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，我们想要确定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、重症肌无力、胰岛素依赖型糖尿病等。其次，我们希望确定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的可行性。为此，我们在以下方面取得了进展：1)我们采用了实验性变态反应性脑脊髓炎的绒猴模型，以表明决定簇的传播在产生免疫反应中是一个重要事件，从而导致髓鞘损伤；2)我们发现反复给药中枢神经系统神经绝缘鞘的一种蛋白质成分(髓鞘)会抑制免疫反应，并改善绒猴的临床结局；3)我们正在继续进行抗原诱导多发性硬化症细胞凋亡的临床试验；4)我们已经创建了一种转基因重症肌无力小鼠模型，该模型对乙酰胆碱受体的多肽具有强大的反应。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。这些研究应该会对自身免疫性疾病的发病机制和治疗产生重要的新见解，这种疾病在美国是一个普遍的健康问题，特别是在职业女性中。-自身免疫性、多发性硬化症、重症肌无力

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 employed the marmoset model of experimental allergic encephalomyelitis to show that determinant spreading is an important event in generating immune responses that cause damage to the myelin sheath; 2) we found that repeated administration of a protein component of the insulating sheath (myelin) of nerves in the central nervous system dampens the immune response and improves clinical outcome in marmosets; 3) we are continuing to progress towards a clinical trial of antigen-induced apoptosis in multiple sclerosis, and 4) we have created a transgenic mouse model of myasthenia gravis which has a powerful response to a peptide from the acetylcholine receptor. 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. - Autoimmunity, multiple sclerosis, myastenia gravis