Immunopathogenesis of Multiple Sclerosis

描述（由申请人提供）：本提案中概述的研究代表了一个非常令人兴奋和雄心勃勃的计划，以解决MS中自身反应性T细胞反应的大小，精细特异性和精确性质等问题，并进一步探索克隆扩增的CSF B细胞对疾病发病机制的潜在贡献。使用高度创新的方法，我们计划在单细胞水平上表征这些反应，并分析TCR的使用和CSF B细胞库，特别是在各种治疗干预的背景下。这些研究将确定免疫重建对髓鞘抗原反应的有效性，并将其与使用米托蒽醌进行更标准的免疫抑制后的免疫反应进行比较。我们还将能够将这些信息与我们正在获得的接受更标准免疫调节疗法的RRMS患者的数据进行比较。我们预计这些研究将为MS的免疫发病机制提供重要的信息，这些研究的数据将允许PI在转化研究的基础上设计临床试验，测试新的MS治疗药物。此外，拟议的奖项将使PI集中精力指导下一代临床科学家，专注于多发性硬化症的研究。

DESCRIPTION (provided by applicant): The studies which are outlined in this proposal represent a very exciting and ambitious plan to address the issues of the magnitude, fine specificity, and precise nature of the autoreactive T cell response in MS and further explore the potential contribution of clonally expanded CSF B cells to disease pathogenesis. Using highly innovative approaches we plan to characterize these responses at a single cell level and analyze the TCR usage and CSF B cell repertoire, specifically in the context of various therapeutic interventions. These studies will determine the effectiveness of immune reconstitution with respect to the response to myelin antigens and compare that with what happens to the immune response following more standard immune suppression using mitoxantrone. We will also be able to compare this information with the data we are generating on patients with RRMS receiving more standard immunomodulatory therapies. We anticipate that these studies will provide important information with regard to the immunopathogenesis of MS. Data from these studies will allow the PI to design clinical trials testing novel therapeutic agents for MS based on the translational studies. In addition, the proposed Award will allow the PI to concentrate his efforts on mentoring the next generation of clinician scientists focusing their efforts on multiple sclerosis.