Immunotherapeutic Regulatory CD8 T cells in Autoimmune Demyelinating Disease

多发性硬化（MS）是中枢神经系统（CNS）的炎性脱髓鞘疾病。一 我们对MS基础免疫过程的大量理解来自于其 实验性自身免疫性脑脊髓炎（EAE）。但绝大多数 EAE和MS的研究集中在评估和靶向CD4 + T细胞应答， 假设这些疾病主要是Th1/Th17介导的和Th2/Treg调节的。最近 来自其他人和我们的报告表明，CD8 + T细胞在发病机制以及调节 自身免疫性脱髓鞘我们最近在MS和EAE中的研究为一种新的， CNS特异性CD8 + T细胞的意想不到的疾病抑制作用，也证明了 在介导醋酸格拉替雷（GA）免疫疗法的作用中需要CD8 + T细胞。基于 根据我们的数据，我们假设一个自身抗原特异性或GA诱导的CD8 T细胞亚群形成了一个特异性的T细胞亚群。 在自身免疫性脱髓鞘疾病期间免疫调节重要手臂。我们建议， 可以利用这一过程来制定有效的免疫战略。的 本申请中提出的实验将利用EAE模型来解决基本的细胞和 内在和治疗性CD8 T细胞免疫调节的分子机制。此外，最 这些人群的有效免疫抑制亚群将被定义，目的是开发一种新的免疫抑制剂。 过继免疫方法我们认为，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，并为新的干预铺平道路 治疗这种疾病和其他免疫介导疾病的策略。

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.