Immunotherapeutic Regulatory CD8 T cells in Autoimmune Demyelinating Disease

多发性硬化症(MS)是一种中枢神经系统(CNS)炎症性脱髓鞘疾病。一个 我们对多发性硬化症的免疫学过程的大量了解来自于对其 自身免疫动物模型，实验性自身免疫性脑脊髓炎(EAE)。然而，绝大多数人 EAE和MS的研究重点是评估和靶向CD4T细胞反应，一般情况下 假设这些疾病主要由Th1/Th17介导和Th2/Treg调节。近期 其他人和我们的报道表明，CD8T细胞在疾病的发生和调节中发挥了作用。 自身免疫性脱髓鞘。我们最近对MS和EAE的研究为一种新的和 对中枢神经系统特异性CD8 T细胞的意外疾病抑制作用 CD8 T细胞在甲氨蝶呤免疫治疗中的调节作用基于 我们的数据，我们假设自身抗原特异性或GA诱导的CD8T细胞亚群形成一个 自身免疫性脱髓鞘疾病中免疫调节的重要环节。我们建议这一点 这一过程可用于开发有效的免疫治疗策略。这个 本申请中提出的实验将利用EAE模型来解决基本的细胞和 内源性和治疗性CD8T细胞免疫调节的分子机制此外，最多的 将定义这些群体中有效的免疫抑制子集，目标是开发一种新的 过继免疫治疗方法。我们相信，拟议的实验将提供更大的 对CD8 T细胞介导的免疫调节的基本见解，并为新的干预措施铺平道路 针对这种和其他免疫介导性疾病的策略。

Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS). A great deal of our understanding about the immunologic processes that underlie MS derives from studies in its autoimmune animal model, experimental autoimmune encephalomyelitis (EAE). However, the vast majority of studies in EAE and MS have focused on evaluating and targeting CD4+ T cell responses, with the general assumption that these diseases are predominantly Th1/Th17-mediated and Th2/Treg-modulated. Recent reports from others and us indicate that CD8+ T cells play a role in the pathogenesis as well as regulation of autoimmune demyelination. Our recent studies in MS and EAE have provided evidence for a novel and unexpected disease suppressive role for CNS-specific CD8+ T cells and also demonstrated the requirement of CD8+ T cells in mediating effects of glatiramer acetate (GA) immunotherapy. Based on our data, we hypothesize that a subset of autoantigen-specific or GA-induced CD8 T cells form an important arm of immune regulation during autoimmune demyelinating disease. We propose that this process can be harnessed for the development of an effective immunotherapeutic strategy. The experiments proposed in this application will utilize EAE models to address the fundamental cellular and molecular mechanisms of immune modulation by intrinsic and therapeutic CD8 T cells. In addition, the most potent immune suppressive subset of these populations will be defined with the goal of developing a novel adoptive immunotherapeutic approach. We believe that the proposed experiments will provide greater fundamental insights into CD8 T cell-mediated immune regulation and pave the way for newer intervention strategies for this and other immune-mediated diseases.