MECHANISMS OF CELLULAR IMMUNE REACTIONS IN THE CNS

中枢神经系统细胞免疫反应的机制

• 批准号: 3412787
• 负责人: RAYMOND A SOBEL
• 金额: $ 14.54万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-12-01 至 1993-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3412787
• 关键词: AIDS; HIV infections; T lymphocyte; antigen presentation; antigen presenting cell; biological models; cellular immunity; central nervous system; delayed hypersensitivity; electron microscopy; encephalitis; experimental allergic encephalomyelitis; fibronectins; gene expression; genetic strain; glycoprotein biosynthesis; guinea pigs; histochemistry /cytochemistry; human immunodeficiency virus 1; human tissue; immunochemistry; in situ hybridization; inflammation; laboratory mouse; laboratory rat; major histocompatibility complex; membrane activity; messenger RNA; monoclonal antibody; multiple sclerosis; myelin; nerve /myelin protein; protein sequence; psychoneuroimmunology; reticuloendothelial system

The overall goal of this project is to understand mechanisms of cellular immune reactions in the central nervous system (CNS). The hypothesis to be tested is that prominent surface expression of specific molecules on CNS resident cells, particularly endothelial cells, play critical roles in the pathogenesis of immune-mediated injury. We will use immunohistochemistry at the light and electron microscopic levels to localize specific proteins in the CNS, and in situ hybridization to determine sites of synthesis. (I). Class II major histocompatibility complex (Ia) molecules will be analyze in animal T cell immune response models. In experimental allergic encephalomyelitis (EAE) in inbred strains of mice and their F1 progeny we will determine if there is preferential expression of susceptible parent strain-specific Ia molecules in the in response to different myelin antigens and will develop an in vitro system for a lysis of Ia regulation on conventional and resident CNS antigen-presenting cells. Temporal sequences and cellular localization of resident cell Ia molecules will be analyzed in delayed hypersensitivity reactions to determine if cell surface Ia expression precedes or is a secondary effect of T cell infiltration in situ. (II). Endothelial cell surface molecules will be analyzed in human CNS inflammatory diseases. Effect of HIV-1 infection on endothelial cell expression of major histocompatibility complex molecules will be analyzed in patients with AIDS; HLA-DR-specific mRNA will be identified in multiple sclerosis (MS) and viral encephalitis; and fibronectin, a glycoprotein which enhances mononuclear cell attachment to endothelial cells, will be identified and its site of synthesis determined in MS. (III). Potential contributions to demyelination of antibodies to external surface myelin peptides will be determined by identifying protein sequences localized outer leaflets of CNS myelin which may be targets of immune-mediated injury and the comparing effects of monoclonal antibodies to synthetic peptides of various regions of myelin on clinical course and demyelination in EAE. These studies will provide further insights into regulation and cell surface interactions of molecules which participate in CNS immune responses and may contribute to the development of specific strategies for treatment of inflammatory and demyelinating CNS diseases.

该项目的总体目标是了解细胞的机制 中枢神经系统（CNS）中的免疫反应。 假设是 测试的是特定分子在CNS上的显着表面表达 居民细胞，尤其是内皮细胞，在 免疫介导的损伤的发病机理。我们将使用免疫组织化学 光和电子显微镜水平将特定蛋白质定位在 中枢神经系统和原位杂交确定合成位点。 （我）。 II类主要的组织相容性复合物（IA）分子将是 分析动物T细胞免疫反应模型。在实验过敏性中 小鼠及其F1后代的近交菌株中的脑脊髓炎（EAE） 将确定易感父的优先表达 响应不同髓磷脂的菌株特异性IA分子 抗原，并将开发一个体外系统，以裂解IA调节 在常规和常驻CNS抗原呈递细胞上。颞 居民细胞IA分子的序列和细胞定位将是 在延迟的高敏反应中分析，以确定细胞表面是否 IA表达先于T细胞浸润的次要作用 原位。 （ii）。内皮细胞表面分子将在人CNS中进行分析 炎症性疾病。 HIV-1感染对内皮细胞的影响 将分析主要组织相容性复合物分子的表达 在艾滋病患者中； HLA-DR特异性mRNA将在多个 硬化症（MS）和病毒脑炎；和纤连蛋白，一种糖蛋白 这增强了单核细胞附着在内皮细胞上的附着，将是 确定及其合成位点在MS中确定。 （iii）。对外部抗体脱髓鞘的潜在贡献 表面髓磷脂肽将通过鉴定蛋白质序列确定 CNS髓磷脂的局部外部小叶，可能是 免疫介导的损伤和单克隆抗体的比较作用 在临床过程中，髓磷脂各个区域的合成肽 EAE的脱髓鞘。 这些研究将为调节和细胞提供进一步的见解 参与CNS免疫反应的分子的表面相互作用 并可能有助于制定特定的治疗策略 炎症和脱髓鞘的中枢神经系统疾病。