The Role of Lipid-specific T cells in Mediating Protection Against M. tuberculosis

脂质特异性 T 细胞在介导结核分枝杆菌保护中的作用

• 批准号: 10415830
• 负责人: CHETAN SESHADRI
• 金额: $ 80.56万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415830
• 关键词: Address; Adoptive Transfer; Adult; Aerosols; Animal Model; Animal Testing; Animals; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoimmunity; BCG Live; Bacille Calmette-Guerin vaccination; CD1 Antigens; Cause of Death; Cell Wall; Cells; Cessation of life; Child; Communicable Diseases; Communities; Computational Technique; Computing Methodologies; Core Facility; Cutaneous; Data; Development; Disease; Epidemic; Epitopes; Flow Cytometry; Foundations; Frequencies; Funding; Glycolipids; Goals; Histocompatibility; Human; Immune system; Immunity; Infection; Intravenous; Jurkat Cells; Lipids; Lung; Macaca mulatta; Malignant Neoplasms; Mediating; Memory; Modeling; Mus; Mycobacterium Infections; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Mycolic Acid; Pathogenesis; Peptides; Phase; Phenotype; Proliferating; Proteins; Pulmonary Tuberculosis; Research; Role; Route; Specificity; Stains; Study models; System; T cell response; T-Cell Antigen Receptor Specificity; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; Transgenic Organisms; Tuberculosis; Tuberculosis Vaccines; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Waxes; Whole Cell Vaccine; antigen binding; antigen-specific T cells; antimicrobial; clinical efficacy; efficacy study; efficacy testing; experimental study; infectious disease model; mouse model; mycobacterial; nonhuman primate; novel vaccines; prevent; public health relevance; tool; unvaccinated

PROJECT SUMMARY (ABSTRACT) ! Mycobacterium tuberculosis (M.tb) was responsible for more than 1.6 million deaths in 2017, making it a leading infectious cause of death worldwide. Currently, Mycobacterium bovis bacille Calmette-Guérin (BCG) is the only licensed vaccine for tuberculosis. BCG provides protection against disseminated forms of the disease in children but is inconsistent in preventing the development of pulmonary tuberculosis in adults. Since adults with pulmonary tuberculosis are highly infectious, control of the epidemic will not be achieved with BCG, and new vaccines are urgently needed. A number of lines of evidence from human and animal studies have revealed the critical importance of T cells in conferring protective immunity to M.tb. However, we still do not know which M.tb antigens are targeted by the T cells that confer protection. This information is critical to developing new vaccines that are more effective than BCG. Classically, T cells are activated by foreign peptide antigens that are bound to highly polymorphic major histocompatibility (MHC) molecules. Alternatively, mycobacterial cell wall lipids have conclusively been shown to activate human T cells when bound to CD1 proteins on antigen- presenting cells. The CD1 system has been shown to mediate protective T-cell responses in mouse models of autoimmunity, cancer, and infectious diseases. However, the lack of an appropriate animal model has impeded research into the importance of CD1-restricted T cells in the pathogenesis of M.tb. Tools to identify CD1- restricted T cells were also unavailable until recently. Over the last ten years, we have established lipid-loaded CD1 tetramers as tools to study the phenotypes and functions of CD1-restricted T cells in humans. We have also developed and validated a humanized CD1 transgenic (hCD1Tg) mouse model and shown that T-cells specific for mycolic acid, a major constituent of the mycobacterial cell wall, confer protective immunity to M.tb challenge. Finally, we are now also developing CD1 tetramers for non-human primate (NHP) models of TB. These preliminary data establish the feasibility of developing small and large animal models for studying the role of CD1-restricted T cells in TB pathogenesis. In Aim 1, we will validate a suite of human CD1 tetramers loaded with synthetic lipid antigens and determine the tissue-specific phenotypes and functions of CD1-restricted T cells after mycobacterial vaccination or infection of hCD1Tg mice and NHP. In Aim 2, we will explore whether BCG administered by different routes (cutaneous, aerosol, or intravenous) or primary M.tb infection induces lipid- specific T cells that confer protective immunity to M.tb challenge in hCD1Tg mice and NHP. We will also study whether lipid antigen-specific T cells confer protective immunity using adoptive transfer experiments in hCD1Tg mice. By the end of the funding period, we will have validated a set of tools that will be available to the broader TB research community and addressed whether lipid-specific T cells should be considered a correlate of protective immunity in Phase II/III clinical efficacy studies of whole cell mycobacterial vaccines.

项目摘要（摘要） 呢 结核分枝杆菌（M.TB）在2017年造成超过160万人死亡，使其成为 全球领先的传染病死亡原因。目前，牛分枝杆菌巴奇氏菌Calmette-guérin（BCG）是 唯一用于结核病的许可疫苗。 BCG为疾病的传播形式提供了保护 在儿童中，但在防止成人肺结核的发展方面不一致。自成年人以来 肺结核具有很高的感染性，BCG无法获得对流行病的控制，并且 迫切需要新的疫苗。来自人类和动物研究的许多证据表明 T细胞在M.TB的会议保护性免疫中的至关重要性但是，我们仍然不知道哪个 M.TB抗原是由会议保护的T细胞瞄准的。此信息对于开发新的信息至关重要 比BCG更有效的疫苗。从经典上讲，T细胞被外国胡椒抗原激活 与高度多态主要的组织相容性（MHC）分子结合。或者，分枝杆菌细胞壁 脂质已最终证明可以激活人类T细胞，与抗原上的CD1蛋白结合时 呈现细胞。 CD1系统已显示在鼠标模型中介导受保护的T细胞响应 自身免疫性，癌症和传染病。但是，缺乏适当的动物模型阻碍了 研究CD1限制的T细胞在M.TB的发病机理中的重要性的研究。识别CD1-的工具 直到最近，受限制的T细胞也无法使用。在过去的十年中，我们已经建立了脂质的负载 CD1四聚体是研究人类CD1限制的T细胞的表型和功能的工具。我们有 还开发并验证了人源化的CD1转基因（HCD1TG）小鼠模型，并表明T细胞 特定于霉菌酸，这是分枝杆菌细胞壁的主要结构，会议保护性免疫对M.TB 挑战。最后，我们现在还为TB的非人类灵长类动物（NHP）模型开发了CD1四聚体。 这些初步数据确定了开发大小动物模型来研究角色的可行性 TB发病机理中CD1限制的T细胞的。在AIM 1中，我们将验证一套装载的人CD1四聚体 使用合成脂质抗原，并确定CD1限制的T细胞的组织特异性表型和功能 分枝杆菌疫苗或HCD1TG小鼠和NHP感染后。在AIM 2中，我们将探讨BCG是否 通过不同的路线（皮肤，气溶胶或静脉内）或原发性M.TB感染诱导脂质 - 在HCD1TG小鼠和NHP中对M.TB挑战的保护性免疫的特定T细胞。我们还将学习 脂质抗原特异性T细胞是否使用HCD1TG中的自适应转移实验赋予保护性免疫 老鼠。到资金期结束时，我们将验证一组工具，这些工具将可以更广泛地使用 结核病研究界，并解决了是否应将脂质特异性T细胞视为 全细胞分枝杆菌疫苗的II/III期临床效率研究中的保护性免疫学。