AUTOIMMUNITY: TREATMENT BY COSTIMULATORY SIGNAL BLOCKADE

在过去的20年里，自身免疫领域取得了巨大的进步，我们对自身免疫疾病机制的理解呈指数级增长。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身耐受性的正常机制的理解的提高，以及操纵这些机制以预防和治疗自身免疫性疾病的能力。作为许多疾病基础的自身免疫机制是相似的，并且用于评估新的和新兴疗法的综合多专业方法将提供整合来自各个专业的知识的机会。我们选择通过阻断共刺激信号来研究自身免疫性疾病的治疗。这个策略有两个优点。首先，这些是T细胞活化和免疫应答中的抗原非特异性步骤。这意味着可以在不需要知道抗原的身份的情况下实现耐受性。第二，信号2的限制性传递和细胞因子产生和分布的改变可能涉及自身耐受的正常机制。我们将重点关注CD 40-CD 40 L通路。我们的项目将重点关注的人类疾病是多发性硬化症（MS）、炎症性肠道疾病（IBD）和银屑病。所有这些都是器官特异性疾病，其中T细胞似乎在启动免疫应答中至关重要，并导致特定的疾病病理学。项目#1的总体目标是在一项初步试验中研究抗CD 40 L治疗在MS中的疗效和安全性。项目#2的目标是在一项初步试验中研究抗CD 40 L治疗在IBD中的疗效和安全性。项目3将重点关注MS和IBD患者中与抗CD 40 L治疗相关的免疫学变化。项目#4将研究牛皮癣的免疫机制。通过阻断T细胞活化的次级信号来治疗自身免疫性疾病的方法是及时的，并且具有很高的成功可能性。有大量证据支持在自身免疫性疾病中使用抗CD 40 L。从试点试验中获得的数据将在设计III期临床试验中有价值，而免疫学研究将有助于确定疾病活动的替代标志物。

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 which 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. This strategy has 2 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 2 and alteration in cytokine production and profiles are probably involved in normal mechanisms of self-tolerance. We will focus on the CD40-CD40L pathway. The human diseases that our program will focus on are multiple sclerosis (MS), inflammatory bowel disease (IBD), 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. The overall goals of project #1 are to study in a pilot trial the efficacy and safety of anti-CD40L therapy in MS. The goals of project #2 are to study in a pilot trial the efficacy and safety of anti-CD40L therapy in IBD. Project #3 will focus on the immunologic changes associated with anti- CD40L therapy in patients with MS and IBD. Project #4 will study the immune mechanisms of psoriasis. The approach of treating autoimmune diseases by blocking secondary signal of T cell activation is timely and has a high likelihood of success. There is a body of evidence supporting the use of anti-CD40L in autoimmune disease. The data obtained from the pilot trials will be valuable in designing phase III clinical trials, while the immunologic investigations will help identify surrogate markers for disease activity.