Molecular Mechanisms Of Autoimmune Disease In Man/Animal

我们研究自身免疫性疾病的细胞和分子基础有两个目的。首先，我们希望确定引起自身免疫性疾病（如多发性硬化症、凝血因子抑制、胰岛素依赖型糖尿病等）的T细胞的致病作用和抗原特异性。其次，我们想确定特异性抗原诱导的细胞凋亡作为治疗这类自身免疫性疾病的一种手段的可行性。为此，我们在以下领域取得了进展：1)我们重新启动了含有可能与多发性硬化症有关的抗原的重组分子的研究，目标是建立合作研究与开发协议，在临床试验中测试这种形式的治疗。目前有越来越多的证据表明髓磷脂蛋白抗原是自身免疫攻击的目标。通过编程使识别这些抗原的T细胞死亡，可以证明消除这些细胞对疾病的影响。2)我们正在研究新的高灵敏度的诊断测试，以检测自身免疫性疾病期间的终末器官损伤，以确定这些测试是否可以提供自身免疫攻击的“预警系统”；3)我们正在启动抗原特异性治疗的研究，以防止血友病患者在给予因子VIII后形成阻断抗体。我们还将启动一种新的自身免疫性甲状腺炎转基因小鼠模型的研究。作为这些研究的一部分，我们正试图了解通过T细胞受体刺激抗原诱导死亡的调控。通过将高度敏感的“早期预警系统”与抗原特异性缺失方法相结合，识别早期免疫介导的器官损伤个体，我们希望在广泛的终末器官损伤之前提供有效的靶向治疗。这些研究应该为自身免疫性疾病的发病机制和治疗提供重要的新见解，这是一个普遍存在的健康问题，尤其是在美国的职业女性中。

We are studying the cellular and molecular basis of autoimmune diseases with two purposes. First, we want to establish the pathogenic role and antigen-specificity of T cells that cause autoimmune diseases such as multiple sclerosis, clotting factor inhibition, insulin-dependent diabetes, among others. Second, we would like to determine the feasibility of specific antigen-induced apoptosis as a means of treating such autoimmune diseases. To these ends, we have made progress in the following areas: 1) we have reinitiated studies of recombinant molecules containing antigens potentially involved in multiple sclerosis with the goal of establishing a Cooperative RFesearch and Development Agreement to test such a form of therapy in a clinical trial. At present there is increasing evidence that myelin proteins antigens are the target of the autoimmune attack. By programmed the T cells that recognize such antigens to die, the effect of eliminating these cells on the disease can be demonstrated. 2) we are studying new highly sensitive diagnostic tests to detect end organ damage during autoimmune diseases to determine if these can provide an "early warning system" of autimmune attack; and 3) we are initiating studies of antigen-specific therapy to prevent the formation of blocking antibodies following factor VIII administration to hemophiliacs. We will also be initiating studies of a new transgenic mouse model for autoimmune thyroiditis. As part of these studies we are trying to understand the regulation of antigen-induced death by T cell receptor stimulation. By combining a highly sensitive "early warning system" to identify individuals with early immune-mediated organ damage with antigen-specific deletion approaches, we hope to provide effectively targeted therapy before there is extensive end-organ damage. These studies should yield important new insights into the pathogenesis and treatment of autoimmune diseases which is a widespread health problem in the U.S. particularly among working women.