T-CELL FUNCTION IN A MURINE MODEL OF MULTIPLE SCLEROSIS

多发性等原发脱髓鞘疾病的病因 硬化症(MS)是未知的。一个可检验的假设是，破坏 髓鞘和少突胶质细胞是由定向的免疫攻击造成的 对抗病毒感染所触发的抗原。我们已经利用感染来 携带泰勒氏鼠脑脊髓炎病毒(TMEV)的小鼠 小核糖核酸病毒，研究免疫反应在脱髓鞘中的作用 以及神经性疾病。这些实验的长期目标是 揭示脱髓鞘与神经系统疾病的免疫机制 希望这将为治疗该病提供新的见解 在拟议的实验中，有两个主要的具体目标。 首先，为了确定哪些病毒基因参与了诱导 保护性免疫反应以及哪些基因是 脱髓鞘病的病原期，我们划分了TMEV 基因组分成三个区域，这样它们就可以在 体外靶细胞和体内转基因。转基因成纤维细胞 使用TMEV编码块将用于确定 T细胞识别的基因在保护性宿主早期出现 对病毒感染的反应和致病阶段的晚期 疾病。相同的编码区块表达为转基因在抗性和 据推测，敏感株可能会诱导对多种病毒的耐受性 抗原，允许评估免疫识别的意义 这些抗原在抵抗病毒感染和在发病机制中的作用 脱髓鞘的症状。在第二个具体目标中，我们将利用Beta2- 巨球蛋白缺陷(-/-)小鼠感染TMEV后发生 脱髓鞘明显，但无神经功能缺陷。这些实验 与多发性硬化症直接相关，在多发性硬化症中经常存在差异 脱髓鞘提供了一个独特的机会来解剖那些 在脱髓鞘中重要的免疫反应成分与那些 在神经性缺陷中很重要。我们首先要确定的是 感染Beta-2m(/)患者中枢神经系统的免疫应答(CTL、Th1、Th2) 敏感和抗性单倍型的Beta-2M(-/-)。到时候我们会的 利用Beta2-m(-/-)模型建立免疫学模型 脱髓鞘宿主神经元损伤的基础。使用一种新技术 在小鼠体内测量运动和感觉脊髓传导， 我们将确定免疫反应中负责 神经生理学异常。这些实验有可能 阐明治疗人类中枢神经系统脱髓鞘的新策略 精神错乱。

The etiologies of primary demyelinating diseases such as multiple sclerosis (MS) are unknown. One testable hypothesis is that destruction of myelin and oligodendrocyte results from an immune attack directed against antigen triggered by virus infection. We have used infection to mice with Theiler's murine encephalomyelitis virus (TMEV), a picornavirus, to study the role of the immune response in demyelination and in neurologic disease. The long term goal of these experiments is to reveal the immune mechanisms of demyelination and neurologic disease with the hope that this will provide new insights into the treatment of MS. There are two major specific aims in the proposed experiments. First, in order to determine which viral genes are involved in inducing a protective immune response and which genes are targeted in the pathogenic phase of demyelinating disease, we have divided the TMEV genome into three regions so that they can be expressed individually in target cells in vitro and as transgenes in vivo. Fibroblasts transfected with the TMEV coding blocks will be used to determine the location of the genes recognized by T cells appearing early during the protective host response to viral infection and late during the pathogenic phase of disease. The same coding blocks expressed as transgenes in resistant and susceptible strains will presumably induce tolerance to sets of viral antigens, permitting to assess the significance of immune recognition of these antigens in resistance to viral infection and in the pathogenesis of demyelination. In the second specific aim we will utilize beta2- macroglobulin deficient (-/-) mice which when infected with TMEV develop prominent demyelination but no neurologic deficits. These experiments have direct relevance to MS, in which frequently there is a discrepancy between demyelination provides a unique opportunity to dissect those components of the immune response important in demyelination versus those important in neurologic deficits. We will first determine the nature of the immune response (CTL, Th1, and Th2) in CNS of infected Beta-2m (+/+) and Beta-2m (-/-) of susceptible and resistant haplotypes. We will then take advantage of the Beta2-m (-/-) model to establish the immunologic basis of neuronal injury in the demyelinated host. Using a new technique in the mouse to measure motor and sensory spinal cord conduction in vivo, we will determine those components of the immune response responsible for neurophysiologic abnormalities. These experiments have the potential to elucidate new strategies for the treatment of human CNS demyelinating disorders.