Mechanisms and Correlates of Immune Protection against Genital Chlamydia in Human

描述（由申请人提供）：沙眼衣原体（CT）感染是最常见的细菌性性传播感染，非洲裔美国人的感染率最高。CT感染导致女性主要的生殖系统疾病。控制措施并没有减少这一流行病;迫切需要一种疫苗。CT疫苗的开发一直受到影响人类保护性免疫的免疫遗传因素的知识不足的阻碍。小鼠模型揭示了CD 4 + T辅助细胞1型（Th 1）免疫应答和Th 1趋化因子受体表达对CT的保护性免疫至关重要，而Th 2应答损害免疫力;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。人体研究揭示了对CT的细胞免疫应答，但很少有有助于保护性免疫的应答被研究;获得良好表征的队列是一个主要障碍。一些高危人群没有CT再感染，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补人类免疫遗传因素介导的CT保护性免疫的知识空白。对CT感染女性患者进行的初步研究显示：1）治疗后6个月CT再感染率为15%，2）未再感染的女性患者更常出现CT特异性Th 1应答（IFN-3和TNF-1）和Th 1趋化因子受体CCR 5表达，而HLA-DQB 1 *05和IL 10基因变异较少。 我们的总体假设是，CT特异性全身和粘膜Th 1细胞因子应答（主要是IFN-3和TNF-1）和趋化因子应答以及Th 1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IL 10基因变异将与再感染风险增加相关。我们验证假设的方法包括三个具体目标：1）证明CT再感染风险在具有CT特异性CD 4 + Th 1应答的女性中降低（主要是IFN-3和TNF-1），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，和3）描绘并进一步细化HLA II类等位基因和IL 10基因变异与女性再感染的关联。将入组来自特征明确人群的CT感染女性，并在3个月和6个月访视时进行重复CT检测。将在有和无CT再感染的受试者中进行全身和粘膜免疫学研究（CT特异性细胞因子和趋化因子应答和T细胞表型分布）以及靶向HLA II类和IL 10基因变体分型和遗传数据分析。该提案的目标是阐明与人类CT再感染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疫苗研究所需的全身和粘膜免疫保护相关性。

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.