Translational applications of Progressive Multifocal Leukoencephalopathy studies

描述（由申请人提供）：进行性多灶性白质脑病（PML）是一种由多瘤病毒JC（JCV）引起的致命性脑机会性感染，发生于免疫抑制个体。PML尚无治疗方法，自高效抗逆转录病毒治疗（HAART）可用以来，HIV+患者中该疾病的发病率并未显著降低。此外，越来越多的器官移植受者也面临PML的风险，以及接受新型免疫调节药物那他珠单抗治疗的多发性硬化症和克罗恩病患者。未来的挑战是利用我们对JCV发病机制的病毒学和免疫学决定因素的理解，并将其转化为旨在预防PML的预诊断标志物以及该疾病的治疗选择，同时培训下一代年轻医生进行以患者为导向的研究。在本申请中，我们将：1）表征PML的预诊断标志物; 2）分析骨髓中JCV潜伏期和再活化的分子决定因素，并确定JCV感染的骨髓细胞的表型; 3）确定HLA I类等位基因在PML结果中的作用; 4）将MRI/1H-MRS、组织学、免疫学和病毒学参数随时间与PML患者的病变体积、神经功能缺损和临床结果相关联; 5）研究用那他珠单抗治疗的MS患者中JCV的再活化，并探索VLA-4阻断对JCV特异性CD 8 + T细胞的影响; 6）表征与JCV颗粒细胞神经元病（JCV GCN）相关的JCV变体的发病机制; 7）开发用于PML的基于树突状细胞的免疫疗法;和8）探索在HLA不匹配的肾移植物的情况下针对多瘤病毒BK的抗病毒免疫应答。为指导年轻的医生，科学家，初级教师和学生的机会进行了讨论，为每个具体目标。这些研究肯定会吸引有兴趣在神经学，神经成像，传染病，病毒学，免疫学，血液学，肾脏学和病理学领域开展职业生涯的年轻人。

DESCRIPTION (provided by applicant): Progressive Multifocal Leukoencephalopathy (PML) is a deadly opportunistic infection of the brain caused by the polyomavirus JC (JCV), which occurs in immunosuppressed individuals. There is no treatment for PML, and the incidence of this disease has not decreased significantly in HIV+ patients since the availability of highly active antiretroviral therapy (HAART). In addition, a growing number of organ transplant recipients are also at risk for PML, as well as patients with multiple sclerosis and Crohn's disease treated with the novel immunomodulatory medication natalizumab. The challenges that lies ahead is to harness advances in our understanding of the virological and immunological determinants of JCV pathogenesis and translate them into both pre-diagnostic markers aiming at preventing PML, as well as therapeutic options for this disease, while training the next generation of young physicians in patient-oriented research. In this application, we will: 1) Characterize pre-diagnostic markers of PML; 2) Analyze the molecular determinants of JCV latency and reactivation in bone marrow, and determine the phenotype of JCV infected bone marrow cells; 3) Determine the role of HLA class I alleles in PML outcome; 4) Correlate MRI/1H-MRS, histological, immunological and virological parameters over time with lesion volume, neurological deficit and clinical outcome of the PML patients; 5) Study JCV reactivation in MS patients treated with natalizumab, and explore the effect of VLA-4 blockade on JCV-specific CD8+ T cells; 6) Characterize the pathogenesis of the JCV variant associated with JCV Granule Cell Neuronopathy (JCV GCN); 7) Develop dendritic cell-based immunotherapy for PML; and 8) Explore the antiviral immune response against the polyomavirus BK in the context of HLA mismatched kidney grafts. Opportunities for mentoring young physicians, scientists, junior faculty and students are discussed for each specific aim. These studies will certainly appeal to young individuals interested to launch their careers in the fields of Neurology, Neurolmaging, Infectious Diseases, Virology, Immunology, Hematology, Nephrology and Pathology.