AUTOIMMUNITY CENTERS OF EXCELLENCE

自身免疫卓越中心

• 批准号: 6534197
• 负责人: Leonard Chess
• 金额: $ 62.18万
• 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/6534197
• 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.

该中心提案的总体目标是在哥伦比亚建立一个跨学科的基础和临床研究项目，主要侧重于评估五种自身免疫性疾病的新治疗方法；类风湿性关节炎（RA）、系统性红斑狼疮（SLE）、多发性硬化症（MS）、一型糖尿病（TIDM）和硬皮病。对于这些疾病中的每一种，都有正在进行的涉及病理生理学和/或临床免疫治疗研究的基础和临床研究项目。我们假设这些疾病的免疫发病机制涉及四个主要事件：（1）诱发基因建立了能够识别自身免疫过程固有的自身肽的T细胞库； (2)先前耐受的自身反应性效应T细胞； (3) 调节机制，包括通过克隆删除或细胞因子环境变化等过程，激活 TH1 和 TH2 CD4+ T 细胞亚群以及涉及 CD8 T 细胞的机制失败；(4) 通过认知 T 产生致病性自身抗体- 影响组织损伤的细胞 B 细胞相互作用。在这些疾病中，人们预测，通过阻断 T 细胞受体信号传导或中断 CD40 配体依赖性途径来减少相关自身反应性 T 细胞的克隆表达，可以下调疾病活动。此外，中断 TNF 或 CD40L 介导的 T 细胞炎症效应功能同样会降低疾病的可能性。我们建议在上述患者的疾病自然史和特异性免疫干预期间测试这些假设。特别是，我们将研究接受抗 CD40L 治疗的 SLE 患者；接受 IFN-β 或抗 CD40L 治疗的 MS 患者；接受抗 CD3 治疗的 T1DM 患者和接受重组 TNF 受体抑制剂 (Embrel) 的 RA 患者。在这些研究中，我们将：（1）通过基于 PCR 的谱型技术和 TCR 测序来识别 CD4 字母 TCR 库中的寡克隆和自身抗原驱动的扩展； (2) 识别 T 细胞对自身抗原功能反应的变化；(3) 直接研究 TH1、TH2 和 CD8+ T 细胞在控制 TCR 库方面的调节相互作用。在选定的患者中，我们将使用 HVS 永生化技术直接研究炎症部位（中枢神经系统、关节）T 细胞的功能和全部功能。