AUTOIMMUNITY CENTERS OF EXCELLENCE

自身免疫卓越中心

• 批准号: 7068110
• 负责人: Leonard Chess
• 金额: $ 91.14万
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7068110
• 关键词: autoimmune disorder; clinical research; cooperative study; human subject

DESCRIPTION (provided by applicant): The overall goals of this ACE renewal application will be to further develop our interdisciplinary basic and clinical research program at Columbia primarily focused on the evaluation of novel therapeutic approaches to human autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid and psoriatic arthritis (RA), multiple sclerosis (MS), type I diabetes mellitus (TIDM), biliary cirrhosis 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 T-cell clones are activated, expand to change the T cell repertoire to reflect autoreactive effector T cells and migrate to sites of inflammation; (3) regulatory mechanisms, including cytokines and CD4+ and CD8+ regulatory T cells fail and (4) pathogenic autoantibodies and T cells effect tissue injury. We predict that reducing the clonal expansion and migration of relevant autoreactive T cells by blockade of TCR signaling with agents like anti-CD3 or interruption of the signaling and migration of autoreactive memory T cells with agents like anti-VLA-1 could down-modulate disease activity. We propose to test these hypotheses during the natural history of disease and during specific immune intervention. In this ACE renewal, we plan to continue ongoing studies of anti-CD3 therapy of TIDM, initiate trials of biliary cirrhosis employing Mycophenolate Mofetil and continue pre-clinical assessment of the VLA-1 pathway as a prelude to clinical trials with anti-VLA-1 moAbs anticipated to begin in 2004. During these studies, we will: (1) identify by PCR based CDR3 length techniques and TCR sequencing, autoantigen-driven expansions in the CD4 and CD8 cz_ TCR repertoire; (2) Identify changes in the T cell functional response to autoantigens and (3) directly study the regulatory interactions of TH1, TH2 as well as CD4+ and CD8+ T cells in controlling the TCR repertoire. In select patients, we will directly study cells at the site of inflammation (CNS, skin, kidney, joints) using HVS immortalization techniques as well as by laser capture technology for repertoire and microarray analysis of activated genes. In addition, we plan new basic studies of the control of the autoreactive T cell repertoire in autoimmune disease by analysis of EAE in the mouse and studies of human regulatory cells in TIDM.

描述（由申请人提供）： 此次 ACE 更新申请的总体目标是进一步发展我们在哥伦比亚大学的跨学科基础和临床研究项目，主要侧重于评估人类自身免疫性疾病的新治疗方法，包括系统性红斑狼疮 (SLE)、类风湿性关节炎和银屑病关节炎 (RA) 、多发性硬化症 (MS)、I 型糖尿病 (TIDM)、胆汁性肝硬化和硬皮病。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 T 细胞克隆被激活、扩展以改变 T 细胞库，以反映自身反应性效应 T 细胞并迁移到炎症部位； (3) 调节机制，包括细胞因子以及 CD4+ 和 CD8+ 调节性 T 细胞失效；(4) 致病性自身抗体和 T 细胞影响组织损伤。 我们预测，通过使用抗 CD3 等药物阻断 TCR 信号传导，或使用抗 VLA-1 等药物中断自身反应性记忆 T 细胞的信号传导和迁移，从而减少相关自身反应性 T 细胞的克隆扩增和迁移，可以下调疾病。活动。我们建议在疾病的自然史和特异性免疫干预期间检验这些假设。在本次 ACE 更新中，我们计划继续进行 TIDM 抗 CD3 疗法的研究，启动使用吗替麦考酚酯治疗胆汁性肝硬化的试验，并继续对 VLA-1 通路进行临床前评估，作为抗 VLA-1 临床试验的前奏。 1 moAb 预计于 2004 年开始。在这些研究中，我们将：(1) 通过基于 PCR 的 CDR3 长度技术和 TCR 测序、自身抗原驱动的扩展来鉴定在CD4和CD8 cz_TCR指令库中； (2) 识别 T 细胞功能对自身抗原反应的变化；(3) 直接研究 TH1、TH2 以及 CD4+ 和 CD8+ T 细胞在控制 TCR 库中的调节相互作用。在选定的患者中，我们将使用 HVS 永生化技术以及激光捕获技术直接研究炎症部位（中枢神经系统、皮肤、肾脏、关节）的细胞，以对激活的基因进行库和微阵列分析。此外，我们计划通过分析小鼠的 EAE 和研究 TIDM 中的人类调节细胞来控制自身免疫性疾病中的自身反应性 T 细胞库。