ROLE OF T CELLS IN THE IMMUNE MODULATION OF MS

描述(申请人提供)：多发性硬化症(MS)是一种中枢神经系统(CNS)的炎症性脱髓鞘疾病，是美国30多万人长期患病的原因。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，因此被认为是T细胞介导的过程。因此，人们正在研究几种免疫调节疗法来对抗这种疾病。绝大多数评估多发性硬化症免疫系统的研究都集中于评估和靶向CD4+T细胞反应。然而，来自他人和我们的一些报告提出了强有力的证据，证明CD8+T细胞在女士的发病和免疫调节中发挥了作用。然而，其作用机制仍然知之甚少。我们提供了第一个直接证据，证明Copaxone不仅能诱导CD4+T细胞反应，还能诱导CD8+T细胞反应。在未经治疗的MS患者中，Copaxone特异性CD8+T细胞反应不足，并在Copaxone治疗期间恢复。因此，我们发现了一种新的机制，这种FDA批准的药物可以通过它来调节其免疫效应。我们假设，Copaxone诱导的CD8+T细胞是重要的调节性细胞群体，通过多种机制调节药物的临床效果。在这个项目中，我们将继续描述这些抑制CD8+T细胞的功能作用和多样性，并剖析适当呈现Copaxone以诱导其反应的要求。我们相信，这些研究将为被忽视的多发性硬化症免疫学领域提供重要的见解，并将有助于制定更好的免疫治疗策略。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。醋酸格列酮(GA，Copaxone)是FDA批准用于治疗RRMS的一种免疫调节剂。然而，其作用机制仍然知之甚少。虽然之前的MS免疫学研究主要集中在CD4+T细胞上，但我们提供了第一个直接证据，证明Copaxone不仅能诱导CD4+T细胞反应，还能诱导CD8+T细胞反应。这些细胞可能不仅在介导该药物的作用方面发挥着非常重要的作用，而且还作为健康免疫系统的重要调节因素。在这个项目中，我们将继续描述这些抑制CD8+T细胞的功能作用和多样性。我们相信，这些研究将为被忽视的多发性硬化症免疫学领域提供重要的见解，并有助于在未来制定更好的免疫治疗策略。

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.