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Tr1-Specific Tolerance: a Novel Treatment of Multiple Sclerosis

Tr1 特异性耐受：多发性硬化症的新疗法

基本信息

批准号：
8328926
负责人：
Kanneganti Murthy
金额：
$ 30.35万
依托单位：
RADIKAL THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8328926
关键词：
Acute Address Adoptive Transfer Aftercare Animals Anti-Inflammatory Agents Anti-inflammatory Antigens Autoantigens Autoimmune Diseases Binding Sites Bypass CD28 gene CD4 Positive T Lymphocytes CD46 Antigen CXC chemokine receptor 3 CXCL10 gene CXCL11 gene CXCL9 gene CXCR3 gene Calcineurin inhibitor Cell physiology Cells Cellular Immunity Chimeric Proteins Clinical Control Groups Defect Deterioration Dexamethasone Disease Equilibrium Etiology Experimental Autoimmune Encephalomyelitis FDA approved Functional disorder Grant Histologic Homologous Gene Human IL2RA gene IgG1 Immune Tolerance Immunity Immunosuppressive Agents In Vitro Incubated Inflammation Inflammatory Inflammatory Response Injury Interleukin-10 Ligand Binding Location Mediating Mitoxantrone Modeling Monitor Multiple Sclerosis Mus Myelin Neurologic Neurons Onset of illness Paralysed Pathway interactions Patients Pharmacodynamics Phase Phenotype Phosphorylation Primates Production Property Receptor Signaling Recombinant Proteins Regulatory T-Lymphocyte Relapse Relapsing-Remitting Multiple Sclerosis Relative (related person)Research Design STAT3 gene Safety Severity of illness Signal Transduction Sirolimus Spinal Cord Spleen Steroids T-Lymphocyte Testing Th1 Cells Therapeutic Tissues Titrations Transgenic Organisms Work chemokine copolymer 1 human FRAP1 protein in vivo innovation interferon therapy lymph nodes mouse model natalizumab novel receptor response transcription factor

项目摘要

DESCRIPTION (provided by applicant): We are developing a novel immunomodulatory therapy, hR-411, to treat relapsing-remitting multiple sclerosis (RRMS). hR-411 restores regulatory T-cell balance by redirecting pathogenic Th1/Th17 cells into tolerance- inducing Tr1 cells. hR-411 is formed from the fusion of human Ig-Fc and CXCL11, a CXCR3-binding ligand that has been recently identified as a counter-regulatory chemokine. In contrast to the pro-inflammatory CXCR3- binding ligands CXCL9 and CXCL10, in vitro exposure of inflammatory effector Th1 and Th17 cells to CXCL11 redirects their polarization into anti-inflammatory Tr1 (FOXp3-CD25-IL-10high) cells. mR-411, the murine homologue of hR-411, profoundly suppresses the neurological and histologic findings of murine EAE, even when initiated after disease onset. The durability of this repolarization is shown in adoptive transfer studies wherein Ag-specific effector Th1 cells isolated from murine EAE donors treated in vivo with mR-411 suppress EAE in recipients with active disease. In contrast to general immunosupresants (steroids, rapamycin, calcineurin inhibitors), mR-411 induces tolerance that is Ag-specific for active disease yet preserves historical cell-mediated immunity to unrelated Ag's. Because CXCL11 interacts via the CXCR3 receptor, it is expected to bypass the CD46 defect in CD4+ cells in MS and fully activate IL-10 expression and induce Tr1 cell polarization. In support of this assumption, CXCL11 strongly induces IL-10 expression in human CD4+ cells co-incubated in vitro with anti-CD28. The purpose of this grant is to establish the pharmacodyamic profile of mR-411 in a classic murine EAE model of relapsing MS ("R-EAE"). The scientific hypothesis to be tested is that mR-411 decreases R-EAE by inhibiting the activation and differentiation of autoantigen-specific pro-inflammatory Th1/Th17 responses predominantly by promoting the activation of Tr1 cell function. Aim #1: Establish a pharmacodynamic profile of mR-411 in a murine model of R-EAE A titration of mR-411 (1, 3, or 10 mg/kg QOD IP) or an irrelevant IgG1 control will be tested in R-EAE, with groups of mice receiving treatment after the acute phase of disease (16-21 days). These treatment groups will be compared to a negative (sham) control group not exposed to PLP139-151, and a positive control group treated with dexamethasone. Animals will be monitored for overt neurological deterioration over a period of 1 month. Spinal cord tissue will be examined for histologic evidence of inflammation and tissue injury. Aim #2: Determination of the in vivo mechanism by which mR-411 decreases disease severity in R-EAE We will test the working hypothesis that mR-411 treatment decreases EAE disease severity by inhibiting the activation of autoantigen-specific Th1/Th17 effector responses. The same experimental paradigm will be employed as in Aim #1. We wil determine how mR-411 treatment alters the number, phenotype, induction, and function of CD4+ Th1/Th17 cells present within the CNS, spleen, and draining lymph nodes following treatment. These studies will use a combination of actively induced and transfer models of EAE employing myelin-specific 5B6 PLP139-151-specific TCR transgenic T cells.

描述（由申请人提供）：