Research Interests: Bioinformatics, Immunology, Biology, Kidney transplantation, Medicine, and 15 moreGene expression, Cellular, Humans, Female, Male, Immunosuppression, Cluster Analysis, Aged, Immune system, Kidney Transplant, Adult, Graft Rejection, Immune Tolerance, Biochemistry and cell biology, and Gene expression profiling
The GH receptor (GHR) is a member of the cytokine/hematopoietic growth factor family, and protein tyrosine phosphorylation has been implicated in the signaling cascade of these receptors. It was recently shown that the tyrosine kinase... more
The GH receptor (GHR) is a member of the cytokine/hematopoietic growth factor family, and protein tyrosine phosphorylation has been implicated in the signaling cascade of these receptors. It was recently shown that the tyrosine kinase JAK2 is associated with the GHR. GH induces the activation of JAK2, which phosphorylates itself and the receptor. Mitogen-activated protein (MAP) kinase activation and transcriptional stimulation of specific genes, such as Spi 2.1, have also been reported to be induced by GH. To identify functionally important regions in the cytoplasmic domain of the GHR, we compared the actions of the wild-type receptor, two truncated mutants, and one internal deletion mutant (similar to the intermediate Nb2 form of the PRL receptor) in transfectants of the Chinese hamster ovary cell line. A region of 46 amino acids adjacent to the membrane was found to be sufficient for activation of both JAK2 and MAP kinases. This region contains a proline-rich sequence (box 1) conserved in the cytokine receptor family that is important for signal transduction. For transcriptional activity, the C-terminal region of the GHR is required, and we found that the last 80 terminal residues contain sequences allowing activation of the Spi 2.1 promoter. Tyrosine phosphorylation of the receptor also requires the C-terminal portion of the GHR cytoplasmic domain, and we found that GHR tyrosine phosphorylation appears to be linked to activation of the Spi 2.1 transcription pathway. Thus, the GHR could be composed of at least 2 functional regions: the 46 proximal amino acids required for activation of JAK2 and sufficient to stimulate the MAP kinase pathway, and an additional carboxy-terminal region necessary for transcriptional activation.
Research Interests: Endocrinology, Biology, Medicine, Biological Sciences, DNA, and 15 moreGrowth Hormone, Internal Medicine, Mutation, Animals, Phosphorylation, Mitogen Activated Protein Kinase, Growth Hormone Receptor, Base Sequence, Cytoplasm, Molecular Sequence Data, janus kinase, CHO cells, Cricetinae, Protein tyrosine kinases, and Medical and Health Sciences
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Research Interests: Immunology, Flow Cytometry, Kidney transplantation, Innate immunity, Medicine, and 15 moreTacrolimus, Humans, American, Cyclosporine, Phenotype, T lymphocytes, In Vivo, Immune system, Calcineurin, Sirolimus, Gene expression profiling, Immunosuppressive Agents, Monocyte, Medical and Health Sciences, and Peripheral blood
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p120 GTPase-activating protein (p120GAP) is a major negative regulator of p21ras activity in several cell types including T cells. Catalytic activity of this enzyme is regulated in part by its interaction with several associated... more
p120 GTPase-activating protein (p120GAP) is a major negative regulator of p21ras activity in several cell types including T cells. Catalytic activity of this enzyme is regulated in part by its interaction with several associated tyrosine-phosphorylated proteins. Sam68 was initially described as associated with p120GAP. It has been further established that Sam68 is a substrate of src kinases in mitosis and that it is not associated with p120GAP in transformed fibroblasts. We describe herein that Sam68 associates with p120GAP and PLCγ1 in human mature T cells and in a T cell line expressing the CD4 molecule HUT78 CD4+. This association is present in nonactivated cells and increases after anti-CD3 activation. It is dependent on CD4 expression and, in part, on the association of CD4 with p56lck, as shown by the strongly decreased association of Sam68 with p120GAP in the CD4− mutants, HUT78 CD4−, and by the reduced association of Sam68 with both p120GAP and p56lck in the HUT78 T cell lin...
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Ligands binding to the CD4 molecule can inhibit TCR-mediated T cell activation. We have previously reported that transcription factors regulating the expression of the IL-2 gene, NF-AT, NF-kappaB, and AP-1, are targets of this inhibitory... more
Ligands binding to the CD4 molecule can inhibit TCR-mediated T cell activation. We have previously reported that transcription factors regulating the expression of the IL-2 gene, NF-AT, NF-kappaB, and AP-1, are targets of this inhibitory effect in an in vitro model using peripheral human CD4+ T cells activated by a CD3 mAb. Two T cell activation pathways involved in the regulation of these transcription factors, calcium flux and the p21ras pathway, were investigated as potential targets. Binding of HIV envelope glycoprotein gp160/gp120 or a CD4 mAb to the CD4+ T cells, prior to TCR/CD3 activation, inhibited the intracellular calcium elevation. This event strongly suggested an inhibition of PLCgamma1 activity. Tyrosine phosphorylation of PLCgamma1, induced by CD3 activation, was not affected, but its association with tyrosine-phosphorylated proteins, including a 62-kDa protein, was disrupted. This PLCgamma1-associated p62 was found to be immunoreactive to p62-Sam68 Abs. The activatio...
Research Interests: Immunology, Biology, Calcium, Cell Biology, Immunology of the Gut, and 15 moreMedicine, T cell receptor, Signal Transduction, Humans, T Cell, Monoclonal Antibodies, The, Phosphorylation, Proteins, Mitogen Activated Protein Kinase, T lymphocytes, Isoenzymes, Protein Binding, Ligands, and Tyrosine Phosphorylation
Nephrolog
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Whereas a B cell-transcriptional profile has been recorded for operationally tolerant kidney graft patients, the role that B cells have in this tolerance has not been reported. In this study, we analyzed the role of B cells from... more
Whereas a B cell-transcriptional profile has been recorded for operationally tolerant kidney graft patients, the role that B cells have in this tolerance has not been reported. In this study, we analyzed the role of B cells from operationally tolerant patients, healthy volunteers, and kidney transplant recipients with stable graft function on T cell suppression. Proliferation, apoptosis, and type I proinflammatory cytokine production by effector CD4(+)CD25(-) T cells were measured after anti-CD3/anti-CD28 stimulation with or without autologous B cells. We report that B cells inhibit CD4(+)CD25(-) effector T cell response in a dose-dependent manner. This effect required B cells to interact with T-cell targets and was achieved through a granzyme B (GzmB)-dependent pathway. Tolerant recipients harbored a higher number of B cells expressing GzmB and displaying a plasma cell phenotype. Finally, GzmB(+) B-cell number was dependent on IL-21 production, and B cells from tolerant recipients ...
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BackgroundHuman corneal allografting is an established procedure to cure corneal blindness. However, a shortage of human donor corneas as well as compounding economic, cultural, and organizational reasons in many countries limit its... more
BackgroundHuman corneal allografting is an established procedure to cure corneal blindness. However, a shortage of human donor corneas as well as compounding economic, cultural, and organizational reasons in many countries limit its widespread use. Artificial corneas as well as porcine corneal xenografts have been considered as possible alternatives. To date, all preclinical studies using de‐cellularized pig corneas have shown encouraging graft survival results; however, relatively few studies have been conducted in pig to non‐human primate (NHP) models, and particularly using genetically engineered donors.MethodsIn this study, we assessed the potential benefit of using either hCTLA4‐Ig transgenic or α1,3‐Galactosyl Transferase (GT) Knock‐Out (KO) plus transgenic hCD39/hCD55/hCD59/fucosyl‐transferase pig lines in an anterior lamellar keratoplasty pig to NHP model.ResultsCorneas from transgenic animals expressing hCTLA4‐Ig under the transcriptional control of a neuron‐specific enolas...
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Research Interests: Genetics, Biology, Kidney transplantation, Medicine, Humans, and 15 moreHaplotypes, Chronic Disease, Gene, Risk factors, Phenotype, Single Nucleotide Polymorphism, Analysis of Variance, Linkage Disequilibrium, Immune tolerance and transplantation, Chi Square Distribution, Risk Factors, Graft Rejection, Case Control Studies, Gene frequency, and Medical and Health Sciences
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Under physiological conditions, activation of CD4+ T cells by major histocom‐patibility complex (MHC) antigen complexes requires engagement of both the T cell receptor and the CD4 molecule. However, CD4 ligands binding to the CD4 molecule... more
Under physiological conditions, activation of CD4+ T cells by major histocom‐patibility complex (MHC) antigen complexes requires engagement of both the T cell receptor and the CD4 molecule. However, CD4 ligands binding to the CD4 molecule has also been shown to inhibit T cell proliferation and interleukin (IL)‐2 production in human CD4+ T cells, in an MHC‐independent way. We have previously shown that this inhibition was associated with a diminished binding activity of the IL‐2 transcription factors NF‐AT, NF‐χB, and AP‐1. AP‐1 plays a key role in the regulation of IL‐2 transcription, and ERK and JNK activities are necessary for regulating AP‐1 at both the transcriptional and the post‐transcriptional levels. We therefore studied, in human peripheral CD4+ T cells, the regulation of the activities of extracellular signal‐regulated protein kinases (ERK) and c‐Jun N‐terminal kinases (JNK) by two CD4 ligands, gpi60 the envelope glycoprotein of human immunodeficiency virus (HIV) and an an...
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We have previously shown that CD4 ligands inhibit interleukin-2 (IL-2) production and T cell proliferation in human peripheral CD4+ T lymphocytes, in an MHC-independent way. Two major pathways implicated in T cell activation are inhibited... more
We have previously shown that CD4 ligands inhibit interleukin-2 (IL-2) production and T cell proliferation in human peripheral CD4+ T lymphocytes, in an MHC-independent way. Two major pathways implicated in T cell activation are inhibited by binding of CD4 ligands to the CD4 molecule, i.e. Ca2+ signaling by phospholipase Cgamma1 (PLCgamma1), and ERK-2 activation, suggesting a p21ras inhibition. We have correlated these inhibitions with the disruption of multifunctional complexes containing PLCgamma1, p120GAP and Sam68, induced by T cell activation. We report here that T cell activation through the TCR/CD3 induces an association of the phosphoinositide 3 kinase (PI3 kinase) with PLCgamma1, both in peripheral CD4+ T lymphocytes and the HUT-78 CD4+ T cell line. PI3 kinase is present in the multifunctional complexes that we have described previously. Preincubation of human peripheral CD4+ T cells and HUT-78 CD4+ T cells with gp160 or a peptide analogue of the HLA class II DR molecule precludes the association of PLCgamma1 with PI3 kinase. We also demonstrate, using two specific inhibitors of PI3 kinase activity (LY294002 and wortmannin), that this activity plays a key role in the association of PLCgamma1 with PI3 kinase. Moreover, we demonstrate the implication of the PI3 kinase activity in the negative signal mediated by HIV gp160 binding to CD4 molecules. We propose that the products of the PI3 kinase are important mediators of the negative signaling induced by the binding of CD4 ligands to the CD4 molecule implicated in the regulation of the formation of multifunctional complexes.
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ABSTRACT
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Long-term allograft survival generally requires lifelong immunosuppression (IS). Rarely, recipients display spontaneous “operational tolerance” with stable graft function in the absence of IS. The lack of biological markers of this... more
Long-term allograft survival generally requires lifelong immunosuppression (IS). Rarely, recipients display spontaneous “operational tolerance” with stable graft function in the absence of IS. The lack of biological markers of this phenomenon precludes identification of potentially tolerant patients in which IS could be tapered and hinders the development of new tolerance-inducing strategies. The objective of this study was to identify minimally invasive blood biomarkers for operational tolerance and use these biomarkers to determine the frequency of this state in immunosuppressed patients with stable graft function. Blood gene expression profiles from 75 renal-transplant patient cohorts (operational tolerance/acute and chronic rejection/stable graft function on IS) and 16 healthy individuals were analyzed. A subset of samples was used for microarray analysis where three-class comparison of the different groups of patients identified a “tolerant footprint” of 49 genes. These biomark...
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Humoral antibody-mediated rejection (AMR) has been recently described after intestinal transplantation (ITx). We report our experience in the diagnosis and the therapeutics engaged. Since 06/2008 to 07/2012, 28 children (18 boys) were... more
Humoral antibody-mediated rejection (AMR) has been recently described after intestinal transplantation (ITx). We report our experience in the diagnosis and the therapeutics engaged. Since 06/2008 to 07/2012, 28 children (18 boys) were enlisted, 19 (12 boys) transplanted: 11 isolated ITx (SBTx), 5 liver combined ITx (L-SBTx), 1 multivisceral transplantation with kidneys (MVT-k), 1 modified MVT. Median age of transplanted children: 6.9 years (18months-15years). 16/28 had antiHLA antibodies (DSA) screening pre or post ITx. Immunosuppression associated Tacrolimus, Methylprednisolone (MP) and Basiliximab. When AMR was suspected on DSA over 2000 MFI or pathology or C4d staining, the patient received MP, IVimmunoglobulins (IVIg) and plasmapheresis (PP). Six children were excluded from this study: no AMR was detected for 3, and 3 had early surgical complications. 6/19 patients had pre-transplant anti-HLA antibodies, including 2 retransplantations. At the end 13/19 patients had DSA over 2000 MFI after Tx (68%), 7 SBTx, 5 L-SBTx2 retransplantations, and 1 MVTx-k. In 6/13 patients the finding of DSA was contemporaneous of severe rejection and 3 had early C4d positive staining. They received the whole treatment and because of a very resistant rejection Infliximab (1/6), Rituxumab (2/6) and Eculizimab (1/6) were tried. Three children died, and the graft was removed in one, 2 weaned off PN. In 7/13 the biopsies showed a light acute rejection (2/7) or were normal (5/7) with DSA>2000. All children received IVIg, 2 also received MP and PP. Two children died 10 and 12 months after L-SBTx, due to a sepsis (patient suffering from severe GVH and from exfoliative rejection). 5/7 are weaned off PN with a normal graft function. AMR is a severe complication after ITx that could lead to graft loss and even death. Mortality rate is high (38%) in this group and graft survival in living patients is 54%, median follow-up 18months. Pathological lesions need to be better identified but C4d staining seems to be an early helpful staining. In order to better define and treat AMR, systematically screening of anti-HLA antibodies and further studies are needed.
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Research Interests: Genetics, Immunology, Molecular Biology, Polymorphism, Biology, and 15 moreAsthma, Japan, Medicine, Immunoglobulin E, Biochemical, Great Britain, Immune system, Genotype, Ethnic Group, Genetic variation, Genetic Association, Atopy, Biochemistry and cell biology, Interferon gamma, and Medical biochemistry and metabolomics
Key PointsCLEC-1 is restricted to CD16− myeloid DCs in human blood and acts as an inhibitory receptor to restrain downstream Th17 activation. CLEC-1–deficient rats highlight an in vivo function for CLEC-1 in preventing excessive T-cell... more
Key PointsCLEC-1 is restricted to CD16− myeloid DCs in human blood and acts as an inhibitory receptor to restrain downstream Th17 activation. CLEC-1–deficient rats highlight an in vivo function for CLEC-1 in preventing excessive T-cell priming and effector Th responses.
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Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University... more
Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University launched a European-wide survey to identify new patients, describe them and estimate their frequency for the first time. Seventeen coordinators distributed a questionnaire in 256 transplant centres and 28 countries in order to report as many 'operationally tolerant' patients (TOL; defined as having a serum creatinine <1.7 mg/dL and proteinuria <1 g/day or g/g creatinine despite at least 1 year without any immunosuppressive drug) and…
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Research Interests: Biology, Kidney transplantation, France, Gene expression, Human, and 15 moreHumans, Liver, Female, Male, Immunosuppression, Liver Transplantation, Allografts, Clinical Sciences, Aged, Genotype, Graft Rejection, Genetic Markers, Gene Expression Regulation, Gene expression profiling, and Immunosuppressive Agents
The role of Foxp3(+) regulatory T cells (Tregs) in operational tolerance remains elusive, as initial results revealed an increased frequency of this subset in tolerant patients but no functional differences compared with immunosuppressed... more
The role of Foxp3(+) regulatory T cells (Tregs) in operational tolerance remains elusive, as initial results revealed an increased frequency of this subset in tolerant patients but no functional differences compared with immunosuppressed recipients. In addition, recent studies of regulatory B cells strongly suggest that Tregs may not have a central role in kidney transplantation tolerance. However, recent investigations of the crucial role of Foxp3 demethylation in Treg function and the possibility of identifying distinct Foxp3 T cell subsets prompted us to more thoroughly characterize Tregs in operationally tolerant patients. Thus, we studied the level of demethylation of the Foxp3 Treg-specific demethylated region (TSDR) in circulating CD4(+) T cells and analyzed Treg subset frequency in tolerant patients, healthy volunteers, patients with stable graft function under immunosuppression, and chronically rejecting recipients. We observed a higher proportion of CD4(+) T cells with dem...