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: 7643875
• 负责人: Robert Conrad Brunham
• 金额: $ 21.6万
• 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/7643875
• 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; 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; Research; Surface; T-Lymphocyte; T-Lymphocyte Epitopes; Technology; Treatment Cost; Vaccines; Visual impairment; Woman; base; design; novel; pathogen; prevent; programs; protein aminoacid sequence; public health relevance; 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）：衣原体是世界上最普遍的细菌性传播疾病之一，估计每年造成 9200 万例感染，仅在美国就有超过 280 万例感染。沙眼衣原体可导致女性盆腔炎、宫外孕和不孕症，并且是艾滋病毒传播的辅助因素。眼部衣原体导致超过 800 万人视力受损，是可预防性失明的主要原因。由于治疗计划未能阻止疾病在北美的传播，疫苗被广泛认为是预防衣原体造成的痛苦的唯一方法，也是美国国家过敏和传染病研究所 (NIAID) 一直追求的目标。此前研制有效疫苗的尝试已被证明是不成功的。部分原因是衣原体是一种细胞内病原体，需要细胞介导的免疫。该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。受全球对衣原体疫苗需求量的启发，并在蛋白质组学技术、基因组学和衣原体免疫学知识的最新进展的推动下，我们已经确定了对于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，衣原体基因组已被完全解析，并且已推断出保护性 T 细胞抗原的来源蛋白质。衣原体生物学家现在知道，对沙眼衣原体的保护性免疫与 T 细胞干扰素 γ 的产生相关。此外，还有优秀的小鼠模型可用于评估衣原体疫苗。我们组建了一个团队并制定了一项全面的策略来识别新型 T 细胞抗原，并基于对树突状细胞免疫生物学的详细了解，在小鼠感染模型中对其进行评估。我们相信，通过使用免疫蛋白质组学来鉴定衣原体感染的树突状细胞中表达的 T 细胞抗原，我们已经取得了突破，部分原因是我们能够使用能够在亚飞摩尔水平检测肽的最新一代质谱技术。使用质谱法，本研究的第一个具体目的是发现从衣原体感染的树突状细胞表面表达的 MHC I 类和 II 类分子中洗脱的其他衣原体肽的身份。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。根据我们已知的抗原以及我们计划在本研究中发现的其他抗原，这笔赠款概述了我们拟议的在动物模型中诱导细胞介导的免疫的研究，这是开发人类安全有效的衣原体疫苗的重要一步。该项目的资金将加速衣原体疫苗的进展，这将是全球健康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超过 9200 万人，是盆腔炎 (PID) 的主要原因，盆腔炎会导致每年 2-300 万不孕不育病例，并与每年 60,000 名孕产妇因宫外孕死亡有关。在控制计划失败的情况下，开发安全有效的衣原体疫苗将代表全球健康领域的根本性突破，并每年在全球范围内节省超过 135 亿美元的治疗费用。在该提案中，描述了一种新的免疫蛋白质组学方法，该方法基于鉴定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巨大的希望。