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。我们选择通过阻断共刺激信号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。我们将重点介绍CD40-CD40L途径。我们的计划重点关注的人类疾病是多发性硬化症(MS)、炎症性肠病(IBD)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的总体目标是在试点试验中研究抗CD40L治疗在多发性硬化症中的有效性和安全性。项目2的目标是在试点试验中研究抗CD40L治疗在IBD中的有效性和安全性。项目3将专注于MS和IBD患者抗CD40L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细胞激活的次级信号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。有大量证据支持在自身免疫性疾病中使用抗CD40L。从试点试验中获得的数据将对设计第三阶段临床试验有价值，而免疫学调查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.