T CELL ACTIVATION IN AUTOIMMUNE DEMYELINATION

多发性硬化症（MS）是一种中枢神经系统（CNS）的炎性脱髓鞘疾病，在美国影响250，000 - 350，000人。实验性自身免疫性脑脊髓炎（EAE）是一种T细胞介导的疾病，其临床和病理特征与MS相似，使其成为研究MS的高度相关的动物模型。除了致脑炎性T细胞通过T细胞受体（TCR）接收的信号外，完全激活T细胞还需要第二个信号，称为共刺激。细胞表面分子的B7家族能够通过两种受体CD 28和CTLA-4向T细胞提供第二信号。还已知活化或记忆T细胞较少依赖于通过B7：CD 28/CTLA-4途径的共刺激。实验证据表明，与髓鞘成分反应的T细胞参与了EAE和MS的发病机制。在我们之前的工作中的EAE模型的基础上，我们将测试的假设，髓鞘反应性T细胞，这是相关的中枢神经系统炎症性脱髓鞘的发病机制，可以区分从幼稚，幼稚，髓鞘反应性T细胞缺乏依赖共刺激激活。为了实现这一点，我们将检查EAE模型和MS患者中髓磷脂反应性T细胞随时间活化的要求。使用分子生物学中的复杂技术，如单链构象多态性（SSCP）分析，我们将确定我们在体外观察到的不依赖于共刺激的髓磷脂反应性T细胞是否在MS患者体内实际上扩增，表明这些特异性T细胞参与了疾病的病理生理学。我们的研究还将确定B7：CD 28/CTLA-4通路在体内使用T细胞激活疾病中的作用，以及它们在通常对EAE具有抗性的小鼠中调节疾病中的作用。我们还将继续研究EAE模型中外周耐受的机制，重点是共刺激途径。提出的研究将推进我们对MS病理生理学的理解，并可能适用于新的治疗策略的设计。

Multiple Sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) that affects 250,000-350,000 people in the United States. Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated disorder with clinical and pathological features similar to MS, making it a highly relevant animal model for the study of MS. In addition to the signal the encephalitogenic T cell receives through the T cell receptor (TCR), a second signal, termed co-stimulation, is required for complete T cell activation. The B7 family of cell surface molecules is capable of providing this second signal to T cells via two receptors, CD28 and CTLA-4. It is also known that activated or memory T cells are less dependent on co-stimulation through the B7:CD28/CTLA-4 pathway. Experimental evidence suggests that T cell reactive with myelin components are involved in the pathogenesis of EAE and possibly MS. Building upon our prior work in the EAE model, we will test the hypothesis that myelin-reactive T cells, which are relevant to the pathogenesis of CNS inflammatory demyelination, can be distinguished form naive, naive, myelin-reactive T cells by a lack of dependence upon co-stimulation for activation. To accomplish this, we will examine the requirements for the activation of myelin-reactive T cells over time in both the EAE model and in patients with MS. Using sophisticated techniques in molecular biology such as single strand conformation polymorphism (SSCP) analysis, we will determine whether the co- stimulation-independent, myelin-reactive T cells we observe in vitro are actually expanded in MS patients in vivo, implicating these specific T cells in the pathophysiology of the disease. Our studies will also determine the role of the B7: CD28/CTLA-4 pathway in the activation of disease using T cells in vivo, and their role in the regulation of disease in mice normally resistant to EAE. We will also continue our studies examining mechanisms of peripheral tolerance in the EAE model, focusing on co-stimulatory pathways. The studies proposed will advance our understanding of the pathophysiology of MS and may be applicable for the design of new treatment strategies.