Role of Plac8 in natural and vaccine-generated immunity against Chlamydia infections

Plac8 在针对衣原体感染的自然免疫和疫苗免疫中的作用

• 批准号: 9303878
• 负责人: Robert Conrad Brunham
• 金额: $ 34.75万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303878
• 关键词: Adjuvant; Adolescent; Adolescent and Young Adult; Antibiotic Therapy; Antigens; Applications Grants; Assessment tool; Biological Markers; CD4 Positive T Lymphocytes; Cells; Chemicals; Chlamydia; Chlamydia Infections; Chlamydia muridarum; Chlamydia trachomatis; Clinical Trials; Clone Cells; Consensus Development; Data; Development; Epithelial; Epithelial Cells; Female infertility; Fostering; Foundations; Frequencies; Future; Generations; Genes; Goals; Human; Immune; Immune response; Immunity; Immunobiology; Immunologics; Incidence; Infection; Infertility; Interferons; Interleukin-10; Investigation; Knock-out; Knockout Mice; Laboratories; Mediating; Modeling; Mononuclear; Mus; Outcome; Peripheral; Phase; Prevalence; Public Health; Publishing; Research; Role; Safety; Subunit Vaccines; Surrogate Markers; T cell response; T-Lymphocyte; TNF gene; Testing; Translational Research; Tubal Pregnancy; Vaccination; Vaccines; Western Europe; Whole Organism; Work; base; biomarker identification; cost; design; human subject; immunopathology; insight; men; mouse model; novel; public health relevance; reproductive tract; response; screening; trachoma vaccine; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine-induced immunity; young adult

DESCRIPTION (provided by applicant): Chlamydia trachomatis infections have a prevalence of 2-15% in adolescents/young adults in the USA and Western Europe in spite of public health efforts and effective antibiotic therapy. It is widely accepted that development of a Chlamydia vaccine is necessary reduce its prevalence. A critical component of vaccine development is identification of a surrogate biomarker for protective immunity to enable screening of candidate vaccines. Currently there are no practicable biomarkers for Chlamydia protective immunity. The Johnson laboratory has identified a second CD4 T cell-mediated mechanism singly-sufficient for clearing Chlamydia from the genital tract that is dependent on Plac8. The Brunham laboratory has demonstrated that vaccine-generated protective immunity against Chlamydia genital tract infections requires a multifunctional Th1 response. The two laboratories approaching protective immunity from different perspectives have converged on working model for protective immunity that has major potential implications for vaccine development. Supported by published and unpublished data they postulate that the foundation of a protective C. trachomatis vaccine will be generation of a multifunctional CD4Plac8 anti-Chlamydia response, and that multifunctional CD4Plac8 T cell responses will serve as practicable biomarkers for protective immunity and vaccine efficacy. To test that hypothesis and investigate the underlying immunobiology they propose the following specific aims: Specific aim #1- to investigate the role of the Plac8-dependent clearance mechanism in vaccine-generated protective immunity. This aim will utilize the Brunham laboratory's published protective murine PmpG vaccine, and existing knockout mice. Specific aim #2- to investigate the effector mechanism associated with Plac8-dependent immunity. This aim will utilize the Johnson lab's published Chlamydia-specific Plac8pos and Plac8neg CD4 T cell clones, and Plac8 knockout reproductive tract epithelial lines. Specific aim #3- to investigate the frequency and distribution of multifunctional CD4Plac8 T cells in mice and humans, in the absence and presence of Chlamydia infections. This is novel translational research.

描述（由申请方提供）：尽管采取了公共卫生措施和有效的抗生素治疗，但在美国和西欧，沙眼衣原体感染在青少年/年轻人中的患病率为2-15%。人们普遍认为，有必要开发衣原体疫苗，以降低其流行率。疫苗开发的一个关键组成部分是鉴定保护性免疫的替代生物标志物，以筛选候选疫苗。目前还没有切实可行的生物标志物衣原体保护性免疫。约翰逊实验室已经确定了第二个CD 4 T细胞介导的机制，它依赖于Plac 8，足以从生殖道清除衣原体。Brunham实验室已经证明，疫苗产生的针对衣原体生殖道感染的保护性免疫需要多功能Th 1应答。两个从不同角度研究保护性免疫的实验室已经在保护性免疫的工作模型上达成一致，这对疫苗开发具有重要的潜在意义。在已发表和未发表的数据的支持下，他们假设保护性C。沙眼衣原体疫苗将产生多功能CD 4Plac 8抗衣原体应答，并且多功能CD 4Plac 8 T细胞应答将用作保护性免疫和疫苗功效的实用生物标志物。为了验证这一假设并研究潜在的免疫生物学，他们提出了以下具体目标：具体目标#1-研究Plac 8依赖性清除机制在疫苗产生的保护性免疫中的作用。这一目标将利用Brunham实验室发表的保护性鼠PmpG疫苗和现有的基因敲除小鼠。具体目标#2-研究与Plac 8依赖性免疫相关的效应机制。该目标将利用约翰逊实验室发表的衣原体特异性Plac 8 pos和Plac 8 neg CD 4 T细胞克隆，以及Plac 8敲除生殖道上皮细胞系。具体目标#3-研究在不存在和存在衣原体感染的情况下，小鼠和人类中多功能CD 4Plac 8 T细胞的频率和分布。这是一种新颖的翻译研究。