ROLE OF T CELLS IN THE IMMUNE MODULATION OF MS

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统（CNS）的炎性脱髓鞘疾病，在美国造成超过30万人的长期发病率。虽然MS的确切病因尚不清楚，但由于其特有的组织学特征以及血液和脑脊液中存在神经抗原特异性免疫反应，因此认为其为T细胞介导的过程。因此，正在研究几种免疫调节疗法来对抗这种疾病。绝大多数评估MS免疫系统的研究都集中在评估和靶向CD4+ T细胞应答。然而，来自其他人和我们的一些报告提供了CD8+ T细胞在MS的发病机制和免疫调节中的作用的强有力证据。醋酸格拉替雷（GA，Copaxone）是FDA批准用于治疗RRMS的免疫调节剂。然而，其作用机制仍然知之甚少。我们已经提供了第一个直接证据表明，Copaxone不仅诱导CD4+ T细胞应答，而且诱导CD8+ T细胞应答。在未经治疗的MS患者中，Copaxone特异性CD8+ T细胞应答是缺乏的，并且在Copaxone治疗期间恢复。因此，我们发现了一种新的机制，通过这种FDA批准的药物可以介导其免疫作用。我们假设，克帕松诱导的CD8+ T细胞是重要的调节细胞群，通过多种机制介导药物的临床作用。在这个项目中，我们将继续描绘这些抑制性CD8+ T细胞的功能作用和多样性，并剖析适当的Copaxone介绍，以诱导他们的反应的要求。我们相信这些研究将为MS免疫学的一个被忽视的领域提供重要的见解，并将有助于产生更好的免疫策略。公共卫生相关性：多发性硬化症（MS）是一种免疫介导的中枢神经系统（CNS）疾病。醋酸格拉替雷（GA，Copaxone）是FDA批准用于治疗RRMS的免疫调节剂。然而，其作用机制仍然知之甚少。虽然MS免疫学的先前研究集中在CD4+ T细胞，但我们提供了第一个直接证据，表明Copaxone不仅诱导CD4+ T细胞应答，而且诱导CD8+ T细胞应答。这些细胞可能不仅在介导这种药物的作用方面发挥非常重要的作用，而且还作为健康免疫系统的重要调节剂。在这个项目中，我们将继续描绘这些抑制性CD8+ T细胞的功能作用和多样性。我们相信这些研究将为MS免疫学的一个被忽视的领域提供重要的见解，并将有助于在未来产生更好的免疫策略。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) and is responsible for long-term morbidity in over 300,000 people in the United States. Although the precise etiology of MS is unknown, it is thought to be a T-cell-mediated process due to characteristic histologic features and the presence of neuroantigen-specific immune responses in the blood and cerebrospinal fluid. Thus, several immunomodulatory therapies are being investigated to combat this disease. The vast majority of studies assessing the immune system in MS have focused on evaluating and targeting CD4+ T cell responses. However, several reports from others and us present strong evidence for a role of CD8+ T cells in the pathogenesis and immune regulation of MS. Glatiramer acetate (GA, Copaxone) is an immune modulatory agent that is FDA-approved for the treatment of RRMS. However, the mechanism of its action still remains poorly understood. We have provided the first direct evidence that Copaxone induces not only CD4+, but also CD8+ T cell responses. Copaxone-specific CD8+ T cell responses are deficient in untreated MS patients and are restored during Copaxone therapy. We have thus uncovered a novel mechanism through which this FDA- approved drug may mediate its immunologic effects. We hypothesize that Copaxone-induced CD8+ T cells are important regulatory populations of cells that mediate the clinical effects of the drug through multiple mechanisms. In this project, we will continue to delineate the functional role and diversity of these suppressor CD8+ T cells and dissect the requirements of appropriate presentation of Copaxone to induce their response. We believe these studies will provide important insights into an overlooked area of MS immunology and will help generate better immunotherapeutic strategies. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system (CNS). Glatiramer acetate (GA, Copaxone) is an immune modulatory agent that is FDA-approved for the treatment of RRMS. However, the mechanism of its action still remains poorly understood. While prior studies in MS immunology have focused on CD4+ T cells, we have provided the first direct evidence that Copaxone induces not only CD4+, but also CD8+ T cell responses. These cells may play a very important role not only in mediating the effect of this drug but also as important regulators of the healthy immune system. In this project, we will continue to delineate the functional role and diversity of these suppressor CD8+ T cells. We believe these studies will provide important insights into an overlooked area of MS immunology and will help generate better immunotherapeutic strategies in the future.