MOLECULAR MECHANISMS OF AUTOIMMUNE DISEASE 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，我们想确定T细胞的致病作用和抗原特异性，这些T细胞会导致自身免疫性疾病，如多发性硬化症、重症肌无力、胰岛素依赖型糖尿病等。 其次，我们想确定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的可行性。 为此，我们在以下领域取得了进展：1）我们已经建立了转基因T细胞受体小鼠重症肌无力模型，该模型对来自乙酰胆碱受体的肽具有强大的反应。2)我们已经建立了在各种免疫细胞谱系如T细胞、B细胞和树突细胞中携带凋亡抑制基因的转基因小鼠，以确定如果凋亡在这些谱系中的每一个中被抑制，发展自身免疫的风险。3)我们已经完成了对多发性硬化症的绒猴模型的研究，这些研究表明抗原特异性治疗是有用的。 作为这些研究的一部分，我们还试图了解T细胞受体刺激对抗原诱导死亡的调节。 这些研究应该对自身免疫性疾病的发病机制和治疗产生重要的新见解，这是美国特别是职业女性中普遍存在的健康问题。

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, myasthenia gravis, 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 created a transgenic T cell receptor mouse model of myasthenia gravis which has a powerful response to a peptide from the acetylcholine receptor. 2) we have created transgenic mice that harbor an apoptosis inhibition gene in various immune cell lineages such as T cells, B cells,and dendritic cells to determine the risk to developing autoimmunity if apoptosis is inhibited in each of these lineages. 3) we have completed studies on the marmoset model of multiple sclerosis that indicate the usefulness of antigen-specific therapy. As part of these studies we are also trying to understand the regulation of antigen-induced death by T cell receptor stimulation. 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.