Mechanisms and Correlates of Immune Protection against Genital Chlamydia in Human

人类生殖器衣原体免疫保护的机制和相关性

• 批准号: 8386559
• 负责人: WILLIAM M GEISLER
• 金额: $ 41.88万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386559
• 关键词: African American; Alleles; Animal Model; Antigens; Blood; CCR5 gene; CD3 Antigens; CD8B1 gene; CXC Chemokines; CXCR3 gene; Cells; Cervical; Chlamydia; Chlamydia trachomatis; Clinical; Data; Data Analyses; Dependence; Enrollment; Epidemic; Flow Cytometry; Frequencies; Funding; Genetic; Genetic Determinism; Genetic Variation; Genital system; Goals; HLA-DQB1; HLA-DR Antigens; Histocompatibility Antigens Class II; Homing; Human; IL10 gene; Immune; Immune response; Immunity; Immunoassay; Immunogenetics; Individual; Infection; Interferons; Interleukin-10; Interleukin-2; Irrigation; Knowledge; Measures; Mediating; Modeling; Mononuclear; Morbidity - disease rate; Mus; Pathway interactions; Peripheral Blood Mononuclear Cell; Phenotype; Population; Prevention; Risk; Risk Estimate; Risk Marker; Sexually Transmitted Diseases; Staining method; Stains; Swab; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Translating; Vaccines; Variant; Visit; Woman; base; chemokine; chemokine receptor; cohort; cytokine; enzyme linked immunospot assay; follow-up; genetic variant; human data; monocyte; promoter; receptor expression; reproductive; response; screening; vaccine development

DESCRIPTION (provided by applicant): Chlamydia trachomatis (CT) infection is the most prevalent bacterial sexually transmitted infection, and infection rates are highest in African Americans. CT infection causes major reproductive morbidity in women. Control measures have not diminished the epidemic; a vaccine is urgently needed. CT vaccine development has been hindered by inadequate knowledge of immunogenetic factors influencing protective immunity in humans. Murine models reveal CD4+ T helper type 1 (Th1) immune responses and Th1 chemokine receptor expression are essential for protective immunity to CT, while Th2 responses impair immunity; however, differences between animal models makes translating findings to humans challenging. Human studies reveal cellular immune responses to CT, but rarely have responses contributing to protective immunity been studied; access to well-characterized cohorts is a major obstacle. Some at risk individuals do not have CT re-infection, likely in some because immunogenetic factors mediate protection. Sparse data suggests genetic determinants influence risk for re-infection, but underlying immune pathways remain elusive. Our long range goal is to bridge gaps in knowledge of immunogenetic factors mediating protective immunity to CT in humans. Preliminary studies in a well-characterized cohort of CT-infected women revealed: 1) CT re-infection in 15% by 6 months after therapy and 2) women without re-infection more often had CT-specific Th1 responses (IFN-3 and TNF-1) and expression of Th1 chemokine receptor CCR5 and less often HLA-DQB1*05 and IL10 gene variants. Our overall hypothesis is that CT-specific systemic and mucosal Th1 cytokine responses (mainly IFN-3 and TNF-1) and chemokine responses and also expression of Th1 chemokine receptors will be associated with decreased CT re-infection risk, while select HLA class II alleles and IL10 gene variants will be associated with increased re-infection risk. Our approach to verify the hypothesis consists of three specific aims: 1) Demonstrate that CT re-infection risk is reduced in women with a CT-specific CD4+ Th1 response (mainly IFN-3 and TNF-1), 2) Determine the phenotype of systemic and mucosal T cell subsets associated with CT re- infection risk in women, and 3) Delineate and further refine associations of HLA Class II alleles and IL10 gene variants with re-infection in women. CT-infected women from a well-characterized population will be enrolled and undergo repeat CT testing at 3- and 6-month visits. Systemic and mucosal immunological studies (of CT- specific cytokine and chemokine responses and T cell phenotype distributions) as well as targeted HLA class II and IL10 gene variant typing and genetic data analyses will be carried out in subjects with and without CT re- infection. The goal of the proposal is to elucidate cellular immune responses and cell phenotypes associated with protective immunity to CT re-infection in humans, and to expand our understanding of the relationship of immune correlates with genetic variants that influence re-infection risk. Study findings should provide systemic and mucosal immune correlates of protection needed for CT vaccine studies.

描述（申请人提供）：沙眼衣原体（CT）感染是最常见的细菌性性传播感染，非裔美国人的感染率最高。 CT 感染导致女性主要生殖疾病。控制措施并没有减弱疫情；迫切需要疫苗。由于对影响人类保护性免疫力的免疫遗传因素了解不足，CT 疫苗的开发受到阻碍。小鼠模型揭示 CD4+ T 辅助细胞 1 型 (Th1) 免疫反应和 Th1 趋化因子受体表达对于 CT 的保护性免疫至关重要，而 Th2 反应会损害免疫力；然而，动物模型之间的差异使得将研究结果转化为人类具有挑战性。人体研究揭示了 CT 的细胞免疫反应，但很少研究有助于保护性免疫的反应；获得具有良好特征的群体是一个主要障碍。一些高危人群没有发生 CT 再次感染，这可能是因为免疫遗传因素介导了保护作用。稀疏的数据表明遗传决定因素影响再次感染的风险，但潜在的免疫途径仍然难以捉摸。我们的长期目标是弥合人类对 CT 保护性免疫的免疫遗传因素的知识空白。对一组特征明确的 CT 感染女性进行的初步研究显示：1) 治疗后 6 个月，CT 再次感染率为 15%；2) 未再次感染的女性更常出现 CT 特异性 Th1 反应（IFN-3 和 TNF-1）以及 Th1 趋化因子受体 CCR5 表达，较少出现 HLA-DQB1*05 和 IL10 基因变异。 我们的总体假设是，CT 特异性全身和粘膜 Th1 细胞因子反应（主要是 IFN-3 和 TNF-1）和趋化因子反应以及 Th1 趋化因子受体的表达将与 CT 再感染风险降低相关，而选择的 HLA II 类等位基因和 IL10 基因变异将与再感染风险增加相关。我们验证该假设的方法包括三个具体目标：1) 证明具有 CT 特异性 CD4+ Th1 反应（主要是 IFN-3 和 TNF-1）的女性 CT 再感染风险降低，2) 确定与女性 CT 再感染风险相关的全身和粘膜 T 细胞亚群的表型，以及 3) 描绘并进一步细化 HLA II 类等位基因和 IL10 的关联 女性再次感染的基因变异。来自特征明确的人群的 CT 感染女性将被纳入并在 3 个月和 6 个月就诊时接受重复 CT 检测。系统和粘膜免疫学研究（CT特异性细胞因子和趋化因子反应以及T细胞表型分布）以及有针对性的HLA II类和IL10基因变异分型和遗传数据分析将在有和没有CT再感染的受试者中进行。该提案的目标是阐明与人类 CT 再次感染的保护性免疫相关的细胞免疫反应和细胞表型，并扩大我们对免疫相关性与影响再次感染风险的遗传变异之间关系的理解。研究结果应提供 CT 疫苗研究所需保护的系统和粘膜免疫相关性。