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: 3412792
• 负责人: RAYMOND A SOBEL
• 金额: $ 19.97万
• 依托单位: STANFORD UNIVERSITY
• 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 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3412792
• 关键词: AIDS dementia complex; 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; neuroimmunomodulation; protein sequence; 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.

这个项目的总体目标是了解细胞的机制， 中枢神经系统（CNS）的免疫反应。 假设是 测试的是CNS上特异性分子的显著表面表达， 常驻细胞，特别是内皮细胞，在血管生成中起关键作用。 免疫介导损伤的发病机制。我们将使用免疫组织化学， 光和电子显微镜水平定位特定的蛋白质， CNS和原位杂交以确定合成位点。 （一）. II类主要组织相容性复合体（Ia）分子将被 在动物T细胞免疫反应模型中进行分析。实验性变态反应性 在近交系小鼠及其F1子代中， 将确定是否有易感亲本的优先表达 菌株特异性Ia分子对不同髓鞘的反应 抗原，并将开发用于Ia调节的裂解的体外系统 对传统的和常驻的CNS抗原呈递细胞。时间 常驻细胞Ia分子的序列和细胞定位将被 在迟发型超敏反应中分析，以确定细胞表面 Ia表达先于或为T细胞浸润的继发效应， 原地。 （二）.将在人CNS中分析内皮细胞表面分子 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体分子的表达 在艾滋病患者中; HLA-DR特异性mRNA将在多个 硬化症（MS）和病毒性脑炎;纤连蛋白，一种糖蛋白 增强单核细胞与内皮细胞的粘附， 在MS中鉴定并确定其合成位点。 （三）、抗外膜抗体对脱髓鞘的潜在作用 通过鉴定蛋白质序列 中枢神经系统髓鞘的局部外小叶可能是 免疫介导的损伤及单克隆抗体的比较作用 在临床过程中， EAE中的脱髓鞘。 这些研究将为调控和细胞凋亡提供进一步的见解。 参与CNS免疫应答的分子的表面相互作用 并可能有助于制定具体的治疗策略 炎症和脱髓鞘中枢神经系统疾病。