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，我们想测试特异性抗原诱导的细胞凋亡作为治疗这种自身免疫性疾病的一种手段。为此，我们在以下领域取得了进展：1）我们重新启动了对含有多发性硬化症潜在相关抗原的重组分子的研究，目的是建立一个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靶点。 通过编程识别这些抗原的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，以确定这些是否可以提供自身免疫性攻击的早期预警系统; 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因子VIII给药后形成阻断抗体。这些研究将采用新的重组蛋白质，构建含有T细胞反应的因子VIII的主要表位区域。我们还将在其他自身免疫性疾病的实验动物中开展研究。特别是，我们专注于I型糖尿病，并一直在研究针对胰岛素的免疫反应，作为糖尿病前期小鼠和人类疾病的先兆。 糖尿病前期状态，称为胰岛炎，涉及以胰岛素为主要抗原的胰岛细胞的细胞和数字反应。在任何明显的表位扩散之前的免疫应答的集中性质可以允许使用胰岛素或其同源物作为治疗实体。 作为这些研究的一部分，我们试图了解T细胞受体刺激抗原诱导死亡的分子调控。 部署高度敏感的早期预警系统作为筛查工具，以识别具有早期免疫介导的器官损伤的个体，并使用抗原特异性治疗方法进行早期干预，我们希望提供靶向治疗，以最大限度地减少终末器官损伤和临床疾病。为此，我们已经制备了非常灵敏的电化学发光分析，可以灵敏和特异地检测FVIII抗体和胰岛素自身抗体。这可以更好地部署我们早期成功干预的努力。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，并有望刺激新形式的高度特异性免疫治疗的发展。

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. These studies will employ new recombinant proteins constructed to contain the principal epitopic regions of Factor VIII to which T cells react. We will also be initiating studies in experimental animals of other autoimmune conditions. In particular, we are focusing on Type I diabetes mellitus and have been studying immune responses against insulin as a harbinger of disease in prediabetic mice and humans. The prediabetic state, known as insulitis, involves both cellular and numeral responses against the islet cells with insulin as the primary antigen. The focused nature of the immune response, which precedes any evident epitope spreading, may allow the use of insulin or congeners thereof as a therapeutic entity. 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. to this end, we have prepared extremely sensitive electrochemiluminescence assays that can sensitively and specifically detect FVIII antibodies and insulin autoantibodies. This could better dispose our efforts to intervene early successfully. 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.