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

基本信息

批准号：
8774574
负责人：
WILLIAM M GEISLER
金额：
$ 45.88万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8774574
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 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 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 morbidity response screening vaccine development vaccine trial

项目摘要

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（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，并且在非洲裔美国人中感染率最高。 CT感染会引起女性的主要生殖发病率。控制措施并未减少流行病。迫切需要疫苗。 CT疫苗的开发受到了影响人类保护性免疫的免疫遗传因素的知识不足。鼠模型显示CD4+ T辅助器1型（TH1）免疫反应，Th1趋化因子受体表达对于保护CT的免疫至关重要，而Th2反应会损害免疫力。但是，动物模型之间的差异使得将发现转化为具有挑战性的人类。人类研究表明，细胞免疫反应对CT的反应，但很少研究有助于保护性免疫的反应。获得良好的队列是一个主要障碍。有些处于危险的人没有CT再感染，可能在某些情况下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会影响再感染的风险，但潜在的免疫途径仍然难以捉摸。我们的远距离目标是弥合有关介导对人类CT保护性免疫力的免疫遗传因素知识的差距。 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. 我们的总体假设是，CT特异性的全身性和粘膜Th1细胞因子反应（主要是IFN-3和TNF-1）以及趋化因子反应以及Th1趋化因子受体的表达将与CT重新感染风险降低相关，而选择的HLA II等位基因和IL10基因变异型会增加RE-RE-RE-RE侵蚀风险。 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女性重新感染的基因变异。来自特征良好的人群的CT感染妇女将被招募，并在3个月和6个月的访问中进行重复的CT测试。全身性和粘膜免疫学研究（CT-特异性细胞因子和趋化因子反应以及T细胞表型分布）以及针对性的HLA II类和IL10基因变体分型和遗传数据分析将在患有和没有CT感染的受试者中进行。该提案的目的是阐明与人类CT再感染的保护性免疫相关的细胞免疫反应和细胞表型，并扩展我们对影响重新感染风险的遗传变异的关系的理解。研究结果应提供CT疫苗研究所需的保护性的全身和粘膜免疫相关性。