AUTOIMMUNITY CENTERS OF EXCELLENCE

自身免疫卓越中心

• 批准号: 6374278
• 负责人: Leonard Chess
• 金额: $ 101.69万
• 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/6374278
• 关键词: autoimmune disorder; clinical research; human subject

The overall aim of this center proposal is to establish an interdisciplinary basic and clinical research program at Columbia primarily focused on the evaluation of novel therapeutic approaches to five autoimmune diseases; rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), type one diabetes mellitus (TIDM) and scleroderma. In each of these diseases there are ongoing basic and clinical research programs involving pathophysiologic and/or clinical immunotherapeutic studies. We hypothesize that there are four principal events involved in the immunopathogenesis of these diseases: (1) predisposing genes establish a T-cell repertoire capable of recognizing self peptides intrinsic to the autoimmune process; (2) previously tolerant autoreactive effector T cells; (3) regulatory mechanisms, including the activation of TH1 and TH2 CD4+ T cell subsets as well as those involving CD8 T-cells fail, through processes such as clonal deletion or changes in the cytokine milieu and (4) pathogenic autoantibodies develop through cognitive T- cell B-cell interactions which effect tissue injury. In these diseases, one would predict that reducing the clonal expression of relevant autoreactive T cells by blockade of T cell receptor signaling or interruption of the CD40 ligand-dependent pathway could down-modulate disease activity. Moreover, interruption of the inflammatory effector functions of T cells mediated by TNF or CD40L would similarly reduce disease potential. We propose to test these hypotheses in the above patients during the natural history of disease and during specific immune intervention. In particular, we will study patients with SLE treated with anti-CD40L; MS patients receiving IFN-beta or anti-CD40L; T1DM patients receiving anti-CD3 and RA patients receiving the recombinant TNF receptor inhibitor (Embrel). During these studies we will: (1) identify by PCR based spectratyping techniques and TCR sequencing, oligoclonal and autoantigen-driven expansions in the CD4 alphabeta TCR repertoire; (2) Identify changes in the T cell functional response to autoantigens and (3) directly study the regulatory interactions of TH1, TH2 and CD8+ T cells in controlling the TCR repertoire. In select patients, we will directly study the function and repertoire of T cells at the site of inflammation (CNS, Joints) using HVS immortalization techniques.

该中心建议的总体目的是在哥伦比亚建立跨学科的基本和临床研究计划，主要侧重于评估五种自身免疫性疾病的新型治疗方法；类风湿关节炎（RA），全身性红斑狼疮（SLE），多发性硬化症（MS），一型糖尿病（TIDM）和硬皮病。在每种疾病中，都有涉及病理生理和/或临床免疫治疗研究的持续基础和临床研究计划。我们假设这些疾病的免疫病作用涉及四个主要事件：（1）诱发基因建立了能够识别自身免疫过程固有的自我肽的T细胞库； （2）先前耐受性自动反应效应T细胞； （3）调节机制，包括Th1和Th2 CD4+ T细胞亚群的激活以及涉及CD8 T细胞的激活，通过克隆缺失或细胞因子环境的变化以及（4）致病性自身抗体的变化，通过对认知T-细胞相互作用产生构成构成构成造成群体损伤的认知性T-细胞相互作用。在这些疾病中，人们会预测，通过阻断T细胞受体信号传导或CD40配体依赖性途径的中断可以减少相关自身反应性T细胞的克隆表达。此外，通过TNF或CD40L介导的T细胞的炎症效应功能的中断类似地降低了疾病的潜力。我们建议在疾病的自然病史和特定的免疫干预期间在上述患者中检验这些假设。特别是，我们将研究用抗CD40L治疗的SLE患者；接受IFN-β或抗CD40L的MS患者；接收抗CD3和RA患者的T1DM患者接受重组TNF受体抑制剂（Ambrel）。在这些研究中，我们将：（1）通过基于PCR的频谱技术和TCR测序，CD4 Alphabeta TCR曲目中的寡克隆和自身驱动的扩张识别； （2）确定对自身抗原的T细胞功能反应的变化，（3）直接研究TH1，TH2和CD8+ T细胞在控制TCR库中的调节相互作用。在某些患者中，我们将使用HVS永生技术直接研究炎症部位（CNS，关节）的T细胞的功能和曲目。