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: 2703018
• 负责人: MOSES RODRIGUEZ
• 金额: $ 18.48万
• 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 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2703018
• 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，如多种 硬化症（MS）是未知的。 一个可以验证的假设是 髓鞘和少突胶质细胞的免疫攻击的结果， 对抗病毒感染引发的抗原 我们利用感染来 Theiler小鼠脑脊髓炎病毒（TMEV）， 研究免疫反应在脱髓鞘中的作用 和神经系统疾病。 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 希望这将为治疗 女士 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诱导 保护性免疫反应以及其中针对哪些基因 在脱髓鞘疾病的致病阶段，我们将TMEV分为 基因组分为三个区域，以便它们可以单独表达， 体外靶细胞和体内作为转基因。 转染成纤维细胞 将使用TMEV编码块来确定 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晚期的致病阶段， 疾病 相同的编码区作为转基因在抗性和耐药性中表达， 易感菌株可能会诱导对病毒的耐受性， 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- 巨球蛋白缺乏（-/-）小鼠，当感染TMEV时， 明显脱髓鞘但无神经功能缺损 这些实验 与多发性硬化症有直接关系，其中经常存在差异 脱髓鞘之间的联系提供了一个独特的机会， 脱髓鞘中重要的免疫反应成分与 在神经功能缺损中很重要 我们将首先确定 感染β-2m（+/+）的CNS中的免疫应答（CTL、Th 1和Th 2） 和β-2m（-/-）的易感和抗性单倍型。 然后我们将 利用Beta2-m（-/-）模型建立免疫学 脱髓鞘宿主神经元损伤的基础。 采用了一种新技术 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的那些组成部分， 神经生理异常 这些实验有可能 阐明治疗人CNS脱髓鞘的新策略 紊乱