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）感染是最普遍的细菌性传播感染，感染率最高的是非裔美国人。CT感染是妇女生殖疾病的主要原因。控制措施并未减少疫情；现在迫切需要疫苗。由于对影响人体保护性免疫的免疫遗传因素的认识不足，CT疫苗的开发一直受到阻碍。小鼠模型显示CD4+ T辅助型1 （Th1）免疫应答和Th1趋化因子受体表达对CT保护性免疫至关重要，而Th2应答损害免疫；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的细胞免疫反应，但很少研究有助于保护性免疫的反应；获得特征明确的队列是一个主要障碍。一些有危险的个体没有CT再感染，可能是因为免疫遗传因素介导了保护。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免疫遗传因素介导人类CT保护性免疫的知识差距。在一个特征明确的CT感染女性队列中进行的初步研究显示：1)治疗后6个月有15%的CT再次感染；2)没有再次感染的女性更常出现CT特异性Th1反应（IFN-3和TNF-1）和Th1趋化因子受体CCR5的表达，较少表达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降低CT再感染风险相关，而选择HLA II类等位基因和IL10基因变异将与再感染风险增加相关。我们验证这一假设的方法包括三个特定目标：1)证明具有CT特异性CD4+ Th1应答（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)描述并进一步完善HLA II类等位基因和IL10基因变异与女性再感染的关系。将从特征明确的人群中招募感染CT的妇女，并在3个月和6个月的随访中重复进行CT检查。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）以及靶向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细胞免疫反应和细胞表型与人类CT再感染的保护性免疫相关，并扩大我们对影响再感染风险的免疫相关基因变异关系的理解。研究结果应提供CT疫苗研究所需的全身和粘膜免疫相关保护。

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.