Cytotoxic T-cell Mediated Immunity to Chlamydia

细胞毒性 T 细胞介导的衣原体免疫

• 批准号: 6746865
• 负责人: MICHAEL N STARNBACH
• 金额: $ 43万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6746865
• 关键词: Chlamydia trachomatis; bacterial antigens; bacterial genetics; bacterial proteins; bacterial vaccines; bactericidal immunity; cellular immunity; chlamydial disease; cytotoxic T lymphocyte; epitope mapping; genetically modified animals; host organism interaction; interferon gamma; laboratory mouse; macrophage; molecular cloning; transfection /expression vector; vaccinia virus; vector vaccine

DESCRIPTION (provided by the applicant): The obligate intracellular pathogen Chlamydia trachomatis is the most common cause of sexually transmitted disease in the developed world, causing both overt disease and infertility, and is also the leading cause of preventable blindness worldwide. Infection with C. trachomatis results in a specific immune response against the organism, and CD8+ cytotoxic T-lymphocytes (CTL) specific for C. trachomatis can be cultured from infected mice. Adoptive transfer of cultured CD8+ T-cells into infected mice reduces the number of organisms found in the spleens of these animals. The experiments in this proposal are designed to determine which Chlamydia gene products are recognized by these Chlamydia specific murine CD8+ T-cells. Three independent approaches will be used to identify these antigens. Once the C. trachomatis gene products responsible for priming the CD8+ T-cell response are identified, they will be introduced into vaccinia virus and tested for their ability to stimulate protective T-cells in a vaccine strategy. Because these antigens stimulate CD8+ T-cells, it suggests that they have access to the cytosol of host cells during the C. trachomatis developmental cycle. Experiments to characterize the developmental regulation and subcellular localization of these proteins will be carried out as a first step in understanding the role these proteins may play in C. trachomatis pathogenesis. Additional experiments will focus on the mechanism by which CD8+ T-cells protect against Chlamydia infection. Interferon-g (IFN-g) appears to be the primary effector mechanism used by these T-cells to protect against C. trachomatis infection. IFN-g release by CD8+ T-cells could protect mice against C. trachomatis infection by stimulating the antimicrobial activity of macrophages or by directly inhibiting the replication of C. trachomatis. Experiments to clarify the mechanism by which IFN-g produced by T-cells mediates protection will use radiation bone marrow chimeras in which either the hematopoietic cells (including macrophages) or the resident cells are unable to respond to IFN-g as a result of a disruption in the IFN-g receptor gene. A better understanding of the immune response to C. trachomatis and the development of a vaccine would have a pronounced effect on worldwide morbidity resulting from theseinfections.

描述（由申请人提供）：专性细胞内病原体 沙眼衣原体是性传播疾病的最常见原因 在发达国家，引起明显的疾病和不育，也是 全球可预防失明的主要原因。感染C。 气管瘤会导致针对生物体的特定免疫反应，并 CD8+细胞毒性T淋巴细胞（CTL）特异于沙眼梭状芽孢杆菌可以培养 来自感染的小鼠。将培养的CD8+ T细胞的收养转移到感染中 小鼠减少了这些动物脾脏中发现的生物数量。这 该提案中的实验旨在确定哪种衣原体基因 这些衣原体特异性鼠CD8+ T细胞识别产品。三 独立方法将用于识别这些抗原。一旦C. 负责启动CD8+ T细胞反应的气管体基因产品是 确定，将将它们引入离甲酸病毒并进行了测试 在疫苗策略中刺激保护性T细胞的能力。 由于这些抗原刺激CD8+ T细胞，因此表明它们具有 在发育曲霉内，进入宿主细胞的胞质溶胶的访问 循环。表征发育调节和亚细胞的实验 这些蛋白质的定位将作为第一步 了解这些蛋白质在沙眼发病机理中可能起作用。 其他实验将重点放在CD8+ T细胞的机制上 预防衣原体感染。干扰素G（IFN-G）似乎是 这些T细胞用于预防C的主要效应器机制。 气管体感染。 CD8+ T细胞释放IFN-G可以保护小鼠免受 梭状芽胞庭感染，通过刺激抗菌活性 巨噬细胞或直接抑制沙眼梭状芽孢杆菌的复制。 实验以阐明T细胞产生IFN-G的机制 介导保护将使用辐射骨髓嵌合体，其中 造血细胞（包括巨噬细胞）或居民细胞无法 由于IFN-G受体基因的破坏而响应IFN-G。一个 更好地理解对沙眼梭菌的免疫反应和 疫苗的开发将对全球发病率产生明显影响 由这些感染产生。