Immunoregulation of the TCR repertoire in multiple sclerosis / anti CD40L trial

多发性硬化症/抗 CD40L 试验中 TCR 的免疫调节

• 批准号: 6227080
• 负责人: HONG JIANG
• 金额: $ 20.02万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-28 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6227080
• 关键词: CD40 molecule; CD8 molecule; T lymphocyte; antiidiotype antibody; blood chemistry; cell line; clinical research; clinical trials; human subject; immunoregulation; interferon beta; molecular cloning; multiple sclerosis

The overall aim of this grant is to study the immunopathogenesis of multiple sclerosis (MS) and to define immunoregulatory pathways that may control disease. In addition, we will use the opportunity presented by ongoing treatment of MS patients with IFN-beta and a planned clinical trial of a humanized monoclonal antibody to CD40L in MS to evaluate basic mechanisms of these therapeutic interventions in this disorder. Based on clinical evidence as well as data we have generated in EAE we hypothesize that there are four principal events in the development of MS: (1) genes including MHC alleles predisposing to MS establish a T-cell repertoire capable of recognizing self myelin related peptides intrinsic to the autoimmune process of MS: (2) myelin specific CD4+ T cell clones previous tolerant to autoantigen become activated and expand to change the T cell repertoire to reflect autoreactive CD4 T cells; (3) regulatory mechanisms, including the activation of TH1 and TH2 CD4+ T cell subsets as well as those involving regulatory CD8 T-cells fail, through processes, such as clonal deletion or changes in the cytokine milieu and (4) potentially myelin reactive TH1 CD4+ T-cells migrate to the CNS and induce tissue damage and disease. There will be two interactive aspects of this project. The first aspect will consist of three specific aims designed to study basic aspects of the immunopathogenesis and immunoregulation of human MS. These aims will: (1) determine if regulatory CD8+ T cells which specifically down-regulate MBP specific CD4+ T cells exist in the PBL or CSF of MS patients. (2) determine if the MBP specific CD4+ T cell TCRVB or functional repertoires are different at different disease stages and are modified by CD8+ T cells: (3) identify antigen activated CD4+ T cell clones in the CSF or MS patients, immortalize these clones and use libraries of T cell clones to determine antigen specificity. The second aspect of studies will consist of several specific aims directly concerned with the investigation of immunoregulatory mechanisms and TCRVB functional repertoires in patients being treated with IFN-beta or anti-CD40L.

该赠款的总体目的是研究多发性硬化症（MS）的免疫发病发生，并定义可能控制疾病的免疫调节途径。此外，我们还将利用MS持续治疗IFN-β患者的持续治疗和MS中人性化单克隆抗体的临床试验提供的机会，以评估这种疾病中这些治疗性干预措施的基本机制。基于临床证据和数据，我们在EAE中产生了MS的发展中有四个主要事件：（1）包括MHC等位基因在内的基因建立一个T细胞曲目，能够识别能够识别自我髓磷脂相关的肽对毫无疑问的自动免疫性的过程： T细胞库反映自动反应性CD4 T细胞； （3）调节机制，包括TH1和TH2 CD4+ T细胞子集的激活以及涉及调节性CD8 T细胞的调节机制通过过程，例如克隆缺失或细胞因子环境的变化以及（4）潜在的髓磷脂反应性TH1 CD4+ T-cells迁移到CNS并损害了CNS和疾病。该项目将有两个交互式方面。第一个方面将由三个特定的目标组成，旨在研究人类MS的免疫发育生成和免疫调节的基本方面。这些目的将：（1）确定在MS患者的PBL或CSF中是否存在特异性下调MBP特异性CD4+ T细胞的调节性CD8+ T细胞。 （2）确定在不同疾病阶段的MBP特异性CD4+ T细胞TCRVB或功能曲目是否不同，并通过CD8+ T细胞进行了修改：（3）确定CSF或MS患者中的抗原活化的CD4+ T细胞克隆，使这些克隆的不朽和使用这些克隆来确定T细胞cl剂来确定抗原特异性。研究的第二个方面将包括几个直接与接受IFN-β或抗CD40L治疗的患者的免疫调节机制和TCRVB功能库的研究。