MEMORY T CELLS IN EAE

描述（由申请人提供）：最近人们认识到，在人类中诱导免疫耐受的一个重要障碍是适应性免疫反应，由于进化设计，注定要产生免疫记忆；最初的数据表明记忆T细胞倾向于抵抗诱导耐受。EAE是一种模仿ms某些方面的中枢神经系统炎症性疾病。我们建立了一种不同于效应T细胞介导的疾病，由抗原特异性记忆T细胞介导的EAE新模型。本项目的主要目标是研究记忆T细胞EAE的作用，并研究它们对体内耐受策略的易感性。目的1：我们将研究由记忆与效应T细胞介导的疾病的特征，包括临床特征、中枢神经系统（CNS）病理和外周免疫反应。目的2：我们的假设是，自身反应性记忆T细胞可以被非特异性免疫刺激（病毒感染、炎症、疫苗接种）激活，从而导致临床疾病的再激活/进展。在这个目的中，我们将研究哪些刺激可以激活体内的自反应性记忆T细胞，并定义由这些细胞介导的临床和病理疾病模式及其发生机制。目的3：我们的假设是，自身反应性记忆T细胞较少依赖于传统的（CD28） T细胞共刺激途径激活，需要独特的T细胞共刺激信号才能在体内完全激活、分化和存活。这些协同模拟途径包括ICOS-B7h和CD134-CD143L。利用抗B7h和CD134L的阻断抗体，我们将在体内研究这些途径在调节记忆T细胞介导的自身免疫性疾病中的功能和机制。

DESCRIPTION (provided by applicant): An important recently recognized barrier to induction of immunologic tolerance in humans is the fact that the adaptive immune response, by virtue of evolutionary design, is destined to generate immunologic memory; and initial data suggest that memory T cells tend to be resistant to induction of tolerance. EAE is an inflammatory disease of the central nervous system that mimics certain aspects of MS. We have established a new model of EAE that is mediated by antigen-specific memory T cells that is distinct from disease mediated by effector T cells. The major goal of this project is to investigate the role of memory T cells EAE, and to investigate their susceptibility to tolerance strategies in vivo. Aim1: We will investigate the characteristics of disease mediated by memory versus effector T cells, including clinical features, central nervous system (CNS) pathology, and peripheral immune responses. Aim 2: Our hypothesis is that autoreactive memory T cells can be activated by nonspecific immune stimuli (viral infection, inflammation, vaccination) leading to reactivation/progression of clinical disease. In this aim we will investigate which stimuli can activate autoreactive memory T cells in vivo and define the clinical and pathological disease pattern mediated by these cells and the mechanisms of how this happens. Aim 3: Our hypothesis is that autoreactive memory T cells are less dependent on conventional (CD28) T cell costimulatory pathways for activation and require distinct and unique T cell costimulatory signals for full activation, differentiation and survival in vivo. These cosimulatory pathways include ICOS-B7h and CD134-CD143L. Using blocking antibodies against B7h and CD134L, we will investigate the functions and mechanisms of these pathways in regulating autoimmune disease mediated by memory T cells in vivo.