The role of innate immunity in the acquisition of sterile protection against TB infection

先天免疫在获得针对结核感染的无菌保护中的作用

• 批准号: 9409649
• 负责人: ADRIANA WEINBERG
• 金额: $ 22.21万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-08 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409649
• 关键词: Abbreviations; Adult; Antigens; Biological Assay; Cellular Immunity; Characteristics; Communicable Diseases; Cytometry; Data Set; Development; Disabled Persons; Disease; Enrollment; Exposure to; Flow Cytometry; Goals; Immune; Immunity; Immunologic Memory; Immunologics; India; Individual; Infection; Infection prevention; Interferons; Longevity; Lung; Measures; Mediating; Medical; Memory; Microbe; Morbidity - disease rate; Mycobacterium tuberculosis; Natural Immunity; Observational Study; Peripheral Blood Mononuclear Cell; Preventive vaccine; Protocols documentation; Public Health; Pulmonary Tuberculosis; Recruitment Activity; Research; Rest; Role; Sampling; Site; Sterility; Systems Biology; T cell response; T-Lymphocyte; Technology; Testing; Time; Tuberculin Test; Tuberculosis; Tuberculosis Vaccines; United States National Institutes of Health; Vaccination; Vaccines; Virus; analytical tool; cohort; design; effective therapy; global health; instrument; latent infection; medical schools; mortality; novel vaccines; prevent; prospective; protective effect; reactivation from latency; response; tool; tool development; tuberculosis treatment; tumor; vaccine candidate; vaccine development; vaccine-induced immunity

Summary Tuberculosis (TB) is a major global health problem. Bacille de Calmette et Guérin (BCG), the only TB prophylactic vaccine licensed, is 80% effective against extra-pulmonary TB (extra-PTB), but has variable efficacy against PTB, the site of primary TB infection. A big handicap in the development of TB vaccines more effective than BCG is that immune protection against TB is incompletely understood. BCG generates TB- specific adaptive cell-mediated immunity (aCMI), which is thought to contribute especially to its strong protective effect against extra-PTB, but does not confer sterile immunity against M. tuberculosis (Mtb) and does not protect against latent TB infection (LTBI). We hypothesized that Mtb memory-like innate CMI (iCMI) is a mechanism of protection against primary Mtb infection that prevents LTBI. An important corollary is that TB- specific iCMI will provide a robust measure for vaccine-induced sterile protection against TB, a much needed tool for the development of highly efficacious TB vaccines. Using samples collected in the Cohort For TB Research By The Indo-US Medical Partnership Multicentric Prospective Observational Study (C-TRIUMPH) at the Byramjee Jeejeebhoy Govt. Medical College (BJMC), Pune, India, together with a group of BCG recipients with negligible exposure to TB to be enrolled in the US, we will investigate TB-specific iCMI as a mechanism of sterile protection against Mtb, and the extent to which Mtb memory iCMI can be elicited by BCG vaccination. AIM 1. To identify the Mtb iCMI characteristics that differentiate LTBI- from LTBI+ adults with high exposure to smear-positive PTBI. Hypothesis: LTBI- individuals highly exposed to TB have more robust Mtb memory-like iCMI than LTBI+ individuals. Using CyTOF technology and systems biology analytical tools designed for large datasets, we will measure a large array of NK, NKT,  T and mucosal-associated invariant T (MAIT) cell responses to ex-vivo Mtb antigenic stimulation and analyze the differences between a subset of LTBI- and LTBI+ adults highly exposed to smear-positive PTBI. The most significant independent differences will be used to build a smaller flow cytometry panel that will be used to test the remaining LTBI- and LTBI+ highly TB-exposed adults. AIM 2. To characterize the Mtb-specific iCMI generated by BCG. Hypothesis: Compared with LTBI- individuals highly exposed to TB, BCG administration generates memory-like iCMI to Mtb of lower magnitude and/or restricted to a fraction of the vaccine recipients. We will recruit adults who received BCG and had negligible exposure to TB and compare their Mtb iCMI with that of highly TB-exposed LTBI- adults using the tools described in AIM 1. The results of this study have the potential to shift the paradigm for immune protection against Mtb infection by substituting and/or adding iCMI to aCMI as long term protective responses and, thereby, to revolutionize the field of TB vaccine development. The study will provide added value to C-TRIUMPh by using already collected peripheral blood mononuclear cells (PBMC) to accomplish its immunologic goals. We will also leverage the NIH efforts to develop advanced immunologic capacity at BJMC.

概括 结核病（TB）是一个主要的全球健康问题。巴奇·德·塞莱特（Bacille de Calmette）和瓜恩（BCG），唯一的结核病 预防性疫苗已许可，对肺外结核（超PTB）有效80％，但具有可变 针对PTB的功效，PTB是原发性结核病感染部位。 TB疫苗的开发中有很大的障碍 比BCG生效的是，对TB的免疫保护尚不完全理解。 BCG生成TB- 特定的自适应细胞介导的免疫（ACMI），被认为特别有助于其强 针对外部PTB的保护作用，但不赋予无菌免疫培养基对结核分枝杆菌（MTB）和 不能防止潜在结核病感染（LTBI）。我们假设MTB内存般的先天CMI（ICMI）是 防止原发性MTB感染的保护机制，可防止LTBI。一个重要的推论是TB- 特定的ICMI将为疫苗诱导的无菌保护针对结核病提供强大的测量，这是急需的 开发高效TB疫苗的工具。使用在队列中收集的TB的样品 Indo-US医疗合伙企业多中心前瞻性观察研究（C-Triumph）的研究 Byramjee Jeejeebhoy Govt。印度浦那医学院（BJMC）以及一群BCG收件人 由于在美国招募的TB可以忽略不计，我们将研究TB特异性ICMI作为一种机制 对MTB的无菌保护以及BCG疫苗接种可以引起MTB记忆ICMI的程度。 目的1。确定将LTBI与LTBI+成年人区分开的MTB ICMI特征 涂片阳性PTBI。 假设：高度暴露于TB的LTBI型具有比LTBI+更强大的MTB记忆样ICMI 个人。 使用专为大型数据集设计的技术和系统生物学分析工具，我们将测量 大型NK，NKT，T和粘膜相关的不变t（MAIT）细胞对前体内MTB的反应 抗原刺激并分析LTBI-和LTBI+成年人的子集之间的差异 涂抹阳性PTBI。最重要的独立差异将用于建立较小的流程 细胞仪面板将用于测试其余的LTBI和LTBI+高度TB暴露的成年人。 目的2。表征BCG生成的MTB特异性ICMI。 假设：与高度暴露于结核病的LTBI相比，BCG给药会产生 类似于记忆的ICMI至较低幅度的MTB，并且/或仅限于疫苗接收者的一部分。 我们将招募接受BCG的成年人，并且接触了TB，并将其MTB ICMI与 使用AIM 1中描述的工具，高度暴露于TB的LTBI成年人的ltbi。 这项研究的结果有可能通过通过 在长期保护的响应中替换和/或将ICMI添加到ACMI中，从而彻底改变 结核病疫苗开发领域。该研究将通过使用已经收集的 外周血单核细胞（PBMC）实现其免疫目标。我们还将利用 NIH在BJMC开发先进的免疫能力的努力。