ROLE OF T CELLS IN THE IMMUNE MODULATION OF MS

描述(由申请人提供)：本竞争修订申请是响应NOT-OD-09-058(使RPG能够利用NCRR中心和类似中心的计划)而提交的。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40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。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。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。到目前为止，GA疗法的即时免疫效应还没有研究过。我们假设，治疗开始后72小时内的免疫效应将决定MS患者的长期免疫恢复和临床反应。在这个补充项目中，我们将描述GA治疗对APC和T细胞亚群功能的直接影响。然后将评估这些影响，以确定它们在确定长期免疫学和临床益处方面的预测价值。与目前资助的父母资助的研究类似，我们相信这些补充研究将为多发性硬化症免疫学提供重要的见解，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。在这个项目中，我们将剖析GA治疗开始后的早期免疫学事件。特别是，我们将询问这些早期事件是否可以预测MS患者的长期免疫学和临床益处。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): This competitive revision application is submitted in response to NOT-OD-09-058 (Enabling RPGs to Leverage NCRR Center and Center-like Programs). Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) and is responsible for long-term morbidity in over 400,000 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. 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. The immediate immune effects of GA therapy have not been studied thus far. We hypothesize that the immunologic effects within the first 72 hours of therapy initiation would determine the long- term immune restoration and clinical responsiveness in MS patients. In this supplemental project, we will delineate the immediate effects of GA therapy on the function of APC and T cell subsets. These effects will then be evaluated for their predictive value in determining long-term immunologic and clinical benefit. Similar to studies in the currently funded parent grant, we believe these supplemental studies will provide important insights into 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. In this project, we will dissect the early immunologic events that follow the initiation of GA therapy. In particular, we will ask whether these early events are predictive of long-term immunologic and clinical benefit in MS patients. 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.