Ag-specific gamma delta T cells and immunity to TB/AIDS-related TB

Ag 特异性 γ δ T 细胞和对结核病/艾滋病相关结核病的免疫力

• 批准号: 8670046
• 负责人: Zheng W Chen
• 金额: $ 55.62万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-03 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670046
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Antibiotics; Antitubercular Agents; Binding; Biological Response Modifiers; CD4 Lymphocyte Count; CD8B1 gene; Cells; Chronic; Communicable Diseases; Data; Depressed mood; Diphosphates; Drug Resistant Tuberculosis; Drug resistance; Effector Cell; Extreme drug resistant tuberculosis; HIV; Human; Immune; Immune response; Immunity; Immunotherapeutic agent; Infection; Interferons; Interleukin-2; Intervention; Lesion; Lung; Macaca; Mediator of activation protein; Morbidity - disease rate; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Pharmaceutical Preparations; Play; Pneumonic Plague; Primates; Regimen; Regulation; Role; Surface; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Tuberculosis; Vaccines; antimicrobial; base; cytokine; granulysin; hydroxy compound; immune function; in vivo; mortality; nonhuman primate; novel; perforin; public health relevance; response; simian human immunodeficiency virus; small molecule; trafficking; tuberculosis immunity

DESCRIPTION (provided by applicant): Project Description Tuberculosis (TB) remains one of the major causes of global mortality/morbidity, and has become increasingly prevalent and deadly as a result of HIV/AIDS and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). Global control of TB appears difficult because of the lack of an effective protective vaccine and lack of sterilizing drugs. Since drug resistance is likely to increase, there is a pressed need to develop effective vaccine or immunotherapeutic. We have recently made serial novel observations suggesting that V?2V¿2 T cells, the dominant ?¿ T-cell subset in humans/primates, play a role in host response and immune regulation, and contribute to anti-microbial immunity against infections including M. tuberculosis (Mtb). Particularly, we elucidate that Mtb phosphoantigen (E)-4- hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) can associate with APC surface molecule, bind to TCR on V?2V¿2 T cells, and activate/expand V?2V¿2 T cells. Importantly, HMBPP plus IL-2 treatment of macaques induces massive expansion of multi-functional V?2V¿2 T effector cells. HMBPP-expanded V?2V¿2 T effector cells can traffic to and accumulate in airway/lung, produce anti-TB cytokines IFN?/perforin/granulysin, confer anti-TB immunity after Mtb infection and even induce homeostatic protection against fulminating pneumonic plague lesions in lungs. Based on these findings, we hypothesize that V?2V¿2 T cells can function as anti-TB effectors, homeostatic mediators and immune regulators enhancing CD4/CD8 T-cell responses, and confer anti-TB immunity in Mtb infection. To test this hypothesis, we will I. Determine mechanisms by which HMBPP-expanded V?2V?2 T effector cells confer anti- TB immunity. II. Determine whether V?2V¿2 T-cell-targeted treatments during chronic Mtb infection can confer immunotherapeutics against severe TB lesions and/or TB cavities. III. Determine if HMBPP/IL-2 expansion of V?2V¿2 T cells can overcome depressed responses of CD4/CD8 T cells and protect against HIV-related TB in SHIV-infected macaques with low CD4 counts.

描述（由申请人提供）： 项目描述 结核病（TB）仍然是全球死亡/发病的主要原因之一，并且由于艾滋病毒/艾滋病以及耐多药结核病（MDR-TB）和广泛耐药结核病（XDR-TB）的出现而变得越来越普遍和致命。由于缺乏有效的保护性疫苗和消毒药物，全球结核病控制似乎很困难。由于耐药性可能会增加，因此迫切需要开发有效的疫苗或免疫疗法。我们最近进行了一系列新的观察，表明 V?2V¿2 T 细胞（人类/灵长类动物中占主导地位的 T 细胞亚群）在宿主反应和免疫调节中发挥作用，并有助于针对包括结核分枝杆菌 (Mtb) 在内的感染的抗微生物免疫。特别是，我们阐明了 Mtb 磷酸抗原 (E)-4-羟基-3-甲基-丁-2-烯基焦磷酸 (HMBPP) 可以与 APC 表面分子结合，与 V?2V¿2 T 细胞上的 TCR 结合，并激活/扩增 V?2V¿2 T 细胞。重要的是，HMBPP 加 IL-2 治疗猕猴可诱导多功能 V?2V?2 T 效应细胞的大规模扩增。 HMBPP 扩增的 V?2V¿2 T 效应细胞可以运输到气道/肺并在其中积聚，产生抗结核细胞因子 IFN?/穿孔素/颗粒溶素，在 Mtb 感染后赋予抗结核免疫力，甚至诱导针对肺部暴发性肺鼠疫病变的稳态保护。基于这些发现，我们假设 V?2V¿2 T 细胞可以作为抗结核效应器、稳态介质和免疫调节剂，增强 CD4/CD8 T 细胞反应，并在 Mtb 感染中赋予抗结核免疫力。为了检验这一假设，我们将 I. 确定 HMBPP 扩增的 V?2V?2 T 效应细胞赋予抗结核免疫的机制。二.确定慢性 Mtb 感染期间的 V?2V¿2 T 细胞靶向治疗是否可以针对严重结核病灶和/或结核病空洞提供免疫治疗。三．确定 V?2V¿2 T 细胞的 HMBPP/IL-2 扩增是否可以克服 CD4/CD8 T 细胞的抑制反应，并在 CD4 计数低的 SHIV 感染猕猴中预防 HIV 相关结核。