Identifying a viral cause of Multiple Sclerosis

描述(摘自申请者的摘要)：髓鞘分解为多发性 硬化症(MS)是由辅助性T淋巴细胞(T细胞)Th1亚群介导的 过程类似于动物模型，实验性自身免疫 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 多发性硬化患者血浆MBP和PLP水平与健康对照组的比较 控制。这表明，一种不同的致病机制可能是 行动中。相当多的间接证据支持病毒的作用 多发性硬化症的感染，尽管尚未发现多发性硬化症特有的病毒。因此， 免疫病理改变可能是由持续性中枢神经引起的 系统(CNS)病毒感染，免疫反应针对病毒而不是 比自身蛋白多，但仍由辅助性T淋巴细胞(T细胞)Th1介导 与EAE中的子集相同。 假设是一种新的病毒持续存在于中枢神经系统以驱动多发性硬化症 免疫病理学。假定的病毒在中枢神经系统中持续复制，推动 持续的疾病活动是复发-缓解多发性硬化症病毒的基础 复制可能与泰勒氏小鼠脑脊髓炎病毒相似 (Tme)小鼠感染或冰岛绵羊感染Visna病毒，相关 多发性硬化的实验性病毒模型，因为推测的多发性硬化症病毒可能是 非可培养的动物传播尝试和分子方法 提供最好的检测手段。之前两次尝试传输MS 在20世纪60年代至70年代对非人类灵长类动物的影响并不是最理想的 因此，不应阻止当前的尝试。这项建议 立场与专注于将特定已知的 病原体是MS的原因之一。 我们建议通过接种0.5-1.0对的疫苗将多发性硬化症传播给非人类灵长类动物 一岁大的黑猩猩和松鼠猴脑内注射MS-CSF 单个核炎性细胞(24小时采集)和急性 如果有合适的材料，尸检时会发现斑块。脑白质损害 (连续头颅MRL)和脑脊液细胞增多症(连续脑池抽吸)将检测到 动物中的亚临床疾病。立体定位活检将确认其性质 并使连续的脑对脑通道能够证明 复制剂及其表征。我们还建议建造和 在GT-11中表达MS-CSF cDNA文库作为检测此类病毒的另一种方法 而事先不知道它的性质。

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.