Molecular Mechanisms and Treatment Of Autoimmunity In Man And Animal Models

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，我们想了解导致自身免疫性疾病的T细胞的致病作用和抗原特异性，如多发性硬化症、凝血因子抑制、胰岛素依赖型糖尿病等。其次，我们希望测试特定抗原诱导的细胞凋亡作为治疗此类自身免疫性疾病的一种手段。为此，我们在以下方面取得了进展：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，目标是建立一项合作研究和开发协议，以在临床试验中测试这种形式的治疗。目前，越来越多的证据表明髓鞘蛋白抗原是自身免疫攻击的目标。通过编程让识别这种抗原的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诊断试验，以检测自身免疫性疾病期间的终末器官损害，以确定这些试验是否可以提供自身免疫攻击的早期预警系统；以及3)我们正在启动抗原特异性治疗的研究，以防止血友病患者使用因子后形成封闭抗体。我们还将启动对其他自身免疫状况的实验动物的研究。作为这些研究的一部分，我们试图了解T细胞受体刺激对抗原诱导死亡的分子调控。部署高灵敏度的早期预警系统作为筛查工具，识别早期免疫介导的器官损伤个体，并使用抗原特异性治疗方法进行早期干预，我们希望提供有针对性的治疗，将终末器官损伤和临床疾病降至最低。我们相信，这些研究将为自身免疫性疾病的发病机制提供重要的新见解，并有望刺激高特异性免疫疗法的新形式的发展。

We are studying the cellular and molecular basis of autoimmune diseases with two purposes. First, we want to understand 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 test 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 Research 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 autoimmune 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 in experimental animals of other autoimmune conditions. As part of these studies we are trying to understand the molecular regulation of antigen-induced death by T cell receptor stimulation. The deployment of a highly sensitive early warning system as a screening tool to identify individuals with early immune-mediated organ damage with early intervention using antigen-specific treatment approaches, we hope to provide targeted therapy to minimize end-organ damage and clinical disease. We believe these investigations will provide important new insights into the pathogenesis of autoimmune diseases and hopefully stimulate the development of new forms of highly specific immune therapy.