Identifying a viral cause of Multiple Sclerosis

确定多发性硬化症的病毒原因

• 批准号: 7223493
• 负责人: HOWARD Lee LIPTON
• 金额: $ 38.42万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7223493
• 关键词: Pan; Saimiri; antigen antibody reaction; biopsy; brain imaging /visualization /scanning; cell transplantation; cerebrospinal fluid; clinical research; disease /disorder etiology; disease /disorder model; expression cloning; genetic library; host organism interaction; human genetic material tag; human subject; immunoregulation; injection /infusion; latent virus infection; magnetic resonance imaging; model design /development; multiple sclerosis; neuroimmunomodulation; virus; virus classification; virus diseases; virus infection mechanism

DESCRIPTION (Adapted from applicant's abstract): Myelin breakdown in multiple sclerosis (MS) is mediated by me helper T Iymphocyte (T cell) Th1 subset by a process analogous with that of the animal model, experimental autoimmune encephalomyelitis (EAE). Extensive efforts have failed to show dear differences in T cell reactivity to candidate autoantigen peptides of myelin basic protein (MBP) and proteolipid protein (PLP) in individuals with MS compared to healthy controls. This suggests that a different pathogenetic mechanism may be operative. Considerable circumstantial evidence supports a role for a viral infection in MS, although an MS-specific virus has not been identified. Thus, the immunopathologic changes could be caused by a persistent central nervous system (CNS) viral infection with the immune response directed at viral rather than self proteins, but still mediated by the helper T Iymphocyte (T cell) Th1 subset as in EAE. The hypothesis is that a novel virus persists in the CNS to to drive the MS immunopathology. The putative virus replicates continuously in the CNS, driving continuous disease activity that underlies relapsing-remitting MS Viral replication may be similar to that in Theiler's murine encephalomyelitis virus (TME\/) infection in mice or Visna virus infection in Icelandic sheep, relevant experimental viral models of MS. Since the putative MS virus may be noncultivatable, transmission attempts to animals and molecular approaches provide the best means of its detection. Two previous attempts to transmit MS to non-human primates in the 1960s to 1970s were not optimal by current standards, and therefore should not dissuade current attempts. This proposal stands in contrast to studies focused on incriminating a specific known pathogen as a cause of MS. We propose to transmit MS to non-human primates by inoculating pairs of 0.5-1.0 year-old chimpanzees and squirrel monkeys intracerebrally (ic) with MS CSF mononuclear inflammatory cells (24 hr collection) and also with acute post-mortem plaques if optimum material becomes available. White matter lesions (serial cranial MRls), and CSF pleocytosis (serial cisternal taps) will detect subclinical disease in the animals. Stereotaxic biopsy will confirm the nature of developing lesions and enable serial brain-to-brain passage to demonstrate a replicating agent and its characterization. We also propose to construct and express MS CSF cDNA libraries in gt-11 as another way of detecting such a virus without prior knowledge of its nature.

描述（改编自申请人的摘要）：髓鞘分解为多个 硬化症（MS）由辅助性T淋巴细胞（T细胞）Th 1亚群介导， 与动物模型类似的过程，实验性自身免疫性 脑脊髓炎（EAE）。广泛的努力未能显示出明显的差异 T细胞对髓鞘碱性蛋白候选自身抗原肽的反应性 (MBP)和蛋白脂质蛋白（PLP）在MS个体相比，健康 对照这表明，一个不同的发病机制可能是 操作。相当多的间接证据支持病毒的作用， 感染MS，尽管尚未鉴定出MS特异性病毒。因此，在本发明中， 免疫病理改变可能是由持续性中枢神经系统损伤引起的， 系统（CNS）病毒感染，免疫应答针对病毒，而不是 但仍由辅助性T淋巴细胞（T细胞）Th 1介导 如EAE中的子集。 假设是一种新型病毒持续存在于中枢神经系统中以驱动多发性硬化症 免疫病理学假定的病毒在CNS中持续复制， 复发缓解型MS病毒的持续疾病活动 复制可能与Theiler鼠脑脊髓炎病毒相似 (TME\/）小鼠感染或冰岛绵羊Visna病毒感染，相关 MS的实验病毒模型。由于推定的MS病毒可能是 非可培养的，向动物传播的尝试和分子方法 提供最好的检测手段。之前两次尝试将MS 在20世纪60年代到70年代，非人类灵长类动物的研究并不是目前最理想的。 标准，因此不应劝阻目前的尝试。这项建议 与专注于指控特定已知 病原体作为MS的原因。 我们建议将MS以0.5-1.0的双对数传播给非人灵长类动物 1岁黑猩猩和松鼠猴脑内（ic）感染MS CSF 单核炎性细胞（24小时收集）和急性 如果有最佳材料的话，白色病变 （系列头颅MRI）和CSF细胞增多症（系列脑池穿刺）将检测 动物的亚临床疾病。立体定位活检可以确认 发展中的病变，并使连续的脑到脑通道，以证明一个 复制剂及其表征。我们还建议建立和 在gt-11中表达MS CSF cDNA文库作为检测这种病毒的另一种方法 而不事先了解其性质。