Mechanisms of CD4+CD25+ T Regulatory Cells in EAE

描述（由申请人提供）：多发性硬化症（MS）是一种免疫介导的中枢神经系统（CNS）疾病，其特征为血管周围CD 4 + T细胞和单核细胞浸润，随后轴突轨道原发性脱髓鞘，导致进行性瘫痪。MS通常被认为是涉及对MBP、PLP和/或髓鞘-少突胶质细胞糖蛋白（MOG）的自身反应性T细胞应答的自身免疫性疾病，然而髓鞘反应性与疾病病理之间的明确因果关系尚未得到证实。尽管MS通常被认为涉及自身免疫病理学，但对其病因学知之甚少，并且可用于特异性抑制和预防正在进行的疾病的治疗策略有限。我们建议调查内在的调节机制，影响MS的易感性和进展，使用两个小鼠模型的实验性自身免疫性脑脊髓炎（EAE），无论是遵循复发缓解（R-EAE）或慢性（C-EAE）疾病过程。CD 4 + CD 25+调节性T细胞（TR）是CD 4 + T细胞应答的有效抑制剂，其通过TCR交联以抗原特异性方式被激活，并且已经显示出介导针对几种自发性自身免疫性疾病（如糖尿病和自身免疫性胃炎）的启动的保护。我们的初步数据清楚地表明，TR的补充显着保护通过抑制幼稚和先前激活的致脑炎性CD 4 + T细胞的增殖和效应功能，而这些细胞的耗尽或失活，导致加重的疾病症状的EAE的启动。我们还发现TR介导的疾病抑制与外周淋巴器官内髓鞘肽特异性保护性Th 2细胞的频率增加和浸润CNS的单核细胞数量显著减少相关。本提案中的实验将检验以下假设：CD 4 + CD 25 + TR在赋予对EAE易感性的抗性和通过诱导对疾病相关的自身髓鞘肽的抗原特异性无反应性来调节疾病进展中起关键作用。所提出的实验将阐明TR在急性和复发性EAE中抑制致脑炎效应Thl细胞的功能活性，从而阻断临床脱髓鞘疾病的起始/进展的细胞和分子机制。提出了三个具体目标：AIM 1将确定CD 4 + CD 25 + TR在调节R-EAE和C-EAE的起始、进展和恢复阶段中的作用。AIM 2将确定CD 4 + CD 25 + TR对EAE的年龄、性别和品系相关易感性的贡献。目的3阐明CD 4 + CD 25 + TR影响致脑炎性T细胞活化、扩增、运输和/或效应功能的机制。这些研究将进一步加深我们对TR在调节CNS自身免疫的诱导和进展中的作用的理解，并为优化旨在增强内在调节机制以预防和治疗人类自身免疫性疾病的策略提供重要信息。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an immune-mediated central nervous system (CNS) disease characterized by perivascular CD4 + T cell and mononuclear cell infiltration with subsequent primary demyelination of axonal tracks leading to progressive paralysis. MS is generally considered to be an autoimmune disease involving autoreactive T cell responses to MBP, PLP, and/or myelin-oligodendrocyte glycoprotein (MOG), however a clear cut cause-effect relationship between myelin reactivity and disease pathology has yet to be demonstrated. Although MS is generally considered to involve an autoimmune pathology, little is known regarding its etiology and there are limited therapeutic strategies available to specifically inhibit and prevent ongoing disease. We propose to investigate intrinsic regulatory mechanisms that influence both the susceptibility to and progression of MS using two mouse models of experimental autoimmune encephalomyelitis (EAE) that either follow a relapsingremitting (R-EAE) or chronic (C-EAE) disease course. CD4+CD25 + regulatory T cells (TR) are potent inhibitors of CD4 + T cell responses that are activated in an antigen-specific manner via TCR cross-linking and have been shown to mediate protection against the initiation of several spontaneous autoimmune disorders, such as diabetes and autoimmune gastritis. Our preliminary data clearly demonstrate that supplementation of TR significantly protects against the initiation of EAE by inhibiting the proliferation and effector function of both naive and previously-activated encephalitogenic CD4 + T cells, while depletion or inactivation of these cells leads to exacerbated disease symptoms. We have also shown that TR-mediated disease inhibition is associated with an increased frequency of myelin peptide-specific protective Th2 cells within the peripheral lymphoid organs and significantly decreased numbers of mononuclear cells infiltrating the CNS. The experiments in this proposal will test the hypothesis that CD4+CD25 + TR play a critical role in conferring resistance to EAE susceptibility and in regulating disease progression by inducing antigen-specific unresponsiveness to disease-relevant self-myelin peptides. The proposed experiments will elucidate the cellular and molecular mechanisms by which TR inhibit the functional activity of encephalitogenic effector Thl cells in acute and relapsing EAE, thus blocking the initiation/progression of clinical demyelinating disease. Three specific aims are proposed: AIM 1 will determine the role of CD4+CD25 + TR in modulating the initiation, progression, and recovery phases of R-EAE and C-EAE. AIM 2 will determine the contribution of CD4+CD25 + TR to age-, gender-, and strain-associated susceptibility to EAE. AIM 3 will elucidate the mechanisms by which CD4+CD25 + TR influence encephalitogenic T cell activation, expansion, trafficking, and/or effector function. These studies should further our understanding of the role of TR in regulating both the induction and progression of CNS autoimmunity and provide vital information relative to optimizing strategies designed to enhance intrinsic regulatory mechanisms for the prevention and treatment of human autoimmune diseases.