Translational applications of Progressive Multifocal Leukoencephalopathy studies

描述（由申请人提供）：进行性多灶性脑白质病（PML）是一种由多瘤病毒JC （JCV）引起的致命的脑机会性感染，发生在免疫抑制的个体中。目前还没有治疗PML的方法，自从高效抗逆转录病毒疗法（HAART）问世以来，这种疾病在HIV+患者中的发病率并没有显著下降。此外，越来越多的器官移植受者也面临PML的风险，以及多发性硬化症和克罗恩病患者接受新型免疫调节药物natalizumab治疗。摆在我们面前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的诊断前标记物，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。在这个应用中，我们将：1)表征PML的诊断前标志物；2)分析骨髓中JCV潜伏和再激活的分子决定因素，确定JCV感染骨髓细胞的表型；3)确定HLA I类等位基因在PML转归中的作用；4)将MRI/1H-MRS、组织学、免疫学和病毒学参数随时间的变化与PML患者的病变体积、神经功能缺损和临床预后相关联；5)研究natalizumab治疗MS患者的JCV再激活，探索阻断VLA-4对JCV特异性CD8+ T细胞的影响；6)明确与JCV颗粒细胞神经病变（JCV GCN）相关的JCV变异的发病机制；7)发展基于树突状细胞的PML免疫治疗；8)探讨HLA错配肾移植对多瘤病毒BK的抗病毒免疫应答。指导年轻医生、科学家、初级教师和学生的机会针对每个具体目标进行了讨论。这些研究肯定会吸引有兴趣在神经病学、神经影像学、传染病、病毒学、免疫学、血液学、肾脏病学和病理学等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.