Cervical T Cell Immunity to C. trachomatis

宫颈 T 细胞对沙眼衣原体的免疫

• 批准号: 6866134
• 负责人: ALISON J. QUAYLE
• 金额: $ 23.4万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6866134
• 关键词: Chlamydia trachomatis; MHC class I antigen; MHC class II antigen; T lymphocyte; antigen presentation; bactericidal immunity; cellular immunity; cervix; clinical research; clone cells; cooperative study; cytokine; cytolysis; epithelium; female; human subject; mucosal immunity; sexually transmitted diseases

Chlamydia trachomatis is the most prevalent sexually transmitted bacterial infection. Devastating reproductive consequences of chronic C. trachomatis disease and a predisposition to HIV infection make progress towards the development of effective vaccination strategies imperative. However, limited information in several key areas has severely hampered progress in this area. Animal models have shown that T cell responses are central to host resistance but do not reproduce all the critical features of human disease. C. trachomatis is an obligate intracellular pathogen that primarily infects columnar epithelial cells of the endocervix in women, yet little is known either of the inductive or effector phases of local immunity in these tissues. Immune cells at mucosal sites are phenotypically and functionally distinct from their counterparts in the circulation and it is increasingly clear that the local milieu plays an important role in regulating local immunity. Nevertheless, almost all human studies to date have focused, perhaps inappropriately, on C. trachomatis-specific immunity in the circulation, since great difficulties have, to date, attended isolation of endocervical lymphoid ceils. Here, each of these issues will be addressed. The primary focus of this application is to characterize T cell immune responses at the primary site of C. trachomatis infection in the human endocervix with the underlying hypothesis that activity of these subpopulations, rather than circulating T cells, most accurately reflects the critical host response against this pathogen. Initially, the local immune milieu will be characterized using secretions and cytobrush cell specimens from C. trachomatis-infected women both pre-and post-antibiotic treatment and from uninfected controls. Comparisons with circulating T cell populations will clarify unique features of the mucosal T cell repertoire. Next, the frequencies, cytokine expression profiles and lytic activities of endocervical and circulating C. trachomatis-specific CD4 and CD8 T cells both will be more closely defined both directly ex vivo and in cloned cell populations. Finally, in studies with our T cell clones, processing and presentation of C. trachomatis antigens will be characterized, using immortalized endocervical columnar epithelial cells that are genetically or biochemically manipulated for directed inhibition of specific intraceUular trafficking pathways. This study design will clarify interactions between C. trachomatis and the cervical immune system that will ultimately aid greatly in delineating protective immune responses against C. trachomatis and the development of effective vaccines.

沙眼衣原体是最普遍的性传播细菌感染。慢性梭状瘤疾病和艾滋病毒感染的倾向的毁灭性繁殖后果使得势在开发有效的疫苗接种策略的进展。但是，在几个关键领域的有限信息严重阻碍了该领域的进展。动物模型表明，T细胞反应是宿主抗性的核心，但不重现人类疾病的所有关键特征。沙眼梭状芽胞庭是一种义务的细胞内病原体，主要感染女性内部圆柱上皮细胞，但几乎没有IS 已知这些组织中局部免疫的感应或效应阶段。粘膜部位的免疫细胞在表型和功能上与循环中的免疫细胞不同，越来越明显的是，局部环境在调节局部免疫中起着重要作用。然而，迄今为止，几乎所有的人类研究都集中在循环梭菌特异性免疫上，因为迄今为止遇到的巨大困难已经​​出席了遗传淋巴管的隔离。在这里，每个问题都将被解决。该应用的主要重点是表征人类内核中沙眼感染的主要部位的T细胞免疫反应，其基本假设是，这些亚群的活性而不是循环T细胞，最准确地反映了针对该病原体的关键宿主反应。最初，局部免疫环境将以分泌物和抗心霉菌感染的妇女的分泌物和细胞刺激细胞标本来表征，包括抗生物后和抗生物后治疗以及未感染的对照。 与循环T细胞群体的比较将阐明粘膜T细胞库的独特特征。接下来，室内和循环的沙眼特异性CD4和CD8 T细胞的频率，细胞因子表达谱以及裂解活性都将更加直接定义直接离体和克隆细胞种群。最后，在使用我们的T细胞克隆的研究中，将使用永生化的内颈柱状上皮细胞进行处理和表现，以遗传或生物化学操纵特定的内部贩运途径。这项研究设计将阐明沙眼梭状芽孢杆菌与宫颈免疫系统之间的相互作用，这些系统最终将极大地帮助描述针对沙眼梭状芽胞庭的保护性免疫反应和有效疫苗的开发。