Mechanisms and Correlates of Immune Protection against Genital Chlamydia in Human

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感染在妇女中造成主要的生殖疾病。控制措施并没有减少疫情；迫切需要一种疫苗。由于对影响人类保护性免疫的免疫遗传因素了解不足，CT疫苗的开发一直受到阻碍。小鼠模型显示，CD4+T辅助细胞1型(Th1)免疫反应和Th1趋化因子受体的表达是CT保护性免疫所必需的，而Th2反应损害免疫；然而，动物模型之间的差异使将研究结果翻译到人类具有挑战性。人体研究揭示了对CT的细胞免疫反应，但很少有人研究有助于保护性免疫的反应；获得特征良好的队列是一个主要障碍。一些高危个体没有CT再次感染，可能是因为免疫遗传因素介导了保护。稀少的数据表明，基因决定因素会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免疫遗传因素在人类对CT的保护性免疫中的知识空白。对CT感染女性队列的初步研究表明：1)治疗后6个月CT再感染率为15%，2)未再感染的女性更多地出现CT特异性Th1应答(干扰素-3和肿瘤坏死因子-1)和Th1趋化因子受体CCR5的表达，而较少出现HLA-DQB1*05和IL10基因变异。我们的总体假设是，CT特异性的全身和粘膜Th1细胞因子反应(主要是干扰素-3和肿瘤坏死因子-1)和趋化因子反应以及Th1趋化因子受体的表达将与降低CT再感染风险相关，而特定的人类白细胞抗原II类等位基因和IL10基因变异将与增加再感染风险相关。我们验证这一假设的方法包括三个特定的目标：1)证明CT特异性CD4+Th1应答(主要是干扰素-3和肿瘤坏死因子-1)的女性CT再感染风险降低，2)确定与女性CT再感染风险相关的系统和粘膜T细胞亚群的表型，以及3)描绘和进一步细化人类白细胞抗原II类等位基因和IL10基因变异与女性再感染的关联。来自具有良好特征的人群的CT感染妇女将被登记，并在3个月和6个月的访问中接受重复的CT测试。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和T细胞表型分布)以及针对性的人类白细胞抗原II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。该提案的目的是阐明与人类CT再感染保护性免疫相关的细胞免疫反应和细胞表型，并扩大我们对影响再感染风险的遗传变异与免疫相关性的理解。研究结果应提供CT疫苗研究所需保护的系统和粘膜免疫关联。

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.