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。我们对MS和EAE的研究为一种新的和 CNS特异性CD8 T细胞(CNS-CD8)意外的疾病抑制作用。根据我们的数据，我们 假设CNS-CD8的特定功能和表型亚群形成重要的和 在自身免疫性脱髓鞘疾病中可利用的免疫调节手臂。我们建议这一点 这一过程可以被利用来开发有效的免疫治疗方法。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 免疫调节的分子机制(干扰素γ及其受体，转运和细胞毒性，抑制 在病理部位)，通过这些自身调节的CD8 T细胞，并定义一种强大的和可增强的免疫 CNS-CD8的抑制性亚群。此外，一种可靠地进行疾病逆转的新型疫苗接种策略 CNS-CD8也将作为原则证据进行调查。我们相信， 拟议中的实验将为CD8 T细胞介导的免疫调节提供更基本的见解 并为多发性硬化症和其他免疫介导性疾病的新干预策略铺平道路。

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 studies in MS and EAE have provided evidence for a novel and unexpected disease suppressive role for CNS-specific CD8+ T cells (CNS-CD8). Based on our data, we hypothesize that specific functional and phenotypic subsets of CNS-CD8 form an important and exploitable arm of immune regulation during autoimmune demyelinating disease. We propose that this process can be harnessed for the development of effective immunotherapeutic approaches. The experiments proposed in this application will utilize EAE models to address the fundamental cellular and molecular mechanisms of immune modulation (IFNγ and its receptor, trafficking and cytotoxicity, suppression at the site of pathology) by these autoregulatory CD8 T cells, and to define a potent and enhanceable immune suppressive subset of CNS-CD8. Further, a novel vaccination strategy that reliably engages disease-reversing CNS-CD8 will also be investigated as a proof of principle. We believe that achievable results from the proposed experiments will provide greater fundamental insights into CD8 T cell-mediated immune regulation and pave the way for newer intervention strategies for MS and other immune-mediated diseases.