), including Crohn's disease and ulcerative colitis, psoriasis; multiple sclerosis (uveitis); chronic obstructive pulmonary disease (uveitis) chronic obstructive pulmonary disease), including chronic bronchitis and emphysema; the disease or symptom is characterized by injury or death of cells, tissues, or organs, because the amount of blood or oxygen is reduced to the cells, Tissues or organs, including stroke; with atherosclerosis and organs Rejection by plant. A. Treatment of immune system abnormalities The method of the present invention has the advantage of treating related immune system allergies. Four types of immune system allergies (Clayman, C_B. American Medical Ass_ociation Encyclopedia of Medicine edited by Random House, 1991) New York) is as follows. The first or immediate / allergic, because obese cells respond to allergens (such as pollen), including asthma, hay fever, measles, anaphylactic shock and other allergic diseases. The resulting immune response. 47 20053 ^ 1 The second type: autoimmune allergy, because the antibody directly fights the immune response produced by the detected antigen in its own cell. The third type: allergy forms an antigen / antibody immune complex The body stays in different tissues and initiates more immune responses, as well as immune responses related to serum disease, lung allergies, and sometimes due to large swellings after vaccination. Fourth: Allergies because from the sensitized τ -Cells release lymphatic circulation and cause inflammation, such as contact dermatitis, measles-induced rash And because the drug caused the allergic immune response.

The causes of allergies in some individuals are not fully understood, but genetic and exogenous factors may be involved. For example, bacteria, viruses, or drugs may play such a role to cause an autoimmune response in individuals who already have pre-stored autoimmune abnormality genes. Research recommendations The incidence of certain allergic types is also related to each other. For example, individuals with common allergens are more likely to develop autoimmune abnormalities. Autoimmune disorders can be broadly classified as primarily limiting specific organs or tissues and affecting the entire body. Examples of specific organ abnormalities (i.e. organs affected) include multiple sclerosis (myelin encapsulates nerve processes), type 1 diabetes (pancreas), Hashinotos thyroiditis (thyroid), malignant anemia (stomach), moxa Addison's disease (adrenal), myasthenia gravis (acetylcholine receptor in neuromuscular junction), rheumatoid arthritis (inside the joints), uveitis (eyes), psoriasis (skin) Grubba syndrome [aka: acute infectious polyneuritis] (neurocytes), Graves' disease [aka: exophthalmic goiter] (thyroid). Systemic autoimmune diseases include lupus erythematosus and dermatomyositis ° 48 20053 Other allergic disorders include asthma, eczema, regional dermatitis, contact dermatitis, seborrheic dermatitis, rhinitis, lichen planus , Pemplugixs, bullous pemphigoidosis, epidermolytic vesicular disease, measles, angioedema, vasculitis, erythema, cutaneous eosinophilia, alopecia areata, arteriosclerosis, primary biliary liver Sclerosis, nephropathy syndrome. Related diseases include inflammation of the small intestine, such as celiac disease, proctitis, gastroenteritis with eosinophilia, measles pigmented, inflammatory bowel disease, Crohn's disease and ulcerative colitis, and food-related allergies.

Autoimmune diseases include multiple sclerosis, type 1 diabetic lupus erythematosus, amyotrophic lateral sclerosis, Crohn's disease, rheumatoid arthritis, angular cheilitis, asthma, uveitis allergy, and psoriasis. The therapeutic method of the invention has a particularly proven effect. The treatment method of the present invention is used to treat and slow down autoimmune abnormalities, as described above. The treatment of autoimmune disorders is based on the treatment of autoimmune encephalomyelitis (EAE), using the animal's multiple sclerosis module. When treating autoimmune disorders, interferon-tan (IFNi :) is administered in sufficient doses to obtain a low adenylate synthetase (OAS) increase that can be measured during the initial use of interferon-tau (IFNt). Once the effective dose is reached, the patient will continue to maintain the effective dose of interferon-tan (IFNt) for a period of treatment, and independently observe the subsequent changes in low adenylate synthetase (OAS). At least the patient is treated during the symptomatic period until the relevant autoimmune symptoms cease, and the dose of interferon-tau (ITNτ) will be reduced or discontinued. Patients are given interferon-tau (IFNx) while receiving other therapeutic agents such as known anti-inflammatory drugs or immunosuppressants. B. Treatment of Viral Infections 49 20053 Sicklea The therapeutic method of the present invention is also used to treat conditions related to viral infections. The antiviral activity of interferon-tan (IFNt) has a wide range of therapeutic applications but does not have the toxic effects often associated with IFNs treatment, and the therapeutic effect of interferon-tau (IFNt) release has no side effects on cells. The absence of cytotoxicity makes interferon-tau (IFNt) extremely valuable for in vivo experiments and therefore distinguishes it from other interferon and antiviral drugs.

Formulations include interferon-tan (IFNt) to inhibit viral replication orally. When used to treat viral infections, the protein is administered in sufficient quantities to obtain a measurable increase in low adenylate synthase (OAS) from the patient's blood. Thereafter, the treatment was continued at an effective dose, and changes in blood of low adenylate synthetase (OAS) were independently observed. For example, a decrease in the amount of low adenylate synthase (0AS) indicates that the virus is also reduced. Interferon-tau (IFNt) was administered continuously until the viral infection status decreased and the measured viral titers and related symptoms were alleviated. Specific viral diseases that can be orally treated with interferon-tau (IFNt). Examples include, but are not limited to, Hepatitis A, Hepatitis B, Hepatitis C, Non-A, Non-B, Non-C Hepatitis, Ebovirus Infection, AIDS Virus Infections, herpesvirus infections (EB, CML and herpes simplex), papillary gonorrhoea, papular stomatitis virus, foot-and-mouth disease virus, adenovirus, rhinovirus, HTLVI, HTLVII, and human rotavirus. Patients can be treated with a combination of virions, such as nucleosides, antisense agents, or other analogs. C. Methods for the treatment of cell proliferation conditions In other embodiments, the method of the present invention is also applied to treat the characteristic conditions of transitional proliferation. Interferon-tau (IFNt) is effective against cell proliferation. Therefore, IFNT is administered orally to inhibit cell growth in a manner that inhibits cell growth. 50 200533ά6ί9 > Controls, prevents or slows uncontrolled cell growth. Oral route of administration of IFNt to inhibit specific cell abnormal proliferation such as hairy cell leukemia, Poisi's sarcoma, chronic myelogenous leukemia, multiple myeloma, superficial bladder cancer, skin cancer (basal cell carcinoma and malignant melanin Tumors), cancers of the kidney cells, ovarian cancers, low levels of lymphocytes and lymphatic or gliomas that invade the skin.

The condition used to test cell proliferation is to administer interferon-tan (IFNt) in a sufficient amount to a subject to obtain a measurable low adenylate synthase (OAS) 値 in the subject's blood. After that, continue to treat with effective doses to observe the related changes of low adenylate synthetase (OAS) in the blood. For example, if the decrease of low adenylate synthase (OAS) in blood is due to the number of cancer cells in the body decline. Continued administration at an effective dose until the expected degree of cancer regression is observed, in a measurable manner: for example, the size of a cancer or the range of cancer cells in a specific tissue. Patients are also treated with a second anti-cancer agent for treating cancer, such as cis-platin, doxorubicin, or taxol. D. Combination Therapy Combination of interferon-tan (IFNt) with one or more other agents is also considered, and different combination therapies have been tried, including the administration of a second therapeutic agent (ii) a drug to be effective Stabilize or protect interferon-tan (IFNt) to prevent loss of activity after oral administration; and (iii) a second therapeutic agent and a stable treatment. Different treatment methods will be followed. In one embodiment, oral interferon-tan (IFNt) is administered in combination with a second therapeutic agent. In this embodiment, the interferon-tau (IFNt) is greater than about 5 x 108 units (U) and a second medicament is prescribed by the attending physician every 2005 ¾¾ ^^ days, usually the dosage is based on the recommended course of treatment of the medicament. The choice of the second agent is based on the particular disease or condition, using an appropriate route of administration, prior to, simultaneously with, or subsequent to interferon-tan (IFNt).

A suitable treatment method for the treatment of autoimmune conditions is a combination therapy in a general manner, which includes oral administration of interferon-tau (IFNt) in combination with antibody-to-antibody immune response. Examples include taking myelin basic protein and interferon tau (IFNt) to treat multiple sclerosis when asked; collagen and interferon tau (IFNt) to treat rheumatoid arthritis, and acetylcholine receptors. Polypeptide and interferon tau (IFNt) for myasthenia gravis 〇 In addition, oral interferon tan (IFNt) can be co-administered with immunosuppressants such as steroids to treat autoimmune diseases such as multiple sclerosis disease. Immunosuppressive agents have a synergistic effect with interferon tau (IFNt), which can produce more effective therapeutic effects than single interferon tan (IFN0 or a single immunosuppressant. More commonly, interferon tau (IFN0) can be used with drugs Combined use, such as therapeutic agents to treat autoimmune diseases, representative drugs include but are not limited to azathioprine, cyclophosphamide, corticosteroids [prednisone ), Prednisolone (prednisolone), and others], cephalosporin (cyclosporine), mycophenolate ester (trade name, Sancoto, mycophenolate mofetil), antithymocyte globulin (antithymcycy globulin) ), Muromonab-CD3 monoclonal antibody, 6-mercapine (Mercapurene), $ 50,000 hey password 52 2005333i69c (mercaptopurine), bisoxanrone (mitoxantrone), acetate acetate Latiol [glatiramer acetate, trade name Copaxone], interferon-beta (IFN-β) (trade names Avonex ™, Betaseron ™, RibifTM), Lee daclizumab (daclizumab), methotrexate Ling (methotrexate), sirolimus (sirolimus), tower wide forest yards Division (tacrolimus), and others.

In one embodiment, interferon-tau (IFNt) and a selective adhesion molecule inhibitor, particularly an integrin antagonist, are administered as a combination, for example, an autoimmune disease such as a clone Crohn's disease or multiple sclerosis. Integrins are a group of cell surface attachment molecules that act as a medium for communication between cells and between cells and extracellular matrix. It is a double unit of different units composed of alpha and beta subunits that penetrate the cell membrane to form a functional molecular combination. There are currently 18 alpha and eight beta combined units identified with more than 24 different integrin receptors. (Sandborn, W. J. et al., Am. J. Gastroenterol., Ϋ (11): 2372 (2003)). Alpha-4 integrin is expressed in lymphocytes, monocytes, eosinophils, basophils, and low concentrations of neutrophils. Alpha-4 integrin can be paired with any β subunits βΐ and β7. Alpha-4 beta-1 integrin (α4β1 integrin) is also related to late antibody 4 (VLA-4) and binds to vascular cell adhesion molecule-1 (VCAM-1) presenting on the blood-brain barrier endothelium) or junction site-1 (CS-1) is coated with fibronectin. Alpha-4 beta-1 integrin 53 2005333 (α4β1 integfin) is an important mediator of cell adhesion and endothelial penetration, and it is also a regulator of immune cell activation in inflamed tissues. Alpha-4 beta-7 integrin (α4β7), known to bind to lamina propria-associated molecule-1 (LPAM-1), to mucosal vascular addressin cell adhesion molecule-1 molecule-1) is expressed in gut-associated lymphoid tissue.

Natalizumab (Natalizumab, trade name Antegren®, produced by Elan and Biogen) is an active human monoclonal antibody alpha-4 beta-1 integrin antagonist (α4β1 integrin) (Elices, MJ, Curr. Opin, Investig. Drugs, 4 (11): 1354 (2003); WO 95/19790). The antibody binds to the a4 integrin subunit on the cell surface and inhibits a4-integrin-mediated adhesion and migration of white blood cells. Natalizumab has been evaluated in clinical trials for patients with inflammatory bowel disease and multiple sclerosis (Sandborn, WJ et al., Am. J. Gastroenterol., 98 (11 ): 23 72 (2003); Miller, DH et al.} New Engl. J. Med.} 348 (1): 15 (2003); Elices, MJ ·, Cwrr. Opz · ”· / wvesiz'g · Drwgs (Sheng (11): 1354 (2003)). Short-term use of Natalizumab in relapsing and second-degree worsening multiple sclerosis can reduce the number of progressive injuries and use magnetic resonance imaging. Imaging diagnosis (Sandborn Wa ··, Mpra). A small number of inflammatory brain lesions and a few multiple sclerosis recurrences occurred within six months (Miller e / α / ·, μ). Therefore, the combination The course of treatment includes oral interferon tau (IFN 05, 54 20053, Ro 90c) to patients with autoimmune disorders, and then Natalizumab is also considered and demonstrated in Example 5. The dose course depends on the patient Condition and severity, and other factors. Exemplary dosages include daily oral Interferon tau (IFNt) is administered at a daily dose of greater than about 5 X 108 units (U) and an intravenous Natalizumab dose of about 3 milligrams (mg) per kilogram per month for each course (every 28 days) (Kg). Different interferon tail (IFNi :) and Natalizumab response machines are used to treat autoimmune disorders. It is expected that the treatment effect will be enhanced. ^ In other embodiments, the treatment course for psoriasis is also Provided here. In addition to interferon tan (IFNt) and a second agent useful in the treatment of psoriasis are also administered at the same time. The therapeutic agent can be combined with interferon tan (IFN0) psoriasis treatment including local or systemic. Suitable therapeutic agents Including immunosuppressants, including monoclonal antibodies against tumor necrosis factor-alpha factor (TNF-alPha factOr), hydroxymethylglutaryl coenzyme A inhibitors (statins) and glatiramer acetate It has already been described 'such as collagen, vitamin A derivatives (retinoids), green onion (anthralin), calpotriene, coal tar, salicylic acid, salicylic acid, may Clobetasol propionate, alefacept, hydroxyurea, and etanercept. In other embodiments, interferon tau (IFNt) and hydroxymethylglutaryl coenzyme A inhibitors (statins) are administered concurrently to treat autoimmune conditions, such as multiple sclerosis. Methylglutaryl coenzyme A inhibitors (statins) are a group of 3-Methyl 3-glutaryl coenzyme A inhibitors

55 20053¾ paper

Composition of the drug (3-hydroxy-3-methylglutaryl enzyme-CoA reductase inhibitors) [also commonly referred to as HMG-CoA reduction inhibitors, abbreviated HRIfs, and mevalonic acid biosynthesis inhibitors] . Methylglutaryl coenzyme A inhibitors (statins) change the concentration of cholesterol [cholesterol] in the serum by blocking the liver enzymes that produce cholesterol. Inflammation of the arterial wall also plays an important role in the pathology of arteriosclerosis, while hydroxymethylglutaryl coenzyme A inhibitors (statins) play a role in reducing inflammation. There are some commercially available prescription drugs on the market including lovastatin (trade name Mevacor®), simvastatin (trade name Zocor®; velostatin), pravastatin (trade name Pravachol®), towels Fluvastatin (Lescol®), atorvastatin (Lipitor®), rosuvastatin (Crestor®), and cerivastatin (Baycol). Drugs Basically, it is administered orally at a dose of about 5-40 mg per day. Other hydroxymethylglutaryl coenzyme A inhibitors (statins) also include itavastatin, mevastatin, and the like. Combination therapy agent course Including the administration of interferon-tau (IFNt) orally to inflamed patients such as rheumatoid arthritis and multiple sclerosis, and the addition of hydroxymethylglutaryl coenzyme A inhibitors (statins) are also considered. The dose change course depends on the patient Changes in condition, severity, and other factors. Demonstration dose courses include oral administration of interferon-tan (IFNx) greater than or about 5 X 108 56 2005 3 ^ ¾¾ units per day U) daily doses, and also generally give about 5-50 milligrams (mg) of hydroxymethyl glutaryl coenzyme A inhibitors (statins).

In other embodiments, interferon-tau (IPNτ) and the immunosuppressant mycophenolate mofetil '(produced by fii at Hoffman-La Roche AG, Grenzach, Germany) are combined to reduce or prevent the risk of organ rejection . This embodiment is demonstrated in Example 6. My cophenol ate mo fetil is an inosine monophosphate dehydrognase inhibitor and inhibits purine synthesis, especially for T cells and B cells (Groetzner J., W al ·, Transplantation, 77 (4): 568 (2004)). The compounds have been shown to extend the survival rate of allergic transplantation in animal modules (kidney, heart, liver, intestine, amputation, small intestine, islets, bone marrow, etc.). Drugs have been shown to respond to the progressive acute rejection of canine animal kidney and rat heart allograft modules, while suppressing proliferative arterial lesions in aorta and cardiac muscle allografts in rat and primate myocardial xenografts. Celkept® (mycophenolate mofetil) is orally administered and absorbed and hydrolyzed to mycophenolic acid to activate metabolites. Mycophenolic acid is an effective non-selective and non-competitive inversion type inosine monophosphate dehydrognase inhibitor and inhibits guanosine nucleotides in the nascent pathway (nucleotide) synthesis does not require binding to DNA. This substance has a potent cell-stabilizing effect on T- and B-lymphocytes, and is related to the proliferation of purine neosynthesis. Mycophenolate mofetil can be an oral capsule, 57 2005333 ^ 6 ^ lozenge, or a powder for suspension or intravenous injection. The recommended dose for kidney transplant patients is an oral dose of 1 g or twice daily (two grams per day). For heart transplant patients, an intravenous or oral dose of 1.5 grams twice daily is the recommended dose.

The combined treatment course considered includes oral interferon tau (IFN0 and Mycophenolate mofetil), which is administered to patients undergoing organ transplantation to reduce the risk of organ rejection or reduce the chance of organ rejection. The phenolic ester (Mycophenolate mofetil) is more preferably in a free base or salt condition. The dosage course varies depending on the patient, the type of transplanted organ, and other factors. The exemplary dose course includes the administration of a daily dose greater than about 5 x 10 units U), and the dose of Mycophenolate mofetil can be up to 3 grams per day (orally or intravenously). In the treatment of non-C virus cancer or viral infection, interferon tau (IFNt) can be Effective doses are administered concurrently with one or more chemotherapeutic agents. Exemplary species such as treatment of cell proliferation include, but are not limited to, nitrogen mustards, ethylenimines, methylmelamines ), Alkyl sulfonates, nitrosoureas, triazenes, folic acid anlo gs), pyrimidine analogs, purine analogs, vinca alkaloids, epipodophyllotoxins, antibiotics, enzymes, and biological response regulators [Examples: cytokines], tritium coordination complexes, anthracenedione, substituted urea, methylhydrazine derivatives, adrenal cortex inhibition 58 2050 3

Drugs (Adrenocortical suppressants), progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin releasing hormone anlogs). Representative drugs include, but are not limited to, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, hexamethyl dense Hexamethylmelamine, thiotepa, busulfan (busulfan), carmustine (carmustine), lomustine, simustine (Semustine), streptozocin, dacarbazine, methotrexate, fluorouracil, floxuridine, Cytarabine, sparse Mercaptopurine, thioguanine, pentostatin, vinblastine, vincristine, etoposide, tenipo teniposide), dactinomycin, daunorubicin, doxorubicin, bleomycin hydrochloride, blemycin, plicamycin, mitomycin , Asparaginase, interferon-alpha, interferon-alpha, cisplatin, carboplatin, mitoxantrone, hydroxyurea, cypress Procarbazine, mitotane, mitotane, aminoglyethimide, prednisone, 5920053 ^ ft.

Luteal hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, diethylstilbestrol, Ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, leuprolide, zidov [Zidovudine (AZT)], leucovorin, melphalan, cyclophosphamide, dacarbazine, dipyridamole, and other medicines. Exemplary and oral interferon tau (IFN) drugs to treat viral infections include, but are not limited to, antiherpesvirus agents, antiretroviral agents, and antiviral agents .Representative medicines include acyclovir, famciclovir, foscarnet, ganciclovir, iodoxuridine, sorivudine, and trifluridine Uridine (trifluridine), valacyclovir, vidarabine, didanosine, stavudine, zalcitabine, zidovudine ( zidovudine), amantadine, interferon-alpha, ribavirin, rimantadine, lamivudine, protease inhibitor inhibitors), acyclic nucleoside phosphonates and others. 60 20053 ^ 6®

Alzheimer's disease is effective in administering interferon tau (IFNt) in combination with other agents as described below, such as amyloid beta, neurotransmission enhancing drugs, including Anti-cholinesterase inhibitors such as tacrine, donepezil, rivastigamine, metrifonate, and mestigmine (Epastigimine), nicotine (pyridostigimine), neostigimine, physostigimine, ambenomium chloride, and Gingko biloba ); Can increase brain catecholamines and / or reduce oxidative damage to neurons, including selegiline and vitamin E; nonsteroidal drugs have anti-inflammatory effects including hydroxymethylglutar Statins (hydroxymethylglutaryl coenzyme A inhibitors also have immunosuppressive effects), such as lovastatin, simv astatin), pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin, aminoarylcarboxylic acid acid derivatives), such as enfenamic acid, etofenamate, flufenamic acid, isoxin, meclofenamic acid, and care Fenamic acid; aromatic acetic acid derivatives, such as aceclofenac, acemetacin, bromine 61 200533 ^ 6® bromfenac , Clopirac, etodolac, fentiazac, indomethacin, oxametacine, and tropesin; aromatic Arylbutyric acid derivatives, such as buma

Bumadizon, butibufen, fenbufen, and xenbucin; arylcarboxylic acid derivatives, such as clidanac, ketones Ketorolac, tinoridine, and arylpropionic acid derivatives, such as alminoprofen, carprofen, and fenoprofen ), Ibuprofen, indoprofen, ketoprofen, naproxen, pirpro fen, and zaltoprofen; compare Sit (pyr azoles), such as difenamizole and epirizole; pyrazolones, such as apazone, benzpiperylon, fenpyridine Feprazone, oxyphenbutazone, pipebuzone, ramifenazone, and thiazolinobutazone; salicylic acid derivatives derivatives), such as acetamidine Acetaminosalol, aspirin, balsalazide, diflunisal, gentisic acid, imidazole salicylate, osa Olsalazine, parsalmide, salicylsulfuric acid, salicylic acid, sodium salicylate, 62 200531¾½¾

With sulfasalzine; with thiazine carboxyamides; for example J such as ampiroxicam, droxicam, isoxicam, lornoxicam, Piroxicam and tenoxicam; and cholinergic agonists, including xanomeline, milameline, AF 102B, or milox ( memric). Example 7 describes a murine model of Alzheimer's Disease and how to use interferon-tau (IFNt) alone or a combination of one or more

effect.

Therapeutic agents can be combined with interferon-tau (IFNt) to treat liver fibrosis. The choice of agents is based on the causes of fibrosis. For example, liver fibrosis is caused by a hepatitis virus infection, such as hepatitis C infection. Different antiviral agents can be used, including monoclonal antibodies, such as palivizumab, paitimid ( peptidomimetics), such as amprenavir, indinavir, lopinavir, nelfinavir, ritonavir (trade name Novyya), and Saquinavir; polynucleotides, such as ampligen and fomivirsen; purines, pyrimidones, such as Jiergang ( abacavir), acyclovir, adefovir, cidofovir, cytarabine, didanosine, dioxano 6363

(dideoxyadenosine), edoxudine, emtricitabine, famciclovir, floxuridine, ganciclovir, iodoxuridine, Yin Inosine, pranobex, lamivudine, MADU, penciclovir, sorivudine, stavudine, tenofovir tenofovir), trifluridine, valacyclovir, valganciclovir, vidarabine, zalcitabine, zidovudine; Sialic acid analogs, such as oseltamivir and zanamivir; and interferon-alpha, interferon-beta, and Interferon-gamma. Example 8 describes the liver fibrosis module and shows how to use interferon-tan (IFNi :) alone or one or more second therapeutic agents to treat liver fibrosis and evaluate the effect of treatment. Liver fibrosis is secondary to cancer, and many anti-cellular abnormalities can be used, including nitrogen mustards, ethyleneimines, methylmelamines, and sulfonate Salts (alkyl sulfonates), nitrosoureas, triazenes, folic acid analogs, pyrimidine analogs, purine analogs, vinca Vinca alkaloids, ePipodophyllotoxins, antibiotics 64 20053i ^ 3j6.9c (antibiotics), enzymes, physiological response modifiers, such as cytochromes cytokines )], Platinum coordination complexes, anthracenedione, substitutedas, methylhydrazine derivatives, adrenocortical suppressants, Progestins, estrogens, antiestrins

(antieStrogens), male hormones (androgens), antiandrogens (antiandrogens), and gonadotropin-releasing hormone analogues (gonadotropin releasing homi analogs). Representative medicines include, but are not limited to, the following medicines such as: mechlolamine, cyclophosphamide, ifosfamide, melphalan , Nitrogen mustard acid (chi〇rambucil), hexamethylmelamine (hexamethylmelamine), thiotepa (thiotepa), busulfan (bumesan), carmustine (carbazepine , Carmustine), lomustine, lomustine, semustine, streptozocin, dacarbazine, methotrexate, fluorouracil ( flu〇r〇uracil), fluoxuridine, Cytarabine, merxaptopurine, thiguanguanine, pentostatin, scopolamine (Vinblastine), vincristine (vincristine), etoposide (teposide), teniposide (dactinomycU), daunorubicin (dau_ubicin), and doxorubicin ( doxorubicin), bleomycin hydrochloride (bleomycin), Piri 65 2 005332 ^ 1 ^ 0:

Plicamycin, mitomycin, asparaginase, interferon-alpha (IFN-α, interferon-alpha), j 暝 pin (cisplatin), carboplatin , Mitoxantrone, hydroxyurea, procarbazine, mitotane, aminoglyethimide, prednisone, Via hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, diethyl diphenethyl estrone (diethylstilbestrol), ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, leuprolide , Zidovudine (AZT), leucovorin, melphalan, cyclophosphamide, dacarbazine, to be able Up to (dipyridamole), and other medicines. When liver fibrosis is the second symptom of other diseases or symptoms, those skilled in the art can match and choose other suitable agents. Therapeutic agents can be combined with interferon tau (IFN0 to treat pulmonary fibrosis including immunosuppressants such as alemtuzumab, azathioprine, basiliximab, brequinar ), Cyclophosphamide, corticosteroids [prednisone, prednisolone, triamcinolone, betamethasone 66 20053 ^ 9.

(betamethasone, dexamethasone, etc.), cyclosporine, gusperimus, 6-mercaptopurine, mizoribine, P Pimecrolimus, rapamycin, mycophenolate mofetil, antithymocyte globulin, muromonab-CD3 monoclonal antibody, Mercaptopurine, mitoxantrone, glatiramer acetate (Copaxone®), interferon-gamma (IFN-γ), interferon-beta (IFN-β) (AvonexTM, Betaseron ™, RibifTM), daclizumab, methotrexate, sirolimus, tacrolimus, and others. Galtiramer acetate is a synthetic basic random mixed polymer composed of tyrosine, glutamate, alanine and lysine, and With anti-inflammatory properties. When interferon-tau (IFNt) was applied, glatiramer acetate caused higher interleukin 10 (IL-10) and TGF-beta blood concentrations (Soos, JM et al., J / mm㈣〇). / ·, M: 2231 (2002). In some cases, pulmonary fibrosis caused by underlying diseases is known, such as rheumatoid arthritis and tuberculosis, which are known to treat such diseases. Agents can be used. For example, antibiotic treatment can be used to treat tuberculosis, anti-inflammatory drugs can be used to treat rheumatoid arthritis, for example including non-steroidal anti-inflammatory drugs, as previously discussed 67 20053 ^ 9

Cox-2 inhibitors, including valdecoxib, lumiracoxib, and celecoxib; and the immunosuppressants mentioned above, including methotrexate ) Can take advantage of this, such as immunosuppressive agents. Example 9 describes the pulmonary fibrosis module and shows how to treat patients with pulmonary fibrosis using interferon-tan (IFNt) alone or in combination with one or more second therapeutic agents to evaluate the effect of treatment.

Therapeutic agents may be used in combination with interferon-tau (IFNt) for the treatment of anti-phospholipid syndrome including anti-hemagglutinating agents such as unpared heparin, lovenox, acetamidine Acetylsalicylic acid, and coumadin; anti-malarials, including chlorochloroquine, mefloquine, primaquine, rapa Proguanil, deoxycycline with Doxycycline; steroids include prednisolone, triamcinolone, betamethasone, and dexamethasone; and Immunosuppressants include intravenous hemoglobin. Describes the anti-phospholipid syndrome module and explains how to use interferon-tau (IFNt) alone or one or more second therapeutic agents to treat anti-phospholipid syndrome Affect and evaluate the effect of treatment. Therapeutic agents can combine interferon-tan (IFNI) with the treatment of Chinese genus, including cerebral vasodilators, such as bencyclane, ciclonicate, and sinalin 20053S3i69c

(cinnarizine), cyclandelate, diisopropylamine dichloroacetate, eburnamonine, fasudil, fenoxedil, flunarizine ), Ibndilast, ifenprodil, lomerizine, nafronyl, nicametate, nigergoline, nimodipine (Nimodipine), papaverine, pentifylline, vincamine, vinpocetine and viquidil; coronary vasodilators, such as amines Amotriphene, benfurodil hemisuccinate, benziodarone, chloracizine, chromonar, clobenfurol, Clonitrate, cloricromen, dilazep, etafenone, fendiline, hexobendine, mannitol six Nitrate (mannitol hexanitrate), nitroglycerin, pentrinitrol, perhexiline, propatyl nitrate, trapidil, trimetazil ( trimetazidine) and vinadine; and tissue plasminogen activator. Other suitable agents include auto-antigens, such as myelin oligodendrocyte glycoprotein (MOG) or peptides related to hydroxymethylglutaryl coenzyme A inhibitors ( statins) and glatiram acetate (glatiramer 69 20053¾)

acetate). The myelin oligodendritic cell glycoprotein (MOG) is preferably a mammalian myelin oligodendritic cell glycoprotein (MOG), such as human oligosphingomyelin cell glycoprotein (MOG). The human myelin oligodendritic cell glycoprotein (MOG) nucleotide and amino acid sequence (SEQ ID NO: 5) are known in this decree. For example, the accession number in the NIH Gene Bank database is BC035938. Suitable such myelin oligodendritic cell glycoprotein (MOG) peptides include a length ranging from about 10 to about 150 amino acids, the standard being about 30 to about 100 amino acids in length and more preferably about 10 to about 50 amino acids long and effective in treating stroke patients. In one example, the myelin oligodendritic cell glycoprotein (MOG) having a peptide length of 35 to 55 amino acids can be used. As another example, the myelin oligodendritic cell glycoprotein (MOG) having a peptide length of 37 to 46 amino acids can also be used. It can be understood that the myelin oligodendritic cell glycoprotein (MOG) and related peptides are from other mammals, including, for example, ovine, bovine, and porcine, and their functions can also be used in the treatment of stroke. be utilized. Therefore, the application of the myelin oligodendritic cell glycoprotein (MOG) includes amino acid sequences that have at least about 70% similarity, even at least about 80% similarity, or even at least about 90% similarity to the human myelin oligodendron. Synaptic glycoprotein (MOG) amino acid sequence. The similarity percentage can be determined, for example, by comparing sequence information using an advanced BLAST computer program, including version 2.2.9, using the National Institutes of Health, or using other similar computer systems. This BLAST program is based on the comparison methods provided by: Karlin and Altschul., Proc. Natl. Acad. Sci. USA, 87: 2264-2268 (1990); also discussed in Altschul, et al., J. A / W. 5ζ · ο / ·, 215: 403-410 20053iS3i69c (1990); Karlin and Altschul, Proc. Natl. Acad. Sci. USA, 90: 5873-5877 (1993); and Altschul et al ·, iW / c / e / c, U: 3389-3402 (1997). Therefore, the scope of administering interferon tau (IFN0 combined with one or more second therapeutic agents to treat the aforementioned therapeutic agents is included in the scope of the present invention. Example 11 describes a stroke module and illustrates how to use interferon-tau alone (IFNt) or a combination of one or more second therapeutic agents to treat patients with stroke to evaluate the effect of treatment.

Therapeutic agents can be combined with interferon-tau (IFNt) to treat optic neuritis including hydroxymethylglutaryl coenzyme A inhibitors (statins), and previously mentioned immunosuppressants include hydroxymethylglutaryl coenzyme A inhibitors (statins), steroids (corticosteroids) and glatiramer acetate (glatiramer acetate). Example 12 describes the optic neuritis module and shows how to use interferon-tan (IFNt) alone or one or more second therapeutic agents to treat patients with optic neuritis and evaluate the effect of treatment . Therapeutic agents can be combined with interferon-tau (IFNt) to treat chronic obstructive pulmonary diseases including tracheodilators and steroids. Suitable tracheal dilators include ephedrine derivatives such as albuterol, bambuterol, bitoterol (also known as bitolterol), capbutrol (Carbuterol), clenbuterol, dioxethedrine, ephedrine, fenoterol, isoetharine, mabuterol, skin Pirbuterol, protokylol, rimiterol, salmeterol, soterenol, 20053 fiber. c

And terbututerol (tulobuterol); quaternary ammonium compounds, such as flutropium bromide, ipratropium bromide, oxtropromide (also known as bromoethorbutine Oxitropium bromide) and titropium bromide; and xanthine derivatives, such as acefylline, ambuphylline, aminophylline, non Forest (bamifylline), doxofylline, etofy 11 ine, guathylline, theobromine and theophylline. Other suitable agents include hydroxymethylglutaryl coenzyme A inhibitors (statins), glatiramer acetate (steroids) previously mentioned. Example 13 describes the chronic obstructive pulmonary disease module and shows how to treat patients with chronic obstructive pulmonary disease using interferon-tau (IFNt) alone or in combination with one or more second therapeutic agents Patients with obstructive pulmonary disease and evaluate the effect of treatment. Therapeutic agents can be combined with interferon-tan (IFNt) to treat autism including serotonin absorption inhibitors including femoxetine, fluoxetine, and fluvoxamine , Indalpine, indeloxazine hydrochloride, milnacipran, paroxetine, sertraline, and zmeldine; antipsychotic Anti-psychotic drugs, including benzamides, such as amifulpride, nemonapride, remoxipride, sulpiram: s 72 2005333i69c

(sulpiride), and sultopride; benzisoxazoles, such as iloperidone and risperidone; butyrophenones, such as bentopamine antagonists (Benperidol), bromperidol antagonist (droperidol), fluanisone (fluanisone), haloperidol (meloperone), meperone (moperone), Pipamperon, spiperone, timiperone, trifluperidol, trifluperidol, phenothiazines, such as acetophenazine, butyl ratio Accompany with butaperazine, carphenazine, chlorpromazine, clospirazine, cyamemazine, dixyrazine, diphenazine (Fluphenazine), mepazine, and mesoridazine; and thioxanthenes '' such as chlorprothixine, cloopenthion (clopen thixol), flupentioxl and thiothixen; and anti-inflammatory drugs including hydroxymethylglutaryl coenzyme A inhibitors (statins), glatiramer acetate and Previously mentioned steroids. Example 14 describes the autism module and shows how to treat patients with autism using interferon-tan (IFNt) alone or a combination of one or more second therapeutic agents to treat patients with autism. Patients and evaluate the effect of treatment. Therapeutic agents can be combined with interferon-tau (IFNt) to treat diabetes, including insulin, beta cell-associated autoantigens, and heat shock proteins (heat 73 20053S3f6Qc shock proteins), including, for example, heat shock proteins 10'22 , 27'60'65, 70 and 90. He at shock proteins are preferably mammalian heat shock proteins such as human heat shock proteins, and other commercially available proteins or other people skilled in the art can obtain them. protein.

Therapeutic agents can be combined with interferon-tan (IFNt :) to treat atherosclerosis including immunosuppressants. The previously mentioned heat shock proteins include, for example, heat shock proteins 10, 22, 27, 60, 65, 70 and 90. The heat shock proteins are preferably human heat shock proteins. Other suitable therapeutic agents include, for example, anti-platelet coagulants, such as aspirin, clopidogrel, dypridamole, ticlopidine, and sulfinpoyrazone; bile Acids are combined! I (bile acid sequestrants), including colestipol hydrochloride, and cholestyamine resin; fibrinates (fibric acid derivatives), including gefi Gemfibrozil, fenofibrate, and clofibrate; 3-Hydroxy-3-methylglutaryl hydrazone coenzyme A (HMG-CoA) reductase inhibitor ( 3-hydroxy-3-methylglutary 1 coenzyme A (HMG-CoA) reductase inhibitors), such as lovastatin (trade name Mevacor®), simvastatin (trade name Zocor®; velostatin), lovastatin (Pravastatin, trade name Pravachol⑧), 20053 ^ Sc

Fluvastatin (Lescol®), atorvastatin (Lipitor®), rosuvastatin (Crestor®), and cerivastatin (Baycol®) Use antihypertensive medications in patients with hypertension, including diuretics, such as organic powders (organomercurials), including chlormerodrin, meralluride, mercaptomerin sodium And mersalyl; purines include pamabrom, protheobromine, and theobromine; steroids, such as canrenone, and oleandherin ( oleandrin), with spironolactone, sulfonamide derivatives, such as acetazolamide, ambuside, azosemide, butamet (Bumetanide), butazolamide, clofenenamide, clopamide, disulfamide, furosemide emide), and torsemide; and thiazides, such as althiazide, benzthiazide, chlorothiazide, cyclopenthiazide, ethithine Ethiazide, hydrochlorothiazide, indapamide, metolazone, and teclothiazide; acetamidine reverse enzyme inhibitors, such as Alapril, benazepril, captopril, ceronapril, cilazapril, tilapril 75 20053¾ ^

(delapril), enalapril (also known as phenylbutyric acid proline, enalapril), lisinopfil, moviltipril, quinapril, ramipril And tenocarpril; alpha-adrenergic agonists, such as adrafinil, adrenalone, amidephrine, acole (Apraclonidine), burdralazine, clonidine, cyclopentamine, ephedrine, fenoxaz〇line, Matamino (mataraminol), methylated tertiary amine (methoxamine), midodrine, modafinil, ottojun (also known as octodrine), oxygen to D sitting morpholine ( oxymetazline, pholedrine, rilmenidine, and tyramine; beta-adrenergic blockers, such as acebutolol, allyl Alprenolol, amosulalol Atrotinolol, atenolol, befunolol, betaxolol, bevantolol, bimitrolol, hydrochloric acid Butidrine hydrochlride, carazolol, carteolol, dilevealol, indeno101, mepindi (Mepindolol), MoProll (lol), Nadoxolol (Penbutol (lol)), Pindolol (Puldol), Puta Lore (PrOPranOl01), Sulbenicol 76 2005333i69c

(sulfinalol), tertatolol, and xibenolol; calcium channel blockers, including arylalkylamines, such as bepridil, and extractables Clinazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, special Terodiline, verapamil, and dihydropyridine derivatives, such as amlodipine, aranidipine, barnidipin, Bendipin, manidipiine, nilvadipine, and nitrendipine; and piperazine derivatives such as cinnarizine, dotalizine (Dotarizine), flunarizine, lidoflazine, and lomerizine; immunosuppressive agents such as those previously mentioned and agents with anti-inflammatory effects, including Hydroxymethylglutaryl coenzyme A inhibitors (statins), glatiramer acetate and the aforementioned steroids. Example 15 describes the atherosclerosis module and shows how to treat atherosclerosis in patients with atherosclerosis using interferon-tau (IFNt) alone or a combination of one or more second therapeutic agents Patients and evaluate treatment effects. Therapeutic agents can be combined with interferon-tau (IFNt) to treat allergies including allergy-guided agents, including pollen, ovalbumin, food ingredients, such as milk, wheat, animal meat, including meat such as cattle, pig, or cotton; vegetables, Including logic, with 77 2005mm,

Cruciferous vegetables, such as cauliflower, cabbage, white cauliflower Brussels sprouts, and turnips; stone fruits, including peanuts, pistachios, cashews, and mites Endoplasmic reticulum degrading agents, including Deri (from 'for example, Saccharomyces cerevisiae') have been cultured in the literature Knop, M., et al., J., 15 (4) 753-763 (1996); giatiramer acetate and via glutaryl coenzyme A inhibitors (statins) and previously mentioned steroids. In addition, the Deri protein known to other species in the past can be The same method can also be used for Deri-like proteins. Therapeutic agents can be combined with interferon-tan (IFNt) to treat inflammatory bowel disease (including infliximab) against cancer neonatal factor α ( tumor necrosis (a factor, TNF-alpha factor) monoclonal antibody, previously described hydroxymethylglutaryl coenzyme A inhibitor (statins), glatiramer acetate tate), anti-diarrheal agents, such as acetyltannic acid, alkofanone, bismuth subsalicylate, catechin, difen Difenoxin, diphenoxylate, lidamidine, loperamide, racecadotril, trillium, uzarin, and dalida ( zaldaride), and anti-cramp agents, including belladonna, hyoscyamine, clinium bromide, glycopyrrolate, dicyclomine hydrochloride (dicyclomine 2005) ^ umhydrochloride), mebeverine, otilonium bromide, and cimetropium.

Therapeutic agents can be combined with interferon-tan (IFNt) to treat arthritis, including antigens, such as streptococcal cell wall; heat shock proteins, including previously mentioned including the previously mentioned heat shock proteins 60 (heat shock protein 60); collagen includes type II collagen; previously mentioned non-steroidal anti-inflammatory agents, monoclonal antibodies against cancer neo-alpha factor (TNF-alpha factor); previously mentioned methylol Glutaryl coenzyme A inhibitors (statins), glatiramer acetate, methotrexate and previously mentioned special COX-2 inhibitors. Example 16 describes the arthritis module and shows how to use interferon-tau (IFNt) alone or a combination of one or more second therapeutic agents to treat arthritic patients and evaluate the effect of treatment. Therapeutic agents can be combined with interferon-tan (IFNt) to treat multiple sclerosis including myelin basic protein and peptides, myelin oligodendrocyte glycoprotein and previously mentioned peptides , And the previously mentioned monoclonal antibodies against TNF-alpha factor; glatiramer acetate, and the steroids and hydroxymethylglutaryl coenzyme A inhibitors mentioned earlier (Statins). Myelin basic protein is preferably a mammalian myelin basic protein, such as a human myelin basic protein. The nucleotide and amino acid sequence (SEQ ID NO: 6) of the basic protein of human myelin sheath can be found, for example, the accession number in the National Gene Bank database (NIH Genbank database) is NM_002385. Protein 79 2005333i69c

Qualitative, suitable myelin basic protein peptides include from about 5 to 30 amino acids in length. Suitable peptides include amino acid 1 to amino acid 11 fragments, including adjustments to the 5 ' end such as an acetamidine functional group. It can be understood that myelin basic protein and peptides of mammals, including, for example, myelin bask protein and peptides of sheep, cattle, and pigs, can be used to treat multiple sclerosis usage instructions. Therefore, the applicable myelin basic protein includes at least about 70% amino acid sequence similarity. A better condition is at least about 80% amino acid sequence similarity, and a more preferable condition is at least about 90%. Sequence similarity of human myelin basic protein. Therapeutic agents can be combined with interferon-tan (IFNt) to treat uveitis including hydroxymethylglutaryl coenzyme A inhibitors (statins), glatiramer acetate and other previously mentioned immunosuppressants Agents, including steroids, are administered systemically or by eye drops; uveitis agents include retinal S antigen [human retinal S antigen can be obtained by, for example, the following literature methods: Beneski, DA ·, Et al ·, m 5W · 25: 686-690 (1984), and interstitial retinal binding protein (IRBP); human sequences can be found in Liou9 GI? Et al. 5 J. Biol. Chem. 264 (14): 8200-8206 (1989)]; at the same time, human leukocyte antigen (HLA) -binding peptides, including from known HLA-A, HLA-B, HLA-C, The conversion of HLA-E and HLA-G is a well-known technique and has been discussed in the following documents, such as PCT International Application No. PCT / US02 / 243 1 1 and 80 2005332¾¾¾ PCT / GB98 / 03686; Braud, and Document V.M. , et al.? Nature 391: 795-799 (1998).

Therapeutic agents can be combined with interferon-tau (IFNt) to treat organ transplant rejection including the previously mentioned immunosuppressants, such as hydroxymethylglutaryl coenzyme A inhibitors (statins), glatiramer acetate, Azathioprine, steroids, or steroids, cyclophosphamide. Example 17 describes an organ transplant rejection module and shows how to use interferon-tan (IFNt) alone or a combination of one or more secondary therapeutic agents to treat patients and evaluate the effect of treatment. During the combination therapy, the second therapeutic agent may be used before, at the same time, or after the administration of interferon-tau (IFNt). It is easy for a person skilled in the art to select a suitable second agent and administration time. The choice of the route of administration of the second agent is determined by the attending physician. Other interferon-tau (IFNt) -associated therapeutic agents must be effective and / or sufficient to stabilize interferon-tau (IFNt) after oral administration, especially to protect interferon through gastric and / or intestinal stabilizers -tan (IFNt) does not lose the effect of pharmacological activity, that is, it does not lose activity in the stomach and / or intestines. Exemplary examples include buffers, antagonists of gastric acid secretion, amino acids such as glycine and lysine, carbohydrates such as dextrose, mannose, galactose ( galactose, fructose, lactose, sucrose, maltose, sorbitol, mannitol, etc., proteolytic enzyme inhibitors, and the like . 20053 ^ 9〇c

In a preferred embodiment, the stabilizer may be an antacid, such as an organic acid carboxylate, such as citric acid, such as sodium citrate or potassium citrate, or an inorganic salt. Exemplary inorganic salts include, but are not limited to, aluminum hydroxide (Al (OH) 3) or phosphate, magnesium hydroxide (Mg (OH) 2), calcium carbonate (CaC03), sodium bicarbonate, magnesium oxide , Magnesium trisilicate, magnesium carbonate, aluminum hydroxide gel, and the aforementioned compound. Commercial antacid Mylanta ™ contains aluminum hydroxide and magnesium hydroxide and a suitable oral antacid. Antacids are often insoluble in water and are in the form of a suspension. The treatment regimen combining antacid with interferon-tan (IFNt) is preferably administered prior to or simultaneously with interferon-tau (IFNt). For example, let patients take antacids 5-30 minutes before taking interferon-tan (IFNt). Antacids protect interferon-tan (IFNt) from inactivation or degradation in the stomach, and the same protective effect is obtained in the intestine, so the dose of interferon-tan (IFNx) can be reduced to achieve the same effect. As previously discussed, interferon-tau (IFNt) doses greater than 5 X 108 units are needed to guide measurable patient blood interleukin-10 (IL-10) concentrations. Again, the same increase in interleukin 10 (IL-10) concentration can be achieved with a lower dose of interferon-tau (IFNt) because of the participation of antacids. Compound types such as proton pump inhibitors can also be administered as protective or / and stable interferon-tau (IFNt). Proton pump inhibitors prevent gastrointestinal acid release and are often used to treat ulcers, gastric acid reflux, or excessive gastric acid. General proton pump inhibitors are replaced with benzimidazoles 82 20053i3fe3i69, including rabeprazole (trade name Aciphex®), lansoprazole (trade name Prevacid®), omeprazole (omeprazole, trade name Prilosec®), and pantoprazole (trade name Protonix®). Regardless of Interferon-tau (IFNt)

The method of administration is prior to or simultaneously with interferon-tan (IFNt), which protects the effectiveness of interferon-tau (IFNt) and prevents interferon-tau (IFNt) in the stomach, and more importantly in the stomach. Inactivation or degradation in the gut is effective and allows the same effect to be achieved at lower doses. As previously discussed, interferon-tan (IFNt) doses greater than 5 X 108 units are needed without the participation of proton pump inhibitors in order to guide measurable patient blood interleukin-1 (IL-10) concentration. The same increase in interleukin 10 (IL-10) concentration can be achieved with a smaller dose of interferon-tau (IFN1 :) due to the participation of proton pump inhibitors. It is also considered that the simultaneous administration of antacid and the second therapeutic agent during the administration of interferon-tau (IFNt). As previously discussed, in this example, interferon-tau (IFNt) was found to achieve a clinical endpoint. The required dose of interferon-tau (IFNt) is less than that in the absence of antacids, and the presence or absence of antacids in the presence of antacids is considered to multiply the effect of interferon-tau (IFNt) and adjust the effect on the second therapeutic agent. Quantity demand. The treatment combination of patients with viral infections, autoimmune conditions, or cell proliferation symptoms is combined with interferon-tau (IFNt). An effective dose of interferon-tau (IFNt) and a second therapeutic agent have a labor-inducing effect or At least some of the symptoms can be reduced, and the medicaments can be considered in the same package or in separate packages. In one embodiment, the treatment group includes one or more unit doses of interference 83 20053 cellulose-tau (IFNt), the cumulative total daily dose must be greater than 5 x 108 units, (ii) one or more unit doses of the first Two therapeutic agents are used to treat multiple sclerosis, and (iii) instructions for use. The second therapeutic agent is preferably natalizumab, hydroxymethylglutaryl coenzyme A inhibitor (statins) or cyclosporine (mycophenolate mofetil) °

In other embodiments, the 'treatment group includes (i) a unit dose of interferon-tan (IFNt), which is one-third to one-half greater than the recommended dose of 5 x 108 units per day, And the unit dose is a unit dose of (II) a second therapeutic agent for treating multiple sclerosis, which is administered orally, taking one-third to one-half of the doctor's prescribed dose, and (iii) instructions for use. If the dose of the therapeutic agent combination is half of the daily dose, the treating physician prescribes the patient to administer the treatment group twice a day. Or, if the dose of the therapeutic agent combination is half of the daily dose, three times a day, in a preferred embodiment, the second therapeutic agent is natalizumab, hydroxymethylglutaryl coenzyme A inhibitor ( statins) or cyclosporine (mycophenolate mofetil). In other embodiments, the treatment group includes the interferon-tan (IFNt) administered (II) orally as a second therapeutic agent, and (iii) instructions for use. The antacid may use any of the foregoing antacids, and in a preferred embodiment, the second therapeutic agent is natalizumab, statins or cyclosporine Mycophenolate mofetil 〇 A special exemplary combination includes the use of therapeutic doses of hydroxymethylglutaryl coenzyme A inhibitors (statins), a less than therapeutic dose of interferon-tau (IFNt) and antacids are used For treatment, patients with multiple sclerosis follow the instructions for use. In other embodiments, the medicament group includes a therapeutic dose of Natta 84 20053 ^ 6 ^ natalizumab, and a therapeutic dose of interferon-tau (IFNt) to treat patients with multiple sclerosis, and according to the use Instructions for medication. In another embodiment, the medicament group includes a therapeutic dose of natalizumab, and a therapeutic dose of less than interferon-tau (IFNt), and an antacid for treating multiple sclerosis Patient and medication according to the instructions for use. The patient was instructed to take an antacid 5-30 minutes before taking interferon-tau (IFNt). Those who are familiar with this technique can recognize the different combinations, but it is only an exemplary illustration of how to use the dosage. With medication.

E. Formulations and Dosage Oral preparation of dosage forms to contain IFNt is a known method of preparing a pharmaceutical composition. Generally, IFNt treatments are formulated with effective IFNt doses with appropriate additives, carriers, and / or excipients to enhance the effectiveness of the oral dosage form composition. For example, tablets and capsules containing IFNt can use IFNt (lyophilized IFNt protein) in combination with additives such as pharmaceutically acceptable carriers (eg, lactose, corn starch, microcrystalline chlorophyll, sucrose), binders [eg: Alpha type Alpha-form starch, methyl chlorophyll, carboxymethyl chlorophyll, hydroxypropyl chlorophyll, hydroxypropyl methyl chlorophyll, polyvinylpyrrolidone], disintegrating agents (such as carboxymethyl chlorophyll calcium salt, Starch, low-substituted hydroxypropyl chlorophyll), surfactants (such as Tween 80, polyethylene-polypropylene-copolymer), antioxidants (such as: L-cysteine, sodium sulfite, vitamin C sodium) , Lubricant (for example: magnesium stearate, talc) or other similar. Further, the IFNi: protein of the present invention can be mixed with solid, powder or 85 20053¾ ^ other carriers, such as lactose, polysaccharide extract, sorbitol, mannitol, starch, such as potato starch, corn starch, mino fruit Millopectine, chlorophyll derivatives, gelatin, may also include lubricants, such as magnesium or calcium stearate, or polyethylene glycols, compressed to form lozenges. By using several layers of carriers or diluents, sustained release lozenges can also be prepared in this mode.

The liquid preparation of the serving route can also use standing medicines, syrups or suspensions. For example, the solution includes 0.1% to 30% by weight of IFNt, sugar and ethanol, water, glycerol, propylene, glycol, and other possible traditional natural Additives are mixed and compressed. Other suitable formulations are in the form of protective dosages, hoping to pass protein through the stomach and small intestine until it is absorbed by the small intestinal mucosa. The protective dosage form is a conventional technique that includes an outer layer of the intestinal membrane and / or a mucosal adsorption polymer coating. Exemplary mucosal adsorption polymer dosage forms include the use of ethylene chlorophyll, hydroxypropyl methyl chlorophyll, Eudragit®, carboxyvinyl polymers, carbomers, and the like. The dosage form is designed to conduct an effective dosage form of IFNt into the intestine through the stomach and digestion, especially the small intestine. In addition, IFNt can also be administered with protease inhibitors at the same time to stabilize polymer materials or encapsulate a layer of lipid or polymer particles to provide protection in the stomach and / or intestines. The administration of an orally effective IPNτ pharmaceutical composition is based on the effective therapeutic dose required by the subject. The dose may be considered based on the severity of the abnormality and other factors, such as the patient's age, weight, or similar factors that the patient is taking. The dosage is basically determined by the attending physician. The dosage range is from 20053 fiber 1 * 104 to 1 * 101 () units / day, and a more suitable dose is 4 * 108 units / day, preferably greater than 1 * 109 units / day.

The control of some abnormal conditions requires the steady increase of IPNτ in the plasma, and the effective administration interval is every two to four hours; other examples, such as multiple sclerosis, can be treated less frequently than the foregoing, for example, once a day or every 48 hours . The frequency of dose adjustment is also determined by the attending physician, and the dose can be reduced when the condition decreases. As described in the previous method of oral administration, carefully consider the first dose in the patient in need of treatment and simultaneously monitor the physiological target to determine the individual patient's response to the first dose. Patient monitoring can be analysed through a pattern of physiological targets in the blood, such as interleukin 10 (IL-10) in the blood using, for example, ELISA or radioimmunoassay test groups. Therefore, another consideration of the present invention is to use a combination of medicaments to treat patients with interferon response or consider patients treated with interleukin-10 (IL-10). The medicament combination includes a first part, which comprises a device containing one or more dosage form units suitable for oral administration of interferon tau (IFN〇 and a second part comprising an interferon tau (IFNt) which requires monitoring Biomarkers, such as this component, need to analyze the blood concentration of interleukin 10 (IL-10). Interferon tau (IFN0) administration is usually continued for several times until the clinical endpoint is reached. The clinical endpoint changes with the treatment status, the severity of the disease, and Individual patient characteristics (young age, weight, health status). Clinical endpoints are determined by the attending physician or nurse from the stopping range of temporary or permanent symptoms to resolve the condition. For example, patients suffering from autoimmune disorders such as psoriasis and Interferon tau (IFNt) treatment continues until the psoriasis is completely cured or improved to the expected assessment criteria of 87 20053 loop c symptom relief. A suitable clinical endpoint in patients with multiple sclerosis is to reduce the severity of the disease. People with viral infections The appropriate clinical end point for patients is to reduce the virus titer index or reduce the symptoms of related viral infections (onset Fever, pain, discomfort, etc.).

When the patient has the characteristics of cell proliferation, the appropriate clinical endpoint to stop the administration of interferon tau (IFNt) would be to stop the deterioration of the cell proliferation rate, and to measure the size of the tumor, or to delay the proliferation of the cell is like measuring tumor growth Reduced rate. For example, ‘when patients are suffering from Alzheimer ’s disease only, endogenous amyloid plaques and / or neurofibrillary tangles may be observed in some patients. Reduce memory loss, worse language ability, confusion, restlessness, and emotionalization; and improve mental capacity of behavioral ability and distortion of the facts seen, the above can be observed and evaluated using standard methods. For individuals with pulmonary fibrosis, suitable clinical endpoints include improved breathing ability, reduced disease progression, evidence such as a quantitative assessment of reduced lung tissue fibrosis, and / or lung inflammation. Interferon tau (IFN〇 Change the effect of reducing lung function 'includes comparing patients' respiratory function before and after treatment. Measurement methods are known to those skilled in the art and can include measuring forced exhalation within one second. Air volume (FEVI) is described in the following documents, for example ^

Pellegrino, R. W α / ·, Wu " Factory. J ”JJ; 543-54Q μ n. ,, r / 々y \ iyyl) ° |) ^ The method of low lung fibrotic scab tissue is well known Those skilled in the art are known to be 88 2005339, and may include measuring the hydroxyproline content in lung tissue, or other similar procedures known to those skilled in the art, as described in Example 9. Observation methods for inflammation are also known to those skilled in the art, including those discussed in Example 9.

For individuals suffering from liver fibrosis, suitable clinical endpoints include measurement of reduced liver fibrosis and crust tissue. Methods known to those skilled in the art include liver histopathology, and literature such as Desmet, VJ et al, Hepatology J_9: 15 13-1520 (1994) or Chevallier, M. et al., Hepatology, 2_0: 349-355 (1994). Reduce serum hyaluronic acid concentration and hydroxyproline (hydroxixypi * 〇liiie 丨) content, and the measurement method is the observation method described in Example 8. In addition, reduce the concentration of different liver enzymes in the serum, including asparagus Acid transaminase (AST) and alanine transaminase (alt), measurement methods are also known to those skilled in the art, and can be used for monitoring and evaluation. For individuals with a history of stroke, suitable clinical endpoints include Affected vascular blood flow is assessed using computer tomography methods, such as those described in the literature, such as in Nabavi, DG W α / ·, Xinshan · 0 /%, (1999). Further clinical endpoints include a reduction in hemp Conditions such as on the face, arms, or legs; or even reduce the severity of a headache caused by a stroke. Other suitable clinical endpoints include reducing the death of cells or tissues from a stroke. For example, reducing blood or tissue damage can also protect the brain. Using imaging techniques, including computer-assisted tomography (CAT), magnetic resonance imaging methods, or similar methods known to those skilled in the art. Individual neuritis, a suitable clinical endpoint improvement comprising

S 89 200533 Lion vision, stable vision (eg, no further deterioration of vision) or worsening vision loss. Those skilled in the art should know how to determine the clinical endpoint. In individuals with obstructive pulmonary disease, suitable clinical endpoints include improved lung function or other reductions in the degree of obstruction. The determination of clinical endpoints can be achieved by, for example, a pulmonary function test, in which a patient is required to inhale gas into a spirometer, and a mechanical device records the amount of inhaled and exhaled gas in a patient's lungs over time.

In individuals with autism, the clinical endpoint depends on the patient's specific symptoms of autism. Symptoms include abnormal social behavior, speech, repetitive behaviors and abnormal daily behaviors. For example, people with autism often show no speech, non-verbal vocalizations, unconscious imitation of other people's speech, and confusion about pronouns such as "I" and "You", lack of eye contact, lack of reaction to people, and walking on tiptoes. The aforementioned abnormalities can be evaluated by conventional methods. Individuals suffering from different autoimmune disorders, including diabetes, allergies, intestinal inflammation, psoriasis, arthritis, multiple sclerosis, uveitis, and anti-phospholipid syndrome. Clinical endpoints depend on specific diseases and Depending on the situation. For example, when suffering from anti-phospholipid syndrome, suitable clinical endpoints include reducing the amount of antibodies directly against cell membrane anions [such as anti-cardiolipin, anti_phosphatidylserine], or other related plasma Protein [for example, β-2-glycoprotein (β-2-glycoprotein)]. Quantitative titration of antibodies or cytoplasmic proteins can be detected by conventional methods, including the use of enzyme immunoassay (ELISA), 2005333 ^ Sc method, as described in the literature Pierangeli, SS · et al ·, 77 ^ m6. Haemost., 74: 1361-1367 (1995) o Other suitable clinical endpoints for individuals suffering from anti-phospholipid syndrome, including reduction of vascular thrombosis, occur extensively in tissues and / or organs. Observation of reducing vascular thrombosis can be determined by observing the blood flow of affected tissues or organs by computer tomography. For example, the method described in the following, Nabavi, D.G. et al.,

213: 141-149 (1999). Reducing vascular thrombosis can also be detected pathologically. Skin or other involved tissues can be analyzed. For example, pathological sections from the affected kidney may show reduced microembolism of the glomerulus or arterioles. The exception is that the size of the thrombus, the thrombus and the rate of disappearance can all be observed using a fiber optic device. Through the transillumination of the vein and a trilocular stereoscopic operating microscope, a microscopic device is used for monitoring and recording in a closed loop video recording system. Detailed descriptions are described in Pierangeli, SS et al., C / rcw / α "., £ 1: 1746-1751 (1996) and Example 10. Appropriate clinical endpoints for diabetes include controlling blood glucose levels and decreasing the amount of insulin. Appropriate clinical endpoints for different allergies include reducing asthma, sneezing, watery eyes, nausea, vomiting, or diarrhea, etc. and allergies Relevant symptoms' measurement methods can be measured by conventional methods. Suitable clinical endpoints for inflammation of the gastrointestinal tract include Crohn's disease (2005), and Crohn (s disease) and ulcerative colitis (ulcerative colitis), including reducing the symptoms of different diseases, such as the degree of diarrhea, abdominal pain, and / or cramps, cramps, and blood loss Quantity, promote appetite, reduce fever associated with disease. Appropriate clinical endpoints for psoriasis include quantified reductions in the characteristics of the disease, dryness, red shifts of skin covered with silvery fish scales, or reduction of swelling and stiffness in affected joints.

Appropriate clinical endpoints for arthritis, such as rheumatoid arthritis, can observe improvements such as reduced pain and joint swelling, and increased range of patient motion. Enhances the strength of the muscles attached to the joints. Suitable clinical endpoints for multiple sclerosis include reducing the number of episodes of the disorder and reducing the number of brain injury sites. Suitable clinical endpoints for uveitis include anterior uveitis, intermediate uveitis, posterior uveitis, and diffuse uveitis. Including improved vision, including no further visual deterioration, 'reduces the severity of mosquito disease. Reduces painful red eye, and photophobia are observed in patients with anterior uveitis. Suitable clinical endpoints for allergic patients include reduction of allergic reactions, such as swelling of mucosal tissue, reduction of infected tissue and overall IgE concentration. Patients with suitable clinical endpoints in organ transplantation include, for example, increased success rates. Appropriate clinical endpoints of atherosclerosis depend on some specific symptoms of the patient. For example, the blood flow of a patient's blood vessel or vessels has decreased. Therefore, 'appropriate clinical endpoints include increased blood flow in selected vessels. 92 2005333k6ft degrees of measurement are known to those skilled in the art, including Laser Doppler Flowmetry (LDF), NMR Resonance [Magnetic Resonance Imaging (MRI)], Positron Emission Tomography (PET), and computed tomography (Computed Tomography (CT) Imaging], including single photon emission computed tomography [Single Photon Emission Computed Tomography (SPECT)] (Leenders, KL et al. 1 13: 27-47 (1990);

Sakai, F. et al.? J. Cereb. Blood Flow Metab., ^: 207-213 (1988); Rempp, KA et al5 Radiology, 193: 637-641 (1994); Baird, AE et al. 5 J Cereb. Blood Flow Metab., 18: 583-609 (1998); Danus, G. et al.? Radiology, 213: 141-149 (1999); Calamante, F. et al., J. Cereb. Blood Flow Metab., 19: 701-735 (1999); Ginsberg, MD et al. 5 J, Cereb Blood Flow Metab., 2 (1): 89-98 (1982); Fukuda, 0.? Neurosurgery, 36 (2) : 358-364 (1995); Perez-Pinzon et al.? J. Neurolog. Sci., 153 (1): 25-3 1 (1997); Borlongan et al. 5 Brain Res. Im (l-2): 108-116 (2004)). If the patient's condition changes from atherosclerosis to angina, a reduction in the associated pain condition can be observed. If the patient's condition changes from atherosclerosis to peripheral vascular disease, conditions that reduce intermittent claudication and sexual dysfunction can be observed. Other suitable clinical endpoints are known to the skilled artisan. Once the expected clinical endpoint is reached, daily interferon-tan (IFNt) treatment can be stopped. If necessary, the maintenance dose can continue to provide subsequent doses or frequency of administration, but can be reduced regardless of the dose or frequency. # 0 Spoon symptoms persist. IV. Examples The following examples further describe the essence of the present invention without thereby limiting the scope of the present invention. Method A. Bovine production of IFNT

In this example, the synthetic IFNT gene is generated using standard molecular methods (proposed by Ausubel et al., 1988), and the IFNt amino acid sequence is encoded by a DNA sequence comprising a contiguous portion of the oligonucleotide. For the DNA sequence, SEQ ID NO: 1 or 4 or a sequence published by Imakawa et al. In 1987 was used. Causes the IFNt sequence to polymerize the glycine recognition sequence across positions 16 to 531:-each coding sequence is 172 amino acids. In this example, a full-length synthetic gene Stul / SStl fragment (540 bp) can be selected into an adjusted pIN III omp-A expression vector and transformed into a competent SB221 E. coli. To express the IFNt protein, the cells carried the expression vector from L-broth containing ampicillin to a 0.1-1.0 OD (550 nm), which was triggered (isopropyl-1thio-β-D-galactose) for 3 hours And the finished product is collected by centrifugation. Soluble recombinant IFNt is released from the cells by ultrasonic vibration or osmotic separation. When expressed in yeast, the IFNt gene can be amplified by polymerase chain reaction (PCR) (PCR; Mums, KB US Patent No. 4,683,202, approved on July 28, 1987; Mullis, KB US Patent No. 4,683,195 , Approved on July 28, 1987) Polymerase chain reaction 94 200533 ^) 6 (90 primers (PCR Primers) contains Still and Sacl restriction ends, in order at the 5 'and 3' ends, respectively. Still and Sad digest and link to pBLUESCRIPT + (KS) on the SacII and Smal ends to produce pBSY-IFNi. The plastid pBSY-IFNi is digested by SacII and EcoRV and the fragment includes a synthetic IFNt group

Because it was separated. The yeast expression vector pBS24Ub (Ecker, DJ. Et al., J. Biol Chem. 264: 77 1 5-7719, 1989) was digested by Sail. Blunt ends are produced using T4 DNA polymerase. DNA carriers were extracted and precipitated with phenol and ethanol (Sambrook, J., et al., Molclar Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York). The recovered plastids were digested with SacII, purified by agar gel electrophoresis, and ligated with the Sadl-EcoRV fragment isolated from pBSY-INFi. The resulting recombinant plastid was defined as pBS24Ub-IFNT. The recombinant plastid pBS24Ub-IFNi was transfected into E. coli. Recombinant genetically selected clones containing inserted IFNt were isolated and identified by restriction enzyme analysis. The IFNt coding sequence contains an isolate from PBS24Ub-IFNT and is cloned into a yeast vector containing an alcohol oxidase (AOX1) promoter (Invitrogen, San Diego). The vector was used to transform yeast GS115. The performance of host cells and proteins is according to the manufacturer's instructions. The protein was secreted into the culture medium and subsequently analyzed by DEAE-chlorophyll and hydroxylapatite chromatography to homogeneous electrophoresis, and then determined by SDS-PAGE and silver staining. B. Antiviral testing to determine antiviral activity Antiviral activity is performed using a standard cytopathic effect test (Familletti, PC et al. Published in Enzymology, 78: 387-394 in 1981; Rubinstein, S. et al. In JK / ro / , U55-7584 200533 ^^^ published in 1981). Briefly, the diluted IFNt was maintained in a 37 ° C incubator with Madin-Darby bovine kidney (MDBK) cells for 16-18 hours. Subsequent culture inhibition of viral replication is challenged with vesicular stomatitis virus (VSV) using a cytopathic effect test. A virus unit can produce a single-layer destruction with a 50% reduction. For most studies, IFNt has a specific antiviral activity of about 4.9 * 108 virus units / mg protein. Example 1 Administration of interferon-tan (IFNd to patients with multiple sclerosis)

Fifteen patients with multiple sclerosis were screened for clinical investigation and treated with interferon-tau (IFNt). Three patients were randomized into three groups. Group I was given oral interferon-tan (IFNt) at a daily dose of 0.2 milligrams (mg) [meaning 2 X 107 units / day (U / day)]; group II was given oral interferon-tau (IFNt) ) A daily dose of 0.8 milligrams (mg) [meaning 8 x 107 units / day (U / day)]; at the same time, Group III was given an oral interferon-tau (IFNt) daily dose of 1.8 mg ( mg) [meaning 1 · 8 × 108 units / day (U / day)]. Before receiving interferon-tau (IFNt) treatment, each subject took a blood sample to determine the baseline cytochrome concentration in serum on the screening day and the first day of investigation. Treatment started with oral interferon-tau (IFNt) administered to each patient on the first day after blood drawing. Prior to administration, the syringe loaded with interferon-tail [ENT (SEQ ID NO: 3)] was kept in the refrigerator at 2 to 8 ° C. Before self-treatment, the patient takes a vial and syringe from the refrigerator before taking the medication. Remove the cap from the top of the syringe and remove the appropriate amount of medication from the syringe into the bottle into the syringe as indicated on the first day of delivery. The tip of the syringe is placed on the mouth, and the contents are emptied to the mouth by pushing the piston. disease

96 200533 Miscellaneous people then swallow the medicament, which can be accompanied by a glass of water if needed. The patient records the dose taken on his / her diary card. Blood samples were taken from each patient at 1, 4, 8, 15, 29, and 57 during the study period. Sample analysis Interleukin 10 (IL-10) and IFN-γ concentrations were measured using a commercially available ELISA test set (Genzyme, Cambridge, Mass). The results are shown in Figures 1A-1D (IL-10) and Figures 2A-2D (IFN-γ), which are the same as Figures 3A-3E (IL-10 and IFN-γ). A. Statistical analysis of results € 11 Fifteen patients with relapsed polydose were given oral interferon-tau (IFN1 :) (0.2 mg, 0.6 mg, and 1.8 mg) at three different doses daily for four weeks. Serum samples were obtained on screening days and intensive investigations 4, 8, 15, 29, and 57 and the interleukin 10 (IL-10) concentration and the amount of interferon _ gamma (IFN-γ) were measured (pg / ml). The two sets of results were repeatedly analyzed throughout the process and statistical variance analysis measurements were performed. For all 90 data points (Day 1 _ Day 57), nine numbers are using the previous number. Interleukin 10 (IL-10): Analysis found no significant differences in the results of the three groups at different doses. (P = 2 · 92, P = 〇 · 〇927), there was no significant effect from the time analysis (F = 0.70, P = 0.6285). There was also no significant difference in the interaction between the group and time (F = 0.74, P = 0.6803). The results showed that the concentrations of interleukin ι〇 (ΙΣ ^ 1〇) remained unchanged in the three experimental groups after 28 days of interferon-tan (IFNt) administration and tracking. The average change in dose from day 1 to day 29 from low to high dose group was 7%, 3%, and -25% in order. The average change to the 57 days of the three dose groups was 10 ° /. , -10% and. In all cases, the data were highly heterogeneous in the three groups. 97 Interferon-gamma (IFN-γ): Analysis showed no significant difference among the three groups (F = 1.06, P > 0 · 3769), and the effect of time had no significant effect (F = 1.86, P = 0.1140) There was also no significant difference in the interaction between groups and time (F = 1.45, P = 0.1820). Shows three groups of administered doses at 24 days and 28 days

During the tracking period, there was no significant change in the amount of interferon-gamma (IFN-γ). The average change in dose from day 1 to day 29 from lowest to highest was -63%, -14%, and 35%. The average change on day 57 was -27%, 46%, and 22% in the three dose groups. Similar to the analysis of interleukin 10 (IL-10), the data has high variability in the three groups. Example 2 Administration of interferon-tan (IFNd—three times a day to a disease infected with C_A. Preparation of interferon-tail (IFNt) On the first day, a bottle of interferon-tan (IFNt) (SEQ ID NO : 3) Take out from the refrigerator and self-administer the appropriate amount of test substance according to Table 2. Interferon-tau (IFNt) (SEQ ID NO: 2) is also prepared and phased.

Give in the same way.

Table 2 Genetically Recombinant Sheep Interferon-tau (IFNO Dosage to Patients in Dose Group Patients Interferon tau (IFNx) (mg / mL) Volume (mL) Per Dose (TID) Total Daily Dose (mg) Daily Total Dose (U) I 6 1.0 0.33 1.0 1 X 108 II 6 1.0 1.0 3.0 3 X 108 III 6 1.0 3.0 9.0 9 X 108 98 20053 The refrigerator is maintained at 2 to 8. The patient removes a vial and syringe from the refrigerator before self-administration. On the first day, remove the cap from the top of the syringe and place the syringe in the bottle to remove the appropriate amount. The medicine is put into the syringe. The top of the syringe is placed on the mouth, and the contents are emptied to the mouth by pushing the piston. The patient then swallows the medicine, and if necessary, can also drink a glass of water. The patient is on his / her diary card Take the dose on the record. Βι The previous steps are repeated three times a day at approximately eight-hour intervals: once in the morning, once at noon, and once in the evening. C.

Blood samples were collected at regular intervals throughout the 169-day study period. Blood samples were analyzed for interleukin-10 (IL-10) and iFN-γ concentrations in serum using the ELISA test group (Genzyme, Cambridge, Mass) in accordance with the manufacturer's instructions. Virus titration of type C virus can use reverse-transcriptase polymerase chain reaction (RT-PCR), blood concentration 2 ', 5' low adenylate synthetase (〇AS) 2 ', 5' The determination of low adenylate synthase (0.88) and serum alanine transaminase (0.81 ^) concentrations has not been recorded. The results for each subject are shown in Figures 4A-4D [Interleukin 10 (iL-10) concentration] and Figures 5A-5D (IFN-γ) and Figures 6A-6F (IL-10 and IFN-γ). 99 2005¾㈤ Grade D. Statistical analysis results Three sets of results Three sets of results Perform repeated analysis throughout the entire process and make statistical analysis of variance. A patient profile from group Π was not used because of a lack of baseline for serum samples. For all 204 data points (days 1 to 204), seven omissions were made in the two measurements, and the previous data were used to complete them.

Interleukin 10 (IL-10): The analysis found that there were statistically significant differences among the three groups (F = 12.08, P = 0.0009), and the time analysis had a significant impact (F = 11.20, P = 0.0001 ) Moreover, there was no significant difference in the interaction between the groups and time (F = 7.88, P = 0.001) ◦ It was later found that the interleukin 10 (IL-10) response was clearly seen between the three groups during the study period The difference of change. Called the low-dose group [Group I; 0.33 milligrams (mg) —three times a day (TID)] produced a 22% increase in interleukin 10 (IL-10) concentration from day 1 to 43, and group II [1 milligram (mg)-three times a day (TID)] On the 29th day, a peak response was 114%. In contrast, in group III [(3 milligrams (mg) — three times (TID)] increased by 387% on day 43 and a peak response occurred on day 71 and a peak response of 484%. Significant The interaction also supports the trend of a decrease in the concentration of interleukin 10 (IL-10) in the dose group, and the dose stopped on the 84th day: the decrease of the group I was increased from 11% on the 85th day to 4% on the 169th day, And the decrease of group II was from 95% to 0.5% during the same period. So the two lowest groups returned to the baseline six months after the cessation of the drug. The highest dose group [group 111; 3 milligrams (mg) a Three times a day (TID)], however, the decline from 453% to 194% occurred on day 169, so it still showed a substantial increase even after the drug was stopped for six months. Interferon-gamma pseudo (IFN-γ): Analysis It was found that the results of the three groups at different doses (100 2005333 ^ 60) were not significantly different (F = 1.13, P > 0 · 3499), and the analysis found that the results of the three groups at different doses were not significantly different (F = 1.55, P = 0.187) And there was no significant difference in the interaction between groups and time (F = 1.39, P = 0.1275). Interferon-gamma (IFN-γ) concentrations showed no significant changes in the three experimental groups on the 84th day after interferon tan (IFNt) administration and the 84 days following the termination of administration. The average changes from day 1 to day 85 were -6%, 8%, and 7% from lowest to highest, respectively. Interestingly, the three groups on average changed to doses of 4%, 21%, and 31% in order on day 169, showing a dose response after discontinuation. Example 3 Administration of Interferon-tau (IFNi :)-twice a day to a disease infected with type C virus

A

Five patients infected with type C virus were included in this study. Patients were treated with Interferon-tau (IPNτ) according to Example 2. Each patient was given Interferon-tau (IFNt) 7.5 milligrams (mg) twice a day, and the total daily dose was 15 milligrams (mg) 5 X 109 units (U)]. The first dose is taken before breakfast in the morning. The second dose was taken three hours after dinner. Blood samples were taken from each patient on a regular basis for 113 days during the study period. Samples were analyzed for interleukin 10 (IL-10), interleukin 12 (IL-12) concentrations, and interferon-gamma (IFN-γ) concentrations, using a commercially available ELISA test group (Genzyme, Cambridge, Mass). The results are shown in FIG. 7A [Interleukin 10 (IL-10)], FIG. 7B (IFN-γ) and FIGS. 8A-8D. The four patients [IL-10 (IL-10), IL-12 (IL-12), and Interferon-gamma pseudo (IFN-γ)]. 200533¾ ^ Example 4 Administration of Interferon-tan (IFNt) for Psoriasis

Forty-five patients clinically diagnosed with chronic plaque-type psoriasis (vulgaris psoriasis) had at least 10% of the affected area, excluding skin exfoliation, and were randomly assigned to three treatment groups. Group I took 1 milligram (mg) of oral interferon-tan (IFNt) —three times a day for a total daily dose of 3 milligrams of interferon-tau (IFNt). Group II took 3 milligrams (mg) of oral interferon-tail (IFNt) three times daily for a total daily dose of 3 milligrams of interferon-tau (IFNt). ◦ Group III was treated with placebo. The antiviral activity of interferon-tan (IFNi :) is about 5 x 108 antiviral units per milligram (Units / mg) of protein; so a 3 milligram (mg) dose is equivalent to 1.5 X 109 units per day (Units / day), and a dose of 9 milligrams (mg) is equal to 4.5 x 109 Units / day. Interferon-tan (IFNt) is used as a pharmaceutically acceptable carrier in liquid form, allowing each patient to be digested and metabolized immediately after swallowing U-yan. The dose lasted for 84 days. Fourteen days before the start of treatment and the first day of treatment, each patient was evaluated using a physician statistical global assessment (PSGA). As for 0, 1, 2, 3, 4, or 5 of the PSGA score table, each patient is evaluated according to the following conditions: 0 = recovery, except for sequelae such as discoloration; 1 = most wounds have individual evaluations, Such as induration, erythema, the average rating is 1; 2 = most wounds have individual ratings, such as induration, erythema, scale-like debris, the average rating is 2; 3 most of the wounds have individual ratings, such as induration, Red 102 20053 (¾ Secret spot, scale-like debris, average rating is 3; 4 = Most wounds have individual ratings, such as induration, erythema, scale-like debris, average rating is 4; 5 = Most wounds There are individual evaluations, such as induration, erythema, and scale-like debris, and the average evaluation is 5. For the evaluation of induration, there are 0, 1, 2, 3, 4, or 5 based on the following conditions: '〇 = no block protrusion ;

1 = smallest segment protrusion, ~ 0.5 mm; 2 = slight segment protrusion, ~ 1 mm; 3 = moderate segment protrusion, ~ 1.5 mm; 4 = obvious segment protrusion, ~ 2 mm; 5 = Severe lumps, ~ 2.5 mm or more; For the evaluation of scale-like debris on the skin, specify 値, 1, 2, 3, 4, or 5 according to the following conditions: 〇 = no scale-like Debris; 1 = slightest; occasionally small scale-like debris is less than 5% of the wound; 2 = slight; small scale-like debris is dominant; 3 = moderate; rough scale-like debris is dominant; 4 2 Obvious; thick, non-tenacious scale-like debris is predominant; 5 = severe; very thick, tenacious scale-like debris is predominant; there are 0, 1, 2, 3, 4 designated for the red shift assessment , Or 5 according to the following conditions: 20053 〇 = no red shift, there may be pigmentation; 1 = weak red shift; 2 = mild red; 3 = moderate red; 4 bright red; 5 = dim deep red;

Each patient also was provided with a Psoriasis Area and Severity Index (PASI) assessment before treatment (Fredrikkson, Ύ. Et al., Dermatologica, 157: 238 (1978)). As for the psoriasis area and severity index (PASI score), the extent and severity of wounds on the patient's head, trunk, upper limbs, and lower limbs were evaluated as described in the Fredrikkson W a. During the dose on day 84, each patient had a PASI rating and a PSGA rating on days 1, 8, 15, 29, 43, 57, 71, and 85. After the study was terminated, evaluations were performed again on the 113th and 169th days. Patients achieved 0, 1, or 2 PSGA and / or achieved a 75% improvement in PASI. Example 5 Administration of interferon-tan (IFNt) combined with a second therapeutic agent Patients with multiple sclerosis are administered oral interferon-tan (IFNt) at a total dose of 5.5 x 108 units (ϋ) twice a day . Every 28 days, the patient was injected with a dose of 3 mg / kg (mg / kg) of natalizumab by intravenous injection 104 2005333i69c. The patient was treated for six months according to the course of treatment, and then brain damage was detected using unenhanced proton density T2-weighted magnetic resonance imaging, and enhanced τι weighted magnetic resonance image scanning. During the treatment, blood samples were taken for analysis of cytochromes [interleukin 10 (IL-10), interleukin 12 (IL-12), and interferon-gamma (lFN-γ)]. Example 6

Administration of interferon-tau (IFNt) combined with a second therapeutic agent. Oral interferon-tau (IFNt) was used to treat heart transplant patients at a total dose of 5.5 x 108 units (U) twice a day. Oral mycophenolate mofetil (trade name Mycophenolate Mofetil) was dosed at 500 mg / day. Blood samples were taken during the treatment to analyze cytochromes [Interleukin 10 (IL-10), Interleukin 12 (IL-12), and Interferon Gamma Bureau (IFN-γ)]. The patient's life continued while treatment continued. Example 7 Administration of Interferon-tan (IFNt) to treat AIDS This example shows that interferon-tan (IFNt) is advantageous for the treatment of AIDS. This study was performed using a transgenic mouse module with AIDS and AIDS. One group of mouse modules received interferon-tan (IFNt) treatment while the control group received no treatment. It is expected that the transgenic mouse module could confirm the reduction of brain scar and amyloid. Decreased brain microglial and astrocyte activity. 90-day-old hybrid PDAPP with APPV717F denatured transgenic male mice (for example, substituted phenylalanine (Phe) to glutamic acid (Val) and passed through Health 105 2005333f69. Amyloid precursor protein (APP) ] Murrell, J. et al., Sc / Mce, 254 (5028): 97-99 (1991) can be purchased from Taconic Farms (Germantown, NY) as discussed in the following example literature and maintained in the country of reference. The NIH Guide has standard laboratory conditions for the care and use of experimental animals. Rats are raised in a 12-hour light and 12-hour dark environment. Mice can eat and drink animal feed and water freely.

Immunohistochemical staining and pathological staining of mouse brain to determine scar quantification are described in the following literature examples, Weiner, Η 丄. Et al., X⑽.A ^ ro /., Ϋ: 567-579 (2000). In general, formalin, fixed brain tissue can be washed with Tris-buffered saline, dehydrated and dried, and combined with stone processing. Sagittal sagittal sections of brain tissue (for example, 10-micron sections) can be air-dried and baked at 5VC for one hour. Sections can be deparaffinized with a cleanser such as Histoclear (National Diagnostics, Atlanta, GA), and wet with ethanol to water. Mice can be administered different interferon-tau (IFNt) [eg about 1 X 105 units / day (U / day) to about 5 X 1012 units / day (U / day)] orally (in the stomach ) Give. Example 8 Effect of Interferon-tau (IFNt) in Treating Liver Fibrosis This example shows that interferon-tau (IFNt) is advantageous in treating liver fibrosis. Liver fibrosis can be initiated with carbon tetrachloride in experimental animals. 106 200533a6a〇 A group of experimental animals treated with carbon tetrachloride was treated with interferon-tail (IFNt). The control group only gives the carrier. It is expected that experimental animals treated with carbon tetrachloride will demonstrate that interferon-tail (IFNt) treatment delays disease progression. Sprague-Dawley mice weighing 200 to 250 grams can be purchased from Taconic Farms (Taconic Farms, Germany, New York) and raised as described in Example 7.

Liver fibrosis can be achieved by peritoneal injection of carbon tetrachloride as described in the following literature Zhang, L.J. et al., J. GaWroeWero /, 10: 77-81 (2004). In principle, rats received an intraperitoneal injection of a 50% solution of carbon tetrachloride in physiological saline at a dose of 2 ml / kg (ml / kg)-twice a week. Liver fibrotic tissue can be fixed for standard stone processing. (Zhang, LJ et al. 5 World J. Gastroenterol ^ 1_0 (1): 77-81 (2004)) ° Sections can be stained with hematoxylin and eosin (HE) and light microscopy test. The fibrosis stage can be evaluated according to the set conditions as described in Desmet, VJ · et al ·, // epak / og ;;, I2_: 1513-1520 (1994) or Chevallier, M. et al ·, T / epaio / ogy, Division: 349-355 (1994). In order to determine the hydroxyproline content of the liver, the liver's harvest was first uniformly powdered and hydrolyzed with 6M hydrochloric acid (Weng, HL et al ·, RKor / dJ · Huaro / ·, 2 (1): 42- 48 (2001)). The measurement of the hydroxyproline content was performed by the method described in Kivirikko, K.L. et al. 5 Anal, Biochem, 19: 249-255 (1967). Mice can be treated with interferon-tan (IFNt) before, during, or after treatment with carbon tetrachloride. Mice can be administered with different doses of interference 107 20053S3r69c Tau (IFNt). (Eg, about 1 x 105 units / day (u / day) to about 5 x 1012 units / day (U / day)) are administered orally (intragastrically). The control group only accepts vectors. Example 9 Effect of Interferon-1au_ (IFNt) in Treating Pulmonary Fibrosis

This example shows that interferon-tau (IFNt) is advantageous for treating pulmonary fibrosis. Pulmonary fibrosis can be initiated with bleomycin in experimental animals. A group of experimental animals treated with bleomycin were treated with interferon-ta u (IFNt). The control group only gives the carrier. Indicators of inflammation, such as myeloperoxidase activity and serum tumor necrosis factor-alpha (TNF-alpha) in bronchoalveolar lavage fluid can be used for monitoring. Tissue hydroxyproline measurement can be used to monitor the degree of fibrosis. It is expected that experimental animals treated with bleomycin can demonstrate that interferon-tan (IFNt) treatment delays the deterioration of fibrosis and is judged by the content of hydroxyproline. At the same time, it is expected that in the experimental group and the control group, interferon-tan (IFNt) treatment can reduce the inflammation marker [myeloperoxidase] activity and serum tumor necrosis factor-alpha (TNF-alpha) and serum tumor necrosis Factor-alpha message ribonucleic acid (TNF-alpha mRNA)]. Eight-week-old C57BL / 6 males are commercially available from Harlan (Indianapolis, IN). The culture method is described in Example 7. In order to induce pulmonary fibrosis, rats received a single intra-tracheal administration of Bleomycin 108 20053ά3ι69〇 (0.8 mg / kg) (Arai, T. et al., Am. J. Physiol. Lung Cell.

Mol. Physiol., 21i: L914-L922 (2000)). The control group only gives the carrier. Mice were euthanized by inhalation of sevoflurane after the seventh day (to check the inflammation index) or after the 21st day (to check the fibrosis index). Blood from the right ventricle flows through the lungs. With bronchial alveolar lavage fluid (bronchoalveal lavage), 1 ml (ml) of isotonic physiological saline was slowly dripped into an endotracheal tube.

The myeloperoxidase activity of bronchoalveolar lavage is determined by the technique known in the past (Arai, T. et al ·, Am J. Physiol. Lung Cell. Mol. Physiol ·, m: L914 -L922 (2000)). Roughly, bronchoalveolar lavage was centrifuged at 400 g for 5 minutes. Cell pellets were suspended in 0.1 M K2HP04 buffer and sonicated for 90 seconds. 12,000 g of the mixture floating on the surface layer, centrifuged for 10 minutes, containing 0.3 ml of Hanks' BSS containing 0.25% bovine serum globulin, 0.25 ml of 0.1MK2HP04 (pH 7.0), and 0.05 ml of 1.25 mg / ml o-dianisidine (Sigma, St. Louis, MO) and 0.05 ml of 0.05% H202, and incubated at 25QC for 10 minutes. The reaction was measured by the addition of 0.5 ml of 1% NaN3 and its absorption spectrum at 460 nm. Mice treated with bleomycin can be treated with interferon-tan (IFNi :) before, during, and after bleomycin treatment. Mice can be treated with different doses of interferon-tau (IFNt) (eg about 1 X 105 units / day (U / day) to about 5 X 1012 units / day (U / day)) orally (intragastric) Give. Pleomycin 109 20053323i & 9) c (bleomycin) -treated control [group J only received vehicle. Example 10 Effect of Interferon-tau (IFNd in the treatment of anti-phospholipid syndrome (APS)

Examples show the advantages of using interferon-tan (IFNt) to treat anti-phospholipid syndrome (APS). Gravimetric objects were tested for anti-phospholipidation (APS) to inject human immunoglobulin G (IgG) anti-cardiolipin antibodies. The group receiving the anti-phospholipidation group (APS) was treated with interferon-tau (IFNi) and the control group received the vehicle only. The control of contusion of a vein to cause a thrombus, and the formation of a thrombus with the disappearance of the thrombus will be regarded as the effectiveness of treatment with interferon-tan (IFNt). It is expected that treatment with antibodies in mice treated with interferon-tau (IFNt) will increase thrombus formation time and reduce thrombus disappearance time. Normal male CD-1® nude mice (Crl: CD-l®-m ^ BR; outbred), convert naked genes to CD_1 mice through a series of intersections and backcrosses. The mice are T-cell deficient and can be tested from Charles River (Wilmington, MA) was purchased and cultured as described in Example 7.

IgG can be isolated from patients with anti-phospholipidation (APS) by protein G sepharose chromatography. (Pierangeli, SS ·, et al ·, Circulation 94: 1746-1751 (1996)) The purity of IgG can be determined by observing sodium dodecyl sulfate-poly acrylamide gel electrophoresis ( SDS-PAGE)] is determined by a single bond of 150 kD. The protein concentration can be determined by the Lowry 110 20053S3 ^ 9 method. After the protein concentration was adjusted with sterilized physiological saline, the solution was filtered and sterilized again for subsequent injection into experimental animals.

Mice were used at 150, 40-80 on days 14, 14 and 21? 8 Perform an adjuvant immune injection treatment (Adju-Prime, Pierce Chemical Co.) (Pierangeli, S.S., et al., Circulation 94: 1746-1751 (1996)). Blood samples were taken weekly to test the presence of anti-cardiolipin antibodies in mice. Mouse anti-cardiolipin antibodies (such as IgG and IgM) are quantified by enzyme-linked immunosorbent assay (ELISA), which is a method known to those skilled in the art. Literature records are for example in Pierangeli, SS, et al. Thromb. Haemost 74: 1361-1367 (1995). Alkaline phosphatase anti-mouse IgG and anti-mouse IgM are used as secondary and antibody ELISA test structures. When controlled in the forward direction, the color response can be terminated. For example, about 100 G phospholipid units reach 1.0 0D units (usually about 20 or 30 minutes). Anti-cardiolipin antibodies (e.g., about 0.8 OD units; usually occurring two weeks after the immune treatment) are produced in mice at considerable local concentrations, and thrombus initiation can be caused by small pinches such as the literature Pierangeli, SS · , Et al., Circulation 94: 1746-1751 (1996). In general, before the animals were anesthetized [sodium pentobarbital, 60 nmg / kg peritoneal introduction], a longitudinal incision was made in the right groin of the mouse and extended to the knee joint. The right femoral vein was not cut and the wound was standardized for thrombosis. Small pincers can be created with forceps near the vein until the opposite side of the ring (about 0.1 mm in diameter). 20053i32 ^ i ^ .Qc Optical fiber fresh device is used to illuminate veins and a three-dimensional spatial stereo microscope (ERNST, Leitz GMBH, Wetzlar) is installed in a closed loop video recording system (NEC-NC-A / CCD Camera, NEC, USA, Inc. ·), An international 12-inch color monitor (Panasonic 12 丨 丨 color monitor) and U-Matic V-5800 recorder (Sony Corp.) are used to observe and measure the size of blood clots to appear and disappear. Rate, documented in Pierangeli, SS, et al., Circulation 94: 1746-1751 (1996).

Mice were treated with injections of antibodies obtained from patients with post-phospholipidation (APS). Treated mice are then treated with different doses of interferon-tau (IFNt) (eg, about 1 X 105 units / day (U / day) to about 5 X 1012 units / day (U / day)) orally ( Intragastric). The control group only accepts vectors. Example 11 Effect of King Interferon-tau (IFNt) in the Treatment of Stroke This example shows the advantages of interferon-tan (IFNt) in the treatment of stroke. The stroke caused by the experimental animal can be sutured through the lumen to block the middle cerebral blood vessels. _ _ The stroke-prone group was treated with interferon-tau (IFNt) and controlled to prevent receiving carriers. The protective effect of interferon-tau (IFNt) treatment can be performed by assessing the size of the block and measuring the nucleus of apoptotic cells in the brain. The implementation of the measurement method is well known to those skilled in the art. It is expected that compared with the control group, the test mice can confirm that treating stroke with interferon-tau (IFNt) can reduce the size of the obstructed site, reduce the number of nuclei of apoptotic cells in the brain, and improve neural function. Male newborn Sprague Dawley mice (9-11 days old) can be purchased from Taconic Farms (Germantown, NY). Rat breeding methods 112 20053iS3i69 As described in Example 7.

Cerebral ischemia in Sprague Dawley mice can be blocked in the suture cavity as described in the literature Maier, CM et al ·, J. Neurosurg., 94: 90-96 (2001) and Bright, R. et al ·, J · Neurosci ·,

M (3 1): 6880-6888 (2004). Roughly, after the animals were anesthetized with isoflurane, the top of an uncoated 3-0 nylon suture with a length of 30 mm was fired into a round shape. The suture was placed at the root of the external carotid artery and further to the internal carotid artery approximately 19 to 20 mm from the bifurcation to block the small arteries in the midbrain area. 2 hours after ischemia, the suture was removed to allow the animal to recover. Behavior evaluation After 24 hours, reperfusion assessment was performed in four levels of 1-4 using the method described in Bright, R. W α /., M (3 1): 6880-6888 (2004): Level 1, Normal Position, can move spontaneously in any direction; level 2, when lifting from the tail, single claw can extend; level 3, when spontaneously walking, both claws can extend and circle; level 4, abnormal position, claw can The nucleus of apoptotic cells that extend and circle but cannot spontaneously walk can be measured with terminal deoxynucleotidyl transferase-mediated biotinylated UTP nicke end labeling (TUNEL). Bright, R. et al., JL Neurosci., M (31): 6880-6888 (2004). In general, the animals were euthanized after 2 hours of obstruction of the arteries in the middle brain using normal physiological experimental water and 4% paraformaldehyde for 72 hours. The brain can be isolated and fixed in 4% paraformaldehyde, infiltrated in 30% sucrose for 2 to about 3 days and rapidly cooled in OCT cyroprotectant 113 20053iS36Qc (Tissue-Tek, Miles, Eklkart, IN). Coronal sections (16 μm) can be sampled from each equal midbrain site, with each section separated by at least 48 μm. The sections can be stained and each section takes four localized images of the cortex.

Ischemic mice can be treated with interferon-tan (IFNt) before, during, and after ischemia treatment. (Eg, about 1 x 105 units / day (U / day) to about 5 x 1012 units / day (U / day)) are administered orally (intragastric). (Eg about 1 X 105 units / day (U / day) to about 5 X 1012 units / day (U / day)) are administered orally (intragastric). The control group only accepts vectors. Example 12 Interferon-tan (IFNt) treatment is an effect of neuritis This example shows the advantages of interferon-tan (IFNt) in the treatment of optic neuritis. In experimental allergic encephalitis (EAE), the animal model of optic neuritis is triggered in test animals. Animals in the experimental allergic encephalitis group will be treated with interferon-tan (IFNt) while the control group will receive the vehicle only. The protective effect of interferon-tan (IFNt) treatment can be determined by the degree of axon demyelination. It is expected that the rats with experimental allergic encephalitis (EAE) will exhibit the effect of reducing axon demyelination compared with the mice in the control group. SJL / J mice were purchased from Jackson Laboratories (Bar Harbor, Maine) and reared according to Example 7. Experimental rats with experimental allergic encephalitis (EAE) can be injected into the frond of the neck with a complete Freund's adjuvant by means of a spinal cord emulsion of homologous spine. As described in the literature, Guy, J., et al., Proc. Natl. Acad. Sci. USA 95: 13847-13852 (1998). The degree of demyelination can be quantified by measuring the electron micrograph of the transition of each optic nerve myelin sheath from axon, as described in the literature. Guy, J., et al., Proc. Natl. Sci. USA 95:13 847-13 852 (1998).

Approximately, the mice were euthanized and a fixative containing 4% paraformaldehyde in 0.1 M PBS buffer (pH 7.4) was poured into the heart perforation. Eyes with neuritis were removed for sectioning, and tissue samples were placed in 5% acrolein, 0.1 M sodium cacodyl ate, hydrochloric acid buffer (pH 7.4). It was fixed with 7% sucrose and dehydrated, polymerized with alcohol and LR White, and polymerized at 50 ° C overnight. Ultra-thin sections (for example, about 90 mm) are placed on a nickel grid to perform immunocytochemical techniques. Non-specific binding antibodies can be blocked by suspending on the grid of the plate containing 2% bony fish gelatin and 2% fat-free dry milk at 0.01 M TBS (pH 7.2) and Tween 20 for 30 minutes. The plate grid was reacted with rabbit anti-globulin antibodies, washed with water, and then combined with secondary goat anti-rabbit igG antibodies onto 10 nm gold particles and maintained at room temperature for one hour. The grid is then immersed in deionized water. Immunolabeled samples were recorded by electron microscopy without staining. Mice can be treated with interferon-tau (IFNt) before, during, or after treatment with spinal neuroemulsion, or after optic neuritis is initiated. Mice can be treated with different doses of interferon-tan (IFNt) (eg, about 1 X 105 units (U) / day to about 5 X 1012 units (U) / day) by oral (parenteral) administration control controls The mice in the group received the vehicle only. 115 Example 13 The effect of interferon-tau (IFNt) in the treatment of chronic obstructive pulmonary disease This example shows the advantages of interferon-tau (IFNt) in the treatment of chronic obstructive pulmonary disease. Patients diagnosed with chronic obstructive pulmonary disease ' include chronic bronchitis and emphysema and are treated with interferon-tan (ΚΝτ). The protective effects of interferon-tau (IFNt) treatment can be evaluated by improving lung function. It is expected that treatment with interferon-tan (IFNt) will prove effective in improving lung function.

Patients diagnosed with chronic obstructive pulmonary disease are given interferon-tau (IFNu) treatment at 0.5 X 109 antiviral units per θ. Assessment of change Assessment by lung (volume) method is common knowledge known to those skilled in the art. Example 14 Effect of Interferon-tan (IFNd in Treating Barren Autism)

This example shows the advantages of interferon-tan (IFNt) in treating autism. Patients diagnosed with autism are treated with interferon-tau (IFNt). The advantages of interferon-tau (IFNt) therapy are assessed by altering the patient's pre-existing mutational behavior. Patients are expected to have positive behavioral changes due to interferon-tan (IFNt) treatment. Patients diagnosed with autism are treated with interferon-tan (IFNt) greater than 0.5 X 109 antiviral units. Behavior change includes improved social behavior, speech, communication, and / or repetitive behaviors and daily behaviors are assessed in a way that is common knowledge to skilled artisans. 116 200533 Young Example 15

Effect of interferon-tau (IFNt) in treating atherosclerosis The example shows the advantages of interferon-tau (IFNt) in treating atherosclerosis. By feeding a high-cholesterol diet, atherosclerosis can be caused by mice with defective low-density protein (LDL) receptors. One group of mice received interferon-tan (IFNt) and the control group of mice received the vehicle. The protective effect of interferon-tau (IFNt) treatment can be determined by the degree of atherosclerotic scar development in the rat model. It is expected that mice treated with interferon-tau (IFNt) will have an effect on reducing atherosclerotic scar compared to mice in the control group. Low density protein (LDL) receptor defective mice can be purchased from Jackson Laboratories and the breeding method is described in Example 7. Atherosclerosis is triggered when mice are fed a high-fat diet. Cholesterol-related narratives are documented in Lichtman, A.man, et al., Arterioscler. Thromb. Vase. Biol. 19: 1938-1934 (1999) ο Aortic surface damaged by atherosclerosis can be quantified by en face oil red 〇 staining, the method is described in the following literature Lichtman, AH, et al., Arterioscler. Thromb. Vase. Biol. 19: 1938-1934 (1999 ). Roughly, rats were killed by inhalation with ether 12 weeks after the special diet. The left ventricle and arteries are drained with phosphate buffer saline (PBS), and the entire artery connected to the heart can be cut open and placed in formaldehyde overnight. The aorta can be stained with oil red 〇, the adventitial fat of the arteries can be removed and the aorta can be opened longitudinally, nailed on the black sand rubber disc and treated with phosphate buffer saline (PBS) Photographs during infiltration. Sections were scanned into the computer. 20053iS3i69c Oil red O-stained wounds can be identified with image analysis software (NIH Image). ○ When mice are given a high cholesterol diet, interferon-tan (IFNt) treatment can also be given. Mice can be administered orally (parenterally) with different doses of interferon-tan (KNτ) (about 1 x 105 units (U) / day to about 5 \ 1012 units (1;) / day). Control mice received only

Example 16 Therapeutic effects of interferon-tau (IFNt) and autoimmune disorders This example shows the advantages of interferon-tau (IFNt) treatment and / or prevents collagen-induced arthritis in mice [collagen-induced arthritis (CIA )]. Collagen-induced arthritis (CIA) is triggered by type II collagen in Balb C mice. Prior to priming, mice were treated with interferon-tau (IFNt). The advantage assessment of interferon-tau (IFNt) treatment is used to determine the degree of collagen-induced arthritis (CIA) in mice. It is expected that treatment with interferon-tan (IFNt) will reduce the incidence of disease in mice. The development and suppression of collagen-induced arthritis (CIA) in Balb C mice was performed by rejecting Balb C mice taking a single dose of interferon-tau (IFNt) on the day of immunization with type 2 chicken collagen. Causes collagen-induced arthritis (CIA). Collagen can be emulsified in complete Freund's adjuvant and H37Ra and injected into both sides of the mouse tail. Pertussis toxin was injected 48 hours after the date of immunization.

V 118 200533 ^ 6fi〇 gene synthetic cotton sheep ((^ 116) interferon seven 11 (1?) ^) Can be expressed in yeast (Pichia pastoris) using synthetic genes to construct. Protein can be secreted into the culture medium and purified. Continuous DEAE-cellulose and hydroxylapatite chromatography to isophase electrophoresis were determined by SDS-PAGE and then stained with silver.

Rats check the CIA signal daily. The severity of the disease is graded by the arthritis index as follows: 1. One foot is red and swollen. 3. One foot is red and swollen. 4. One foot is deformed. 4. Each additional foot Means that the index can be progressive. Mice receiving kidney transplants can be treated with interferon-tau (IFNt). Mice can be treated with different doses of interferon-tau (IFNt) (eg, about 1 X 105 units (U) / day to about 5 X 1012 units (U) / day) to be administered orally (parenterally). Control mice received only vehicle. Example 17 Effect of Interferon-tan (IFNd on Organ Transplant Rejection) The example shows that interferon-tau (IFNt) is helpful in preventing or improving organ transplant rejection. Kidney transplantation is performed in a mouse module. A group of mice Treatment with interferon-tan (IFNT), while the control group only gave carriers. The therapeutic effect of interferon-tau (IFNt) in allograft rejection was evaluated by the survival rate of renal allograft surgery, and Existing selective immune system cells will also be tested. Treatment with interferon-tan (IFNt) is expected to improve the survival rate of renal allograft surgery and reduce selective immune system cell transplantation. Inbreeding Fisher 3 (F344) and Lewis Rats can be from 119: 1 200533 ^ (^ 0:

Commercialized by Charles River Italia (Calco, Italy). Lewis mice can be recipients and Fisher can be donors. Animal rearing and maintenance is described in Example 7. Matters related to kidney transplantation are described in the following literature Noris, M.W α /., / Jm · 5W · # 卬 心 〇 / ·, 11: 193 7-1946 (2001). Donate roughly left

The kidney will be removed and reset to the correct local position of the recipient. The kidney blood vessels of the recipient will be isolated and clamped, and the original left kidney will be removed. The renal artery was joined point-to-point, and the vein and ureter were sutured with 10-0 Proleri suture. The original kidney on the right was sutured on day 11 after surgery. The failure of a completed allograft operation is defined as the death of the animal, as the animal undergoing the transplant operation must rely on the function of the transplanted kidney. Immunochemical analysis to select immune system cells was performed as described in Noris, M. a /., /. Dm · 1 ^: 1937-1946 (2001). In general, mouse monoclonal antibodies can be used to detect the following antigens: 1) ED1 antibodies; 2) MHC second-class II antigenic monomorphic determinants in mice; 3) CD4 cell surface glycoproteins; 4) CD8 in mice Cell surface glycoprotein; 5) Dendritic cell-restricted antigen in mice. All antigens can be analyzed using non-direct immunofluorescence techniques. After transplantation, mice can be treated with interferon tau (IFNt). Mice received several doses of interferon tau (IFN0 (e.g., about 1 X 105 units (U) per day to about 5 X 1012 units (U) per day)) administered orally (parenterally). Control The mice in the control group only received the carrier. · The present invention is described in detail with several specific examples, but it is not intended to limit the present invention. Without departing from the spirit and scope of the present invention, it can be done a little 120 20053ό ^ 3 ^ 9 Changes and retouching. [Schematic description]

Figures 1A-1C show the serum concentration of interleukin 10 (IL-10) in patients with multiple sclerosis after oral interferon-tau (IFNt :) administration in pg / mL, and the horizontal standard for time and day As a unit, the patient population was divided into groups I, II, and III, and 0.2 mg (mg) of interferon-tan (IFNt) (Fig. 1A) and 0.6 mg (mg) of interferon-tan (IFNi: ) (Fig. 1B), and 1.8 milligrams (mg) of interferon-tan (IFNt) (Fig. 1C) track the conditions from day one to twenty-nine.

Figure 1D shows the mean serum concentration of interleukin 10 (IL-10) in pg / mL. The patient population was divided into groups 1, 11, and 111. 'Interferon-tau was administered with 0.2 milligrams (mg) daily. (IFNi) (diamond pattern, group I), 0.6 milligrams (mg) of interferon-tan (IFNt) (square, group I), and 1.8 milligrams (mg) of interferon-tau (IFNt) ( Triangle 'Group I) Track conditions from day one to twenty-ninth. Figures 2A-2C show the serum concentration of interferon-gamma (IFN-γ) in patients with multiple sclerosis after oral administration of interferon-tau (IFNT) is in pg / mL. Patients were divided into groups of 1, 11, and III on a daily basis. Interferon-tan (IFNt) (Fig. 2A) and 0.6 milligrams (mg) of interferon-tau (mg) were administered daily. IFNt) (Fig. 2B), and 1.8 milligrams (mg) of interferon-tau (IFNt) (Fig. 2C) tracked conditions from day one to twenty-ninth. Figure 2D shows the average serum concentration of interferon-gamma (IFN-γ) in pg / mL. The patient population was divided into groups I, Π, and III, which were administered 0.21 daily.

20053 ^ 369 milligrams (mg) of interferon-tau (iFNi) (diamond pattern, group I), 0.6 milligrams (mg) of interferon-tan (IFNt) (square, group I), and 1.8 milligrams (Mg) of interferon-tau (IPNτ) (triangle, group I) tracked the status from the first to the twenty-ninth day. Figures 3A-3E show the serum concentrations of interleukin 10 (IL-10) (diamond pattern) and interferon-tau (IFNt) (square), both of which are in units of Pg / mL, corresponding to Figures 1 and 2, Individual patients are selected from the treatment groups I, II, and III. Figures 4A-4C show the serum concentration of interleukin 10 (IL-10) in patients with hepatitis C and oral interferon-tau (IFNT) in units of Pg / mL, and the horizontal standard in units of time and day Six patients were divided into group I and 0.33 milligrams (mg) of interferon-tau (IFNi) were administered three times a day (Fig. 4A); six patients were divided into group Η and i · 0 milligrams (mg) ) Of interferon-tau (IFNt) three times (Figure 4B); six patients were divided into group III and 3 mg (mg) of interferon-tau (IFNi) were administered three times a day (Figure 4C). FIG. 4D shows a summary of the groups I, Π, and ΙΠ. The increase in serum interleukin 10 (IL_lO) concentration is plotted in Figs. 4A to 4C. Time is used to plot 'Experimental Group I (diamond pattern, 0.3 mg (mg)-three times a day), Group Η (square, 1 milligram (mg)-three times a day), with group III (triangle '3 milligrams (mg)-three times a day). Figures 5A-5C show that the interferon-gamma (IFN-γ) serum concentration is given in pg / mL and oral interferon-tau (IFNt) is administered to patients suffering from hepatitis C. The time is plotted. On a daily basis, six patients were divided into group 1 and 0.33 milligrams (mg) of interferon-tau (IFNt) was administered three times a day (Figure 122 2005333 > 6r9) c 5A); six patients were divided into groups In Group II, 1.0 mg of interferon-tau (IFNt) was administered three times a day (Figure 5B); six patients were divided into Group III and interferon-tau (IFm) was administered in milligrams (mg) three times a day (Figure 5C) . FIG. 5D shows a summary of groups I, II, and III. The average concentration of interferon-tan (IFNt) is plotted in Figures 4A to 4C, and plotted as a function of time, experimental group I (diamond pattern, 0.3 mg (mg)-three times a day), group II (square, 1 milligram (mg) ) — Three times a day), with group III (triangle, 3 milligrams (mg) three times a day).

Figures 6A-6F show interleukin 10 (IL-10) (diamond graphics) and interferon-tau (IFNt) (square) serum concentrations in pg / mL. Individual patients are selected from treatment groups I, Π, and III relative to the discussion of Figures 4-5. Figures 7A-7B show interleukin 10 (IL-10) serum concentrations (Figure 7A) and interferon-tau (IFNt) serum concentrations (Figure 7B), in pg / mL, orally administered interferon-tan (IFNt ) For patients suffering from Hepatitis C, plot time with daily units at a dose of 7.5 milligrams (mg) of interferon-tau (IFNt) once or twice on an empty stomach. Figures 8A-8D show interleukin 10 (IL-10) (diamond graphics), interferon-gamma (IFN-γ) (square), and interleukin 12 (IL-12 (triangle) serum concentrations, in pg / mL) As a unit, the patient would like to correspond to Figures 7A-7B as described above. [Simplified description of sequence] The sequence SEQ ID NO: 1 is the nucleotide sequence of a synthetic gene encoding sheep interferon τ (IFN〇. 123 20053 · Sequence SEQ ID NO: 2 is the amino acid sequence of mature sheep interferon t (IFNt, oTP-1; gene bank authorization code No. Y00287; PID gl358). The sequence SEQ ID NO: 3 is about mature sheep interferon t (IFNt) The amino acid sequence of which the fifth and sixth residue positions are adjusted relative to the sequence of SEQ ID NO: 2.

The sequence SEQ ID NO: 4 is a synthetic nucleotide sequence encoding the protein of SEQ ID NO: 3. • I sequence SEQ ID NO: 5 is the amino acid sequence of human myelin oligodendrocyte protein (Gene Bank Authorization Code NO.BC035938). The sequence SEQ ID NO: 6 is about the amino acid sequence of the basic protein of human myelin sheath (Gene Bank Authorization Code No. NM-002385).

124 200533369 Sequence detailsPypergen Corporation < 110 > Liu Zhiping, Willard R. Loreley H. < 12〇 > Application of Interferon Tau < 130 > 55600-8014.TWO0 < 140 > Not Yet Assigned < 141 > Filed Herewith < 150 > US 60 / 552,279 < 151 > 2004-03-10 < 150〉 US 10 / 824,710 < 151 > 2004-04-14 < 150 > US 10 / 825,068 < 151 > 2004-04-14

< 150 > US 10 / 825,382 < 151 > 2004-04-14 < 150 > US 10 / 825,457 < 151 > 2004-04-14 < 150 > US 10 / 884,741 < 151 > 2004-07- 02 < 150 &>

tggatccgat cgttactgtt 1 60 120 180 240 300 360 420 480 516 tgctacctgt cgcgaaaact gatgctggac gctcgagaaa atttaaaact gctggaccgt atgaatcgat tgtctccgca cagctgcctg caagaccgga aagacttcgg tctgccgcag gaaatggttg aaggtgacca actgcaaaaa gaccaagctt tcccggtact gtatgaaatg ctgcagcagt ctttcaacct gttctacact gaacattctt cggccgcttg ggacactact cttctagaac aactgtgcac tggtctgcaa cagcaactgg accatctgga cacttgccgt ggccaggtta tgggtgaaga agactctgaa ctgggtaaca; < 400 & gt aaaaaatatt tccagggtat ctacgactac ctgcaggaaa aaggttactc tgactgcgct tgggaaatcg tacgcgttga aatgatgcggg gccctgactg tgtcgactac tctgcaaaaa &&&;; &RT; 212 < 211 &RT; < 210

Cys Tyr Leu Ser Arg Lys Leu Met Leu Asp Ala Arg Glu Asn Leu Lys 1 5 10 15

Leu Leu Asp Arg Met Asn Arg Leu Ser Pro His Ser Cys Leu Gin Asp 20 25 30

Arg Lys Asp Phe Gly Leu Pro Gin Glu Met Val Glu Gly Asp Gin Leu 35 40 45

Gin Lys Asp Gin Ala Phe Pro Val Leu Tyr Glu Met Leu Gin Gin Ser 50 55 60

Phe Asn Leu Phe Tyr Thr Glu His Ser Ser Ala Ala Trp Asp Thr Thr 65 70 75 80

Leu Leu Glu Gin Leu Cys Thr Gly Leu Gin Gin Gin Leu Asp His Leu 85 90 95

Asp Thr Cys Arg Gly Gin Val Met Gly Glu Glu Asp Ser Glu Leu Gly 100 105 110

Asn Met Asp Pro Le Val Thr Val Lys Lys Tyr Phe Gin Gly lie Tyr 115 120 125

Asp Tyr Leu Gin Glu Lys Gly Tyr Ser Asp Cys Ala Trp Glu lie Val 130 135 140

Arg Val Glu Met Met Arg Ala Leu Thr Val Ser Thr Thr Leu Gin Lys 145 150 155 160

Arg Leu Thr Lys Met Gly Gly Asp Leu Asn Ser Pro 165 170 < 210 > 3 < 211 > 172 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Genetic recombination based on sheep sequence Interferon Tau: < 400 > 3

Cys Tyr Leu Ser Glu Arg Leu Met Leu Asp Ala Arg Glu Asn Leu Lys 15 10 15

Leu Leu Asp Arg Met Asn Arg Leu Ser Pro His Ser Cys Leu Gin Asp 20 25 30

Arg Lys Asp Phe Gly Leu Pro Gin Glu Met Val Glu Gly Asp Gin Leu 35 40 45

Gin Lys Asp Gin Ala Phe Pro Val Leu Tyr Glu Met Leu Gin Gin Ser 50 55 60

Phe Asn Leu Phe Tyr Thr Glu His Ser Ser Ala Ala Trp Asp Thr Thr 65 70 75 80

Leu Leu Glu Gin Leu Cys Thr Gly Leu Gin Gin Gin Leu Asp His Leu 85 90 95

Asp Thr Cys Arg Gly Gin Val Met Gly Glu Glu Asp Ser Glu Leu Gly 100 105 110

Asn Met Asp Pro Le Val Thr Val Lys Lys Tyr Phe Gin Gly lie Tyr 115 120 125

Asp Tyr Leu Gin Glu Lys Gly Tyr Ser Asp Cys Ala Trp Glu lie Val 130 135 140

Arg Val Glu Met Met Arg Ala Leu Thr Val Ser Thr Thr Leu Gin Lys 145 150 155 160

Arg Leu Thr Lys Met Gly Gly Asp Leu Asn Ser Pro 165 170 < 210 > 4 < 211 > 516 < 212 > DNA < 213 > artificial sequence / ^ 0 200533369 < 220 > < 223 > according to sheep sequence gene recombination of interferon Tau < 400 > 4 tgctacctgt cggagcgact gatgctggac gctcgagaaa atttaaaact gctggaccgt atgaatcgat tgtctccgca cagctgcctg caagaccgga aagacttcgg tctgccgcag gaaatggttg aaggtgacca actgcaaaaa gaccaagctt tcccggtact gtatgaaatg ctgcagcagt ctttcaacct gttctacact gaacattctt cggccgcttg ggacactact cttctagaac aactgtgcac tggtctgcaa cagcaactgg accatctgga cacttgccgt ggccaagtta tgggtgaaga agactctgaa ctgggtaaca tggatccgat cgttactgtt aaaaaatatt tccagggtat ctacgactac ctgcaggaaa aaggttactc tgactgcgct tgggaaatcg tacgcgttga aatgatgcgg gccctgactg tgtcgactac tctgcaaaaa cggttaacta aaatgggtgg human < 210 > 5 < < 212

60 120 180 240 300 360 420 480 516 < 400 > 5

Met Ala Ser Leu Ser Arg Pro Ser Leu Pro Ser Cys Leu Cys Ser Phe 15 10 15

Leu Leu Leu Leu Leu Leu Gin Val Ser Ser Ser Tyr Ala Gly Gin Phe 20 25 30

Arg Val lie Gly Pro Arg His Pro lie Arg Ala Leu Val Gly Asp Glu 35 40 45

Val Glu Leu Pro Cys Arg Gong Le Ser Pro Gly Lys Asn Ala Thr Gly Met 50 55 60

Glu Val Gly Trp Tyr Arg Pro Pro Phe Ser Arg Val Val His Leu Tyr 65 70 75 80

Arg Asn Gly Lys Asp Gin Asp Gly Asp Gin Ala Pro Glu Tyr Arg Gly 85 90 95

Arg Thr Glu Leu Leu Lys Asp Ala lie Gly Glu Gly Lys Val Thr Leu 100 105 110

Arg lie Arg Asn Val Arg Phe Ser Asp Glu Gly Gly Phe Thr Cys Phe 115 120 125

Phe Arg Asp His Ser Tyr Gin Glu Glu Ala Ala Met Glu Leu Lys Val 130 135 140

Glu Asp Pro Phe Tyr Trp Val Ser Pro Gly Val Leu Val Leu Leu Ala 145 150 155 160

Val Leu Pro Val Leu Leu Leu Gin lie Thr Val Gly Leu Val Phe Leu 165 170 175

Cys Leu Gin Tyr Arg Leu Arg Gly Lys Leu Arg Ala Glu lie Glu Asn 180 185 190

Leu His Arg Thr Phe Asp Pro His Phe Leu Arg Val Pro Cys Trp Lys 195 200 205

He Thr Leu Phe Val Le Val Pro Val Leu Gly Pro Leu Val Ala Leu 210 215 220 lie lie Cys Tyr Asn Trp Leu His Arg Arg Leu Ala Gly Gin Phe Leu 225 230 235 240

Glu Glu Leu Arg Lys Phe Ser Ser Leu Cys Tyr Lys Gin Arg Engineering Lys 245 250 255

Ser Gin Glu Arg Glu Thr Glu Ala Thr Arg Gly Arg Gly Gly Leu Leu 260 265 270

Arg Asp His lie Pro Arg Gly Lys Glu Glu Leu Glu Ser Leu Gly Gly 275 280 285

Gly Lys Thr Pro Pro Gly Arg 290 295/3/200533369

< 210 > 6 < 211 > 186 < 212 > PRT < 213 > human < 400 > 6

Met Ala Ser Gin Lys Arg Pro Ser Gin Arg His Gly Ser Lys Tyr Leu 1 5 10 15

Ala Thr Ala Ser Thr Met Asp His Ala Arg His Gly Phe Leu Pro Arg 20 25 30

His Arg Asp Thr Gly lie Leu Asp Ser lie Gly Arg Phe Phe Gly Gly 35 40 45

Asp Arg Gly Ala Pro Lys Arg Gly Ser Gly Lys Val Pro Trp Leu Lys 50 55 60

Pro Gly Arg Ser Pro Leu Pro Ser His Ala Arg Ser Gin Pro Gly Leu 65 70 Ί5 80

Cys Asn Met Tyr Lys Asp Ser His His Pro Ala Arg Thr Ala His Tyr 85 90 95

Gly Ser Leu Pro Gin Lys Ser His Gly Arg Thr Gin Asp Glu Asn Pro 100 105 110

Val Val His Phe Phe Lys Asn lie Val Thr Pro Arg Thr Pro Pro Pro 115 120 125

Ser Gin Gly Lys Gly Ala Glu Gly Gin Arg Pro Gly Phe Gly Tyr Gly 130 135 140

Gly Arg Ala Ser Asp Tyr Lys Ser Ala His Lys Gly Phe Lys Gly Val 145 150 155 160

Asp Ala Gin Gly Thr Leu Ser Lys lie Phe Lys Leu Gly Gly Arg Asp 165 170 175

Ser Arg Ser Gly Ser Pro Met Ala Arg Arg 180 185 4

Claims (1)

20053i23i6.9c 10. Scope of patent application: 1. A pharmaceutical composition prepared to improve the physiological condition of humans in response to the rise of interleukin-lO (IL-lO) in the blood. The aforementioned composition includes interferon-tau (IFNt). It is prepared by oral route to more than 5 X 108 units per day for patients not suffering from hepatitis C. 2. A pharmaceutical composition prepared as described in item 1 of the scope of patent application to improve the physiological condition of humans in response to an increase in interleukin-10 (IL-10) in blood, wherein the interferon-tau (IFNt) is an interference by sheep -Tan (IFNt) and bovine interferon-tau. 3. A pharmaceutical composition prepared as described in item 1 or 2 of the scope of patent application to improve the physiological condition of humans in response to the rise of interleukin-10 (IL-10) in blood, wherein the interferon-tau (IFNt) Is sheep's interferon-tau (IFNt), which has one of SEQ ID NO: 2 or SEQ ID NO: 3 [J. 4. The pharmaceutical composition prepared as described in item 3 of the scope of patent application to improve the physiological condition of humans' response to the rise of interleukin-10 (IL-10) in blood, the aforementioned oral dosage form is formulated to reach the test via the oral route The intestinal dosage form. 5. A pharmaceutical composition prepared as described in item 3 of the scope of patent application to improve the physiological condition of humans in response to an increase in interleukin-10 (IL-10) in the blood. The physiological condition of the aforementioned reaction refers to autoimmune symptoms or Cell proliferation symptoms. 6. A pharmaceutical composition prepared as described in item 5 of the scope of the patent application to improve the physiological condition of humans' response to the rise of interleukin-10 (IL-10) in blood, wherein the composition is combined with a second therapeutic agent. 7. The pharmaceutical composition prepared as described in item 5 of the scope of the patent application to improve the physiological condition of humans' response to the rise of interleukin-lO (IL-10) in blood, so 20053ι ^ 3 > ι6.δ〇 improvement symptoms are psoriasis Or multiple sclerosis. 8. A pharmaceutical preparation prepared as described in item 7 of the scope of the patent application to improve the physiological condition of human_ response to the rise of interleukin-lO (IL-10) in the blood, wherein the composition of the agent can be simultaneously combined with a second Healing potions. 9. · Pharmaceutical warfare prepared as described in item 6 of the scope of patent application to improve the physiological condition of humans in response to the rise in interleukin-IO (IL-IO) in blood, wherein the second therapeutic agent is selected from antiviral drugs , Anticancer drugs, inflammatory drugs, and agents suitable for improving autoimmunity. X 10. The pharmaceutical composition prepared as described in item 6 of the scope of the patent application to improve the physiological condition of human_ response to the rise of interleukin-10 (IL-10) in the blood, wherein the order of taking the second therapeutic agent can be before, at the same time, Interferon-tau (IFNt) administered after D or later. 11 · A pharmaceutical composition prepared as described in item 6 of the scope of patent application to improve the physiological condition of humans' response to the rise of interleukin-10 (IL-10) in the blood, wherein the second therapeutic agent administered is selected from the group consisting of Antegren Monoclonal antibodies with TysabriR (component name natalizumab), statins, mycophenolate mofetil, and drugs for the treatment of relapsing multiple sclerosis Copaxone ). 12. A pharmaceutical composition prepared as described in item 6 of the scope of the patent application to improve the physiological condition of humans in response to an increase in interleukin-10 (IL_10) in the blood, wherein the first is administered to alleviate or prevent acute organ rejection of transplantation Two therapeutic agents are mycophenolate mofetil (ingredient name mycophenolate mofetil). 13. A pharmaceutical composition prepared as described in item 6 of the scope of the patent application to improve the physiological condition of humans in response to the rise of interleukin-10 (IL-10) in blood 126 2005 36 ¾¾ solution, wherein the subject is administered to improve the inflammatory condition of the subject The second therapeutic agent is statins (HMG Co-A reductase inhibitor, HMG Co-A reductase). 14. A pharmaceutical composition prepared as described in item 8 of the scope of the patent application to improve the physiological condition of humans in response to an increase in interleukin-10 (IL-10) in the blood, wherein The two therapeutic agents are selected from the group consisting of collagen, vitamin A acid (retinoid), anthralin, vitamin D drugs (Cacilpotriene), coal tar, salicylic acid, and Immunosuppressant. 15. A pharmaceutical composition prepared as described in item 3 of the scope of the patent application to improve the physiological condition of humans in response to the rise of interleukin-IO (IL-IO) in the blood, which can be used to slow the deterioration of patients with multiple sclerosis and or Reduce the risk of relapse in patients with multiple sclerosis. 16. A pharmaceutical composition prepared as described in item 3 of the scope of patent application to improve the physiological condition of humans in response to the rise of interleukin-lO (IL-10) in blood can be used to improve the symptoms of psoriasis in patients. 17. The pharmaceutical composition prepared as described in item 3 of the scope of the patent application to improve the physiological condition of humans in response to the rise of interleukin-lO (IL-10) in blood can be used to prevent the administration of the preparation or (^ ) The risk of increased interferon-gamma pseudo-protein (IFN_Y) in the blood of the subject due to its own disease condition. 1 8. A pharmaceutical composition prepared as described in item 17 of the scope of the patent application to improve the physiological condition of humans in response to an increase in interleukin-10 (IL-10) in blood, wherein the interferon in the blood of the subject The increase in gamma (IFN-γ) was 127 200533 due to the administration of interferon alpha (IFN-α) or interferon beta (IFN-β), and the aforementioned agents were administered continuously in the presence of the patient's condition. 19. A pharmaceutical composition prepared as described in item 17 of the scope of patent application to improve the physiological condition of humans in response to an increase in interleukin-10 (IL-10) in blood, wherein a subject suffering from multiple sclerosis is administered Interferon beta (IFN-β) treatment. 20. A pharmaceutical composition prepared as described in item 17 of the scope of the patent application to improve the physiological condition of humans in response to an increase in interleukin-10 (IL-10) in blood, wherein a subject suffering from a viral infection is administered interferon Alpha (IFN-α) treatment. 21. A pharmaceutical composition prepared as described in item 3 of the scope of patent application to improve the physiological condition of humans in response to an increase in interleukin-10 (IL-10) in blood, which can be used for interleukin-12 (IL-12) in blood Falling subjects. 128