Translational applications of Progressive Multifocal Leukoencephalopathy studies

描述(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)引起的致命的脑部机会性感染，发生在免疫抑制的个体中。目前还没有治疗PML的方法，自从获得高效抗逆转录病毒疗法(HAART)以来，艾滋病毒阳性患者中这种疾病的发病率并没有显著下降。此外，越来越多的器官移植接受者也面临患PML的风险，以及使用新型免疫调节药物Natalizumab治疗的多发性硬化症和克罗恩病患者。摆在我们面前的挑战是利用我们对JCV致病的病毒学和免疫学决定因素的理解的进展，并将它们转化为旨在预防PML的诊断前标志物以及这种疾病的治疗选择，同时培训下一代年轻医生进行以患者为导向的研究。在这一应用中，我们将：1)鉴定PML的诊断前标志物；2)分析JCV在骨髓中潜伏期和重新激活的分子决定因素，并确定JCV感染的骨髓细胞的表型；3)确定HLAI类等位基因在PML预后中的作用；4)随着时间的推移，MRI/1H-MRS、组织学、免疫学和病毒学参数与PML患者的病变体积、神经功能缺失和临床转归的相关性；5)研究用他他珠单抗治疗的MS患者JCV的重新激活，并探讨VLA-4阻断对JCV特异性CD8+T细胞的影响；6)确定JCV变异相关的JCV颗粒细胞神经病(JCV GCN)的发病机制；7)发展基于树突状细胞的PML免疫疗法；8)探索针对多瘤病毒BK的抗病毒免疫反应在人类白细胞抗原不相合肾移植的背景下。针对每个具体目标，讨论了指导年轻医生、科学家、初级教职员工和学生的机会。这些研究肯定会吸引有兴趣的年轻人在神经学、脑成像、传染病、病毒学、免疫学、血液学、肾脏病和病理学领域开始他们的职业生涯。

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.