T-CELL FUNCTION IN A MURINE MODEL OF MULTIPLE SCLEROSIS

多发性硬化症小鼠模型中的 T 细胞功能

• 批准号: 2270118
• 负责人: MOSES RODRIGUEZ
• 金额: $ 23.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2270118
• 关键词: MHC class I antigen; MHC class II antigen; T lymphocyte; cell mediated cytotoxicity; cellular immunity; cytokine; disease /disorder model; evoked potentials; fusion gene; gene targeting; genetic promoter element; genetically modified animals; globulins; histocompatibility gene; hybrid cells; immune tolerance /unresponsiveness; laboratory mouse; microorganism immunology; multiple sclerosis; murine encephalomyelitis virus; neural conduction; passive immunization; transfection; viral myelinopathy; virus antigen; virus genetics; virus protein

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.

原发性脱髓鞘疾病的病因学，例如多发性脱髓鞘疾病 硬化症（MS）尚不清楚。 一个可检验的假设是破坏 髓磷脂和少突胶质细胞的形成是由免疫攻击直接导致的 对抗病毒感染引发的抗原。 我们已经用感染来 携带泰勒氏鼠脑脊髓炎病毒（TMEV）的小鼠 小RNA病毒，研究免疫反应在脱髓鞘中的作用 以及神经系统疾病。 这些实验的长期目标是 揭示脱髓鞘和神经系统疾病的免疫机制 希望能为该病的治疗提供新的见解 多发性硬化症。 拟议的实验有两个主要的具体目标。 首先，为了确定哪些病毒基因参与诱导 保护性免疫反应以及哪些基因是针对的 脱髓鞘疾病的致病阶段，我们将 TMEV 分为 将基因组分成三个区域，以便它们可以在 体外靶细胞和体内转基因。 成纤维细胞转染 与TMEV编码块将被用来确定的位置 T细胞识别的基因在保护性宿主早期出现 对病毒感染的反应以及致病阶段的晚期 疾病。 相同的编码块在抗性和抗性中表达为转基因 易感菌株可能会诱导对病毒组的耐受性 抗原，可以评估免疫识别的重要性 这些抗原在抵抗病毒感染和发病机制中 脱髓鞘。 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 后会发育 脱髓鞘明显，但无神经功能缺损。 这些实验 与 MS 有直接关系，其中经常存在差异 脱髓鞘之间的关系提供了一个独特的机会来剖析那些 在脱髓鞘中重要的免疫反应的组成部分与那些 对神经功能缺损很重要。 我们首先要确定其性质 感染 Beta-2m 的 CNS 中的免疫反应（CTL、Th1 和 Th2）（+/+） 和敏感和抗性单倍型的 Beta-2m (-/-)。 我们随后将 利用 Beta2-m (-/-) 模型建立免疫学 脱髓鞘宿主神经元损伤的基础。 使用新技术 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的那些组成部分 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 失调。