Treatment of Autoimmune Disease by Costimulatory Signal*

通过共刺激信号治疗自身免疫性疾病*

• 批准号: 6684513
• 负责人: Samia J. Khoury
• 金额: $ 43.21万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 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/6684513
• 关键词: autoimmune disorder; clinical research; human subject; immunotherapy

DESCRIPTION (provided by applicant): There have been tremendous advances in the field of autoimmunity in the last 20 years, and our understanding of the mechanisms underlying autoimmune disease has grown exponentially. True tolerance is likely to arise not from improved immunosuppression, but from improved understanding of the normal mechanisms that generate and maintain self-tolerance, and the ability to manipulate these mechanisms for the prevention and treatment of autoimmune diseases. The mechanisms of autoimmunity that underlie many diseases are similar, and an integrated multi-specialty approach for evaluating new and emerging therapies would provide the opportunity to integrate knowledge from the various specialties. We have chosen to study therapy of autoimmune disease by blocking co-stimulatory signals with CTLA4Ig and by blocking T cell activation with rapamycin. This strategy has two advantages. First, these are antigen non-specific steps in T cell activation and immune responses. This means that tolerance can be achieved without needing to know the identity of the antigen. Second, restricted delivery of signal two and alteration in cytokine production and profiles are probably involved in normal mechanisms of self-tolerance. Third, by inhibiting T cell activation with rapamycin in addition to costimulatory signal blockade, we may be able to induce long term tolerance by allowing the occurrence of activation induced cell death. The human diseases that our program will focus on are multiple sclerosis (MS), autoimmune diabetes (IDDM), and psoriasis. All are organ specific diseases where T cells appear to be essential in initiating the immune response and lead to the particular disease pathology. Project #1 is the clinical trials project, in which we propose a clinical trial of CTLA4Ig in diabetes, a clinical trial of CTLA4Ig + rapamycin in early MS and describe the available patients and facilities for a potential psoriasis trial. The goals of project #2 are to investigate the role of NK T cells in human diabetes. Project #3 will take a direct approach by cloning T cells and NK T cells from the pancreas and pancreatic lymph nodes of patients with diabetes. The approach of treating autoimmune diseases by preventing T cell activation is timely and has a high likelihood of success. There is a body of evidence including clinical trials supporting the use of CTLA4Ig in autoimmune disease, and also evidence for the synergistic role of rapamycin. The data obtained from the clinical trials and the critical information from the basic science projects will be valuable in getting us closer to our goal of tolerance induction for autoimmune disease.

描述（由申请人提供）： 过去 20 年来，自身免疫领域取得了巨大进展，我们对自身免疫疾病机制的了解也呈指数级增长。真正的耐受性可能不是来自免疫抑制的改善，而是来自对产生和维持自我耐受性的正常机制的更好的理解，以及操纵这些机制来预防和治疗自身免疫性疾病的能力。许多疾病背后的自身免疫机制是相似的，用于评估新疗法和新兴疗​​法的综合多专业方法将提供整合各个专业知识的机会。 我们选择通过用 CTLA4Ig 阻断共刺激信号和用雷帕霉素阻断 T 细胞激活来研究自身免疫性疾病的治疗。这种策略有两个优点。 首先，这些是 T 细胞激活和免疫反应中的抗原非特异性步骤。这意味着无需知道抗原的身份即可实现耐受。 其次，信号二的限制传递以及细胞因子产生和分布的改变可能涉及正常的自我耐受机制。第三，除了共刺激信号阻断之外，通过用雷帕霉素抑制T细胞活化，我们也许能够通过允许活化诱导的细胞死亡的发生来诱导长期耐受。我们的计划重点关注的人类疾病是多发性硬化症 (MS)、自身免疫性糖尿病 (IDDM) 和牛皮癣。 所有这些都是器官特异性疾病，其中 T 细胞似乎对于启动免疫反应至关重要，并导致特定的疾病病理。 项目 #1 是临床试验项目，其中我们提出了 CTLA4Ig 在糖尿病中的临床试验、CTLA4Ig + 雷帕霉素在早期 MS 中的临床试验，并描述了潜在银屑病试验的可用患者和设施。项目#2 的目标是研究 NK T 细胞在人类糖尿病中的作用。项目#3将采取直接方法，从糖尿病患者的胰腺和胰腺淋巴结克隆T细胞和NK T细胞。通过阻止 T 细胞激活来治疗自身免疫性疾病的方法是及时的，并且成功的可能性很高。有大量证据，包括支持 CTLA4Ig 在自身免疫性疾病中使用的临床试验，以及雷帕霉素协同作用的证据。从临床试验中获得的数据和从基础科学项目中获得的关键信息对于让我们更接近诱导自身免疫性疾病耐受的目标非常有价值。