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.

沙眼衣原体是最常见的性传播细菌感染。慢性沙眼衣原体疾病对生殖造成的破坏性后果以及艾滋病毒感染的易感性使得在制定有效的疫苗接种策略方面取得进展势在必行。然而，几个关键领域的信息有限严重阻碍了该领域的进展。动物模型表明，T 细胞反应是宿主抵抗的核心，但并不能再现人类疾病的所有关键特征。沙眼衣原体是一种专性细胞内病原体，主要感染女性宫颈内膜的柱状上皮细胞，但很少感染 已知这些组织中局部免疫的诱导阶段或效应阶段。粘膜部位的免疫细胞在表型和功能上与循环中的对应细胞不同，并且越来越清楚的是，局部环境在调节局部免疫方面发挥着重要作用。然而，迄今为止，几乎所有人类研究都集中在循环中沙眼衣原体特异性免疫上，这也许是不恰当的，因为迄今为止，宫颈内淋巴细胞的分离存在巨大困难。在这里，每个问题都将得到解决。该应用的主要重点是表征人类子宫颈内沙眼衣原体感染原发部位的 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，将使用抗生素治疗前后沙眼衣原体感染女性以及未感染对照的分泌物和细胞刷细胞样本来表征局部免疫环境。 与循环 T 细胞群的比较将阐明粘膜 T 细胞库的独特特征。接下来，宫颈内膜和循环沙眼衣原体特异性 CD4 和 CD8 T 细胞的频率、细胞因子表达谱和裂解活性将在直接离体和克隆细胞群中得到更精确的定义。最后，在我们的 T 细胞克隆研究中，将使用永生化宫颈管柱状上皮细胞来表征沙眼衣原体抗原的加工和呈递，这些细胞经过遗传或生化操作以定向抑制特定的细胞内运输途径。这项研究设计将阐明沙眼衣原体和宫颈免疫系统之间的相互作用，最终将极大地有助于描述针对沙眼衣原体的保护性免疫反应和有效疫苗的开发。