Mechanism(s) of CD8 T cell-mediated Chlamydia-induced reproductive pathology

CD8 T 细胞介导的衣原体诱导的生殖病理机制

• 批准号: 9099463
• 负责人: Ashlesh Krishna Murthy
• 金额: $ 45万
• 依托单位: MIDWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099463
• 关键词: Address; Antigens; Biological Markers; Biological Response Modifiers; Biomedical Research; Blindness; CD4 Positive T Lymphocytes; CD8B1 gene; Cardiovascular Diseases; Cells; Chlamydia; Chlamydia Infections; Chlamydophila pneumoniae; Clinical Trials; Development; Ectopic Pregnancy; Educational process of instructing; Ensure; Female; Frequencies; Funding Mechanisms; Genital system; Goals; Grant; Human; Immune response; Immunization; Infertility; Institution; Interferons; Interleukin-17; Laboratories; Lead; Learning; Lung; Mediating; Mediator of activation protein; Modeling; Mus; Neutrophil Infiltration; Pathogenesis; Pathology; Pathway interactions; Pelvic Inflammatory Disease; Production; Regimen; Reiter Disease; Research; Role; Scientific Advances and Accomplishments; Source; Staging; Stream; Structure; Students; T cell response; T-Lymphocyte; TNF gene; Tumor Necrosis Factor Receptor; Universities; Vaccination; Vaccines; Woman; Work; base; career development; clinically relevant; clinically significant; mouse model; neutrophil; pathogen; preclinical trial; prevent; public health relevance; reproductive; reproductive tract; response; vaccine development

 DESCRIPTION (provided by applicant): Chlamydial infections underlie the development of several clinically significant pathologies including blindness, female reproductive tract pathology cardiovascular diseases, and reactive arthritis. The long term goal of our research is to understand the mechanisms of chlamydial pathogenesis and prevent them. A vaccine is against Chlamydia is thought to be the ideal solution to prevent reproductive pathologies in the female upper genital tract (UGT). Since the host immune response or a subset is also responsible for these pathologies, the question arises: "How do we ensure that a vaccine does not inadvertently induce the pathologies that it was intended to prevent?" To this end, a deep understanding of chlamydial immunopathogenesis is needed, whereas it is currently incompletely understood. We have recently demonstrated various lines of evidence that antigen-specific, TNF-α producing, TNF receptor 2 expressing CD8+ T cells induce upper genital tract pathology following chlamydial infections. In this proposal, we will address the hypothesis that "Antigen- specific CD8+ T cells are a key regulator of pathogenic responses following chlamydial infections" and evaluate the modulation of such responses by protective vaccination regimens. The significance of addressing this hypothesis is as follows: A variety of immunological mediators have been shown to mediate chlamydial pathogenesis and our work demonstrates Chlamydia-specific CD8+ T cells as an additional mediator. Based on this, two important inferences can be made: (A) Various pathogenic mediators appear to function in a serial cascade since pathology can be significantly reduced by deleting one component, for example Ag-specific CD8+ T cells. This suggests that avoiding the elicitation of a key component in this pathway may be sufficient to reduce pathology, and (B) CD8+ T cells mediate pathology in an antigen (Ag)-specific fashion. Thus, the avoiding the elicitation of Ag-specific pathogenic CD8+ T cells would become a superior avoidance strategy when compared to innate immune mediators during preclinical and clinical trials of chlamydial vaccines. We will address our hypothesis with the following subaims: Aim 1. Determine whether Chlamydia-specific CD8+ T-cells engage neutrophils for pathogenesis. Aim 2. Determine whether protective vaccine regimens significantly reduce pathology by circumventing the pathogenic CD8+ T-cell response.

 描述（由申请方提供）：衣原体感染是几种具有临床意义的病理学发展的基础，包括失明、女性生殖道病理学心血管疾病和反应性关节炎。我们研究的长期目标是了解衣原体的发病机制和预防它们。针对衣原体的疫苗被认为是预防女性上生殖道（UGT）生殖病理的理想解决方案。由于宿主免疫应答或亚群也是这些病理的原因，因此出现了以下问题：“我们如何确保疫苗不会无意中诱导其旨在预防的病理？“为此，需要深入了解衣原体免疫发病机制，而目前还不完全了解。我们最近已经证明了抗原特异性的、产生TNF-α的、表达TNF受体2的CD 8 + T细胞在衣原体感染后诱导上生殖道病理的各种证据。在本提案中，我们将解决“抗原特异性CD 8 + T细胞是衣原体感染后致病性应答的关键调节因子”的假设，并评估保护性疫苗接种方案对此类应答的调节。解决这一假设的意义如下：各种免疫介质已被证明介导衣原体的发病机制，我们的工作表明衣原体特异性CD 8 + T细胞作为一个额外的介质。基于此，可以做出两个重要的推论：（A）各种致病介质似乎以串联级联起作用，因为病理可以通过删除一种组分（例如Ag特异性CD 8 + T细胞）而显著减少。这表明，避免引发该途径中的关键组分可能足以减少病理，并且（B）CD 8 + T细胞以抗原（Ag）特异性方式介导病理。因此，在衣原体疫苗的临床前和临床试验期间，与先天免疫介质相比，避免Ag特异性致病性CD 8 + T细胞的激发将成为上级避免策略。我们将通过以下子目标来解决我们的假设：目标1。确定衣原体特异性CD 8 + T细胞是否参与中性粒细胞的发病机制。目标二。确定保护性疫苗方案是否通过规避致病性CD 8 + T细胞应答来显著减少病理。