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项非常令人兴奋和雄心勃勃的计划，旨在解决多发性硬化症患者自身反应性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脑脊液B细胞在疾病发病机制中的潜在贡献。使用高度创新的方法，我们计划在单个细胞水平上表征这些反应，并分析TCR的使用和CSF B细胞谱系，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的反应的有效性，并将其与使用米托蒽醌进行更标准的免疫抑制后对免疫反应的影响进行比较。我们还将能够将这些信息与我们正在生成的接受更标准免疫调节治疗的RRMS患者的数据进行比较。我们预计，这些研究将提供有关MS免疫发病机制的重要信息，这些研究的数据将使PI能够在翻译研究的基础上设计临床试验，测试MS的新型治疗药物。此外，拟议的奖项将使PI能够集中精力指导下一代专注于多发性硬化症的临床医生科学家。

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.