Treatment of Autoimmune Disease by Costimulatory Signal*

描述(由申请人提供)： 在过去的20年里，自身免疫领域取得了巨大的进步，我们对自身免疫性疾病的潜在机制的了解也呈指数级增长。真正的耐受很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的正常机制的更好理解，以及操纵这些机制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，评估新的和新兴的治疗方法的综合多专业方法将提供机会整合来自不同专业的知识。 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。这一战略有两个优势。首先，这些都是T细胞激活和免疫反应中的抗原非特异性步骤。这意味着在不需要知道抗原的身份的情况下就可以实现耐受。第二，信号2的传递受限以及细胞因子的产生和分布的改变可能与正常的自我耐受机制有关。第三，除了共刺激信号阻断外，通过用雷帕霉素抑制T细胞的激活，我们可能能够通过允许激活诱导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有的疾病，其中T细胞似乎是启动免疫反应的关键，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治疗糖尿病的临床试验，CTLA4Ig+雷帕霉素治疗早期MS的临床试验，并描述了可用于潜在牛皮癣试验的患者和设施。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将采取直接的方法，从糖尿病患者的胰腺和胰腺淋巴结中克隆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，成功的可能性很高。有大量证据支持CTLA4Ig用于自身免疫性疾病的临床试验，也有证据表明雷帕霉素具有协同作用。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将有助于我们更接近诱导自身免疫性疾病耐受的目标。

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.