Development of a Chlamydia T Cell Vaccine Based on Dendritic Cell Immunoprotemics

基于树突状细胞免疫蛋白质学的衣原体 T 细胞疫苗的开发

• 批准号: 7532756
• 负责人: Robert Conrad Brunham
• 金额: $ 25.38万
• 依托单位: UNIVERSITY OF BRITISH COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-25 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7532756
• 关键词: Achievement; Americas; Animal Model; Antigen-Presenting Cells; Antigens; Bacterial Sexually Transmitted Diseases; Binding; Blindness; CD8B1 gene; Cellular Immunity; Cessation of life; Chemical Vaccines; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Class; Dendritic Cells; Development; Disease; Ectopic Pregnancy; Funding; Generations; Genome; Genomics; Goals; Grant; HIV; Health; Human; Immunity; Immunobiology; Immunology; In Vitro; Infection; Infertility; Interferon Type II; Knowledge; Link; Major Histocompatibility Complex; Mass Spectrum Analysis; Mediating; Medical; Modeling; Mus; National Institute of Allergy and Infectious Disease; North America; Pelvic Inflammatory Disease; Peptides; Production; Proteins; Proteomics; Public Health; Research; Surface; T-Lymphocyte; T-Lymphocyte Epitopes; Technology; Treatment Cost; Vaccines; Visual impairment; Woman; base; design; novel; pathogen; prevent; programs; protein aminoacid sequence; research study; stem; transmission process; treatment program

DESCRIPTION (provided by applicant): Chlamydia is one of the most widespread bacterial sexually transmitted diseases in the world causing an estimated 92 million infections per year with over 2.8 million infections in America alone. Chlamydia trachomatis can cause pelvic inflammatory disease, ectopic pregnancy and infertility in women and is a co- factor in HIV transmission. The ocular form of Chlamydia has visually impaired over 8 million people and is the leading cause of preventable blindness. With treatment programs failing to stem the disease spread in North America, a vaccine is widely acknowledged as the only way by which to prevent the suffering caused by Chlamydia and a goal that the National Institute of Allergy and Infectious Diseases (NIAID) has been pursuing. Previous attempts to create an effective vaccine have proven unsuccessful; in part because Chlamydia is an intracellular pathogen that requires cell mediated immunity. The discovery described in this proposal makes substantial progress towards a Chlamydia vaccine by uniquely surmounting the technical challenges of stimulating T cell immunity. Inspired by the global magnitude of need for a Chlamydia vaccine and propelled by recent advances in proteomic technology, genomics and knowledge of Chlamydia immunology, we have identified novel antigens critical to the design of an effective C. trachomatis vaccine. The Chlamydia genome has been fully resolved, due to support from the NIAID, and the proteins from which protective T cell antigens are derived have been inferred. Chlamydia biologists now know the correlate for protective immunity to C. trachomatis is T cell interferon gamma production. In addition, excellent murine models exist to evaluate Chlamydia vaccines. We have assembled a team and developed a comprehensive strategy to identify novel T cell antigens and evaluate them in murine models of infection based on a detailed understanding of dendritic cell immunobiology. We believe that we have achieved a breakthrough by using immunoproteomics to identify T cell antigens that are expressed in Chlamydia infected dendritic cells - achieved in part because we have access to the latest generation of mass spectrometry capable of detecting peptides at the subfemtomolar level. Using mass spectrometry, the first specific aim of this study is to discover the identity of additional Chlamydia peptides eluted from MHC class I and class II molecules expressed on the surface of Chlamydia infected dendritic cells. Our second specific aim is to uncover the immunological significance of Chlamydia MHC binding peptides. Based on the antigens we know, and others we plan to uncover in this study, this grant outlines our proposed research to induce cell mediated immunity in animal models, a major step in the development of a safe and effective Chlamydia vaccine for humans. Funding for this project will accelerate progress toward a Chlamydia vaccine, which will be a major medical achievement for global health. PUBLIC HEALTH RELEVANCE: Often asymptomatic, sexually transmitted Chlamydia trachomatis infects over 92 million people per year globally and is a leading cause of pelvic inflammatory disease (PID) that results in 2-3 million annual cases of infertility and is linked to 60,000 maternal deaths per year due to ectopic pregnancy. With control programs failing, the development of a safe and effective Chlamydia vaccine would represent a fundamental breakthrough in global health as well as saving in excess of $13.5 billion per year world wide in treatment costs. In this proposal a novel immunoproteomic approach is described based on identifying Chlamydia peptides capable of producing protective cellular immunity that shows great promise towards the development of a Chlamydia vaccine.

描述（由申请人提供）：衣原体是世界上传播最广泛的细菌性传播疾病之一，估计每年造成9200万例感染，仅在美国就有280万例感染。沙眼衣原体可引起盆腔炎、女性异位妊娠和不孕症，也是HIV传播的一个辅助因素。眼部形式的衣原体已造成800多万人视力受损，是可预防失明的主要原因。由于治疗计划未能阻止这种疾病在北美的传播，疫苗被广泛认为是预防衣原体引起的痛苦的唯一途径，也是国家过敏和传染病研究所（NIAID）一直追求的目标。以前制造有效疫苗的尝试被证明是不成功的；部分原因是衣原体是一种需要细胞介导免疫的细胞内病原体。本提案中描述的发现通过独特地克服刺激T细胞免疫的技术挑战，在衣原体疫苗方面取得了实质性进展。受到全球对衣原体疫苗巨大需求的启发，并受到蛋白质组学技术、基因组学和衣原体免疫学知识的最新进展的推动，我们已经确定了对设计有效的沙眼衣原体疫苗至关重要的新抗原。由于NIAID的支持，衣原体基因组已经完全解析，并且已经推断出保护性T细胞抗原的蛋白质来源。衣原体生物学家现在知道与沙眼衣原体保护性免疫相关的是T细胞干扰素γ的产生。此外，存在很好的小鼠模型来评价衣原体疫苗。我们已经组建了一个团队，并开发了一种全面的策略来识别新的T细胞抗原，并基于对树突状细胞免疫生物学的详细了解，在小鼠感染模型中评估它们。我们相信，通过使用免疫蛋白质组学来鉴定衣原体感染树突状细胞中表达的T细胞抗原，我们已经取得了突破，部分原因是我们可以使用最新一代的质谱法来检测亚股摩尔水平的肽。使用质谱法，本研究的第一个特定目的是发现从衣原体感染树突状细胞表面表达的MHC I类和II类分子中洗脱的额外衣原体肽的身份。我们的第二个具体目标是揭示衣原体MHC结合肽的免疫学意义。基于我们已知的抗原，以及我们计划在这项研究中发现的其他抗原，这笔拨款概述了我们在动物模型中诱导细胞介导免疫的拟议研究，这是开发安全有效的人类衣原体疫苗的重要一步。为这一项目提供资金将加速衣原体疫苗的研制进程，这将是促进全球卫生的一项重大医学成就。公共卫生相关性：通常无症状的性传播沙眼衣原体每年在全球感染9200多万人，是盆腔炎（PID）的主要原因，每年导致200万至300万例不孕症，并与每年6万例因异位妊娠导致的产妇死亡有关。在控制规划失败的情况下，开发安全有效的衣原体疫苗将是全球卫生领域的一项根本性突破，并可在全世界每年节省超过135亿美元的治疗费用。在这个建议中，描述了一种新的免疫蛋白质组学方法，该方法基于识别能够产生保护性细胞免疫的衣原体肽，这对衣原体疫苗的开发显示出很大的希望。