Diesel Exhaust Particle Effects on Human Immunity to Mycobacterium tuberculosis

柴油机尾气颗粒对人体结核分枝杆菌免疫的影响

• 批准号: 7512585
• 负责人: STEPHAN K SCHWANDER
• 金额: $ 23.4万
• 依托单位: UNIV OF MED/DENT NJ-SCH OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7512585
• 关键词: 6-carboxyfluorescein diacetate; Acute; Address; Affect; Air Pollutants; Air Pollution; Antigens; Antimycobacterial Agents; Bacteria; Biological; Biological Models; Blood; Blood Cells; Blood specimen; Breathing; Cell Proliferation; Cell model; Cells; Cities; Clinical; Colony-Forming Units Assay; Condition; Data; Diesel Exhaust; Disease; Dose; Effector Cell; Endotoxins; Epithelial Cells; Esters; Exposure to; Gene Expression; Grant; Growth; Health; Hour; Human; Human body; Immune; Immune response; Immunity; In Vitro; Industry; Infection; Inhalation Exposure; Interferon Type II; Interleukin-10; Interleukin-6; Interleukins; Kinetics; Lipopolysaccharides; Listeria monocytogenes; Lung; Mediating; Memory; Mining; Modeling; Molecular; Monokines; Morbidity - disease rate; Mycobacterium tuberculosis; Occupational Exposure; Particulate; Particulate Matter; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Persons; Phagocytes; Population; Predisposition; Production; Public Health; Receptor Gene; Receptor Signaling; Regulation; Respiration; Respiratory Tract Infections; Respiratory physiology; Rodent; Signal Pathway; Signaling Pathway Gene; Stimulus; Study Subject; System; T-Lymphocyte; Time; Toll-Like Receptor Pathway; Toll-like receptors; Translating; Tuberculosis; Tumor Necrosis Factor-alpha; Virus; Vulnerable Populations; Whole Blood; cytokine; dosage; enzyme linked immunospot assay; healthy volunteer; human TNF protein; in vivo; killings; macrophage; monocyte; mortality; mycobacterial; novel; particle; particle exposure; pathogen; peripheral blood; pollutant; receptor expression; research study; response; size; transmission process; uptake; 6-carboxyfluorescein diacetate; Acute; Address; Affect; Air Pollutants; Air Pollution; Antigens; Antimycobacterial Agents; Bacteria; Biological; Biological Models; Blood; Blood Cells; Blood specimen; Breathing; Cell Proliferation; Cell model; Cells; Cities; Clinical; Colony-Forming Units Assay; Condition; Data; Diesel Exhaust; Disease; Dose; Effector Cell; Endotoxins; Epithelial Cells; Esters; Exposure to; Gene Expression; Grant; Growth; Health; Hour; Human; Human body; Immune; Immune response; Immunity; In Vitro; Industry; Infection; Inhalation Exposure; Interferon Type II; Interleukin-10; Interleukin-6; Interleukins; Kinetics; Lipopolysaccharides; Listeria monocytogenes; Lung; Mediating; Memory; Mining; Modeling; Molecular; Monokines; Morbidity - disease rate; Mycobacterium tuberculosis; Occupational Exposure; Particulate; Particulate Matter; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Persons; Phagocytes; Population; Predisposition; Production; Public Health; Receptor Gene; Receptor Signaling; Regulation; Respiration; Respiratory Tract Infections; Respiratory physiology; Rodent; Signal Pathway; Signaling Pathway Gene; Stimulus; Study Subject; System; T-Lymphocyte; Time; Toll-Like Receptor Pathway; Toll-like receptors; Translating; Tuberculosis; Tumor Necrosis Factor-alpha; Virus; Vulnerable Populations; Whole Blood; cytokine; dosage; enzyme linked immunospot assay; healthy volunteer; human TNF protein; in vivo; killings; macrophage; monocyte; mortality; mycobacterial; novel; particle; particle exposure; pathogen; peripheral blood; pollutant; receptor expression; research study; response; size; transmission process; uptake

DESCRIPTION (provided by applicant): Air pollution and tuberculosis (TB) each present major challenges to public health and specifically to lung health globally. This grant will address the pressing question of whether air pollutants can acutely alter human antimycobacterial immunity. [PARAGRAPH] Urban air pollution, contributes substantially to morbidity and mortality worldwide. Diesel Exhaust Particles (DEP) from diesel engines are generated by various industries, contribute to 40% of particulate respirable matter in big cities and accumulate in underground mines. DEP represent an important model pollutant for the study of biological and health effects of respirable particulate matter (PM). [PARAGRAPH] There is mounting evidence that DEP (PM) alters the function of respiratory immune cells and increases susceptibility to infectious pathogens such as viruses and bacteria. Experimental aerogenic infections with intracellular bacteria such as Mycobacterium tuberculosis (M.tb), Bacille Calmette Guirin (BCG) or Listeria monocytogenes result in increased pulmonary bacterial burden in rodents exposed to DEP. [PARAGRAPH] We have novel preliminary data that indicate that human blood phagocytes take up both M.tb and DEP. During simultaneous addition of DEP and M.tb, M.tb-induced cytokine production from peripheral blood cells is altered (IFN-gamma, TNF-alpha, IL-6 decreased, IL-10 increased) in a DEP dose-dependent manner. Exposure to DEP 20 hours before M.tb infection abrogated M.tb induced IL-6 and IL-10 production, perhaps indicating a DEP-induced state of cellular unresponsiveness/tolerance to subsequent stimuli, similar to endotoxin tolerance. Our unique preliminary studies in healthy volunteers after DEP inhalation exposure show increased M.tb-induced IFN-gamma, and decreased M.tb-induced IL-6 and IL-10 release. Both DEP in vitro addition and in vivo exposure studies indicate that DEP decreases the capacity of blood cells to control M.tb growth in vitro. [PARAGRAPH] The proposed studies in this grant differ from previous DEP (PM) effect studies in several important ways. DEP effects will be studied (1) on immunity to a pathogen of overriding public health importance (M.tb), (2) in humans with and without pathogen (M.tb)-specific memory immunity, and (3) in in vitro and in vivo DEP-exposed primary human blood cells. We propose to expand our studies of dose and time kinetic effects of DEP exposure. Changes in antigen-specific cytokine production, M.tb-induced cell proliferation, growth control of M.tb and Th1 and Th2 as well as toll like receptor (TLR) gene expression and their signaling pathways will be assessed. [PARAGRAPH] We hypothesize that the combined effects of PM (DEP) and M.tb on the human host may alter antimycobacterial immune responses thus increasing susceptibility to M.tb infection and TB disease with potentially important public health effects on a population level. PUBLIC HEALTH RELEVANCE: Air pollution and tuberculosis (TB) present public health challenges to lung health on a global scale. This grant will address whether air pollutants can severely alter the human bodily defenses against tuberculosis. We will investigate how the combination of diesel exhaust particles and tuberculosis on the human body affect human immune response thus increasing vulnerability to tuberculosis infection and TB disease which may impact on the public health on a population level.

描述（由申请人提供）：空气污染和结核病（TB）每个都面临着公共卫生，特别是全球肺部健康的主要挑战。这项赠款将解决空气污染物是否可以急性改变人类抗菌抗菌免疫的紧迫问题。 [段落]城市空气污染，在全球范围内促进了发病率和死亡率。柴油发动机的柴油排气颗粒（DEP）是由各种行业产生的，在大城市中占40％的可颗粒物可吸收物质，并在地下矿山中积聚。 DEP代表了研究可呼吸颗粒物（PM）的生物学和健康影响的重要模型污染物。 [段落]有越来越多的证据表明，DEP（PM）改变了呼吸免疫细胞的功能，并增加了对感染性病原体（例如病毒和细菌）的敏感性。用细胞内细菌（如结核分枝杆菌（M.TB），Bacille Calmette Guirin（BCG）或单核细胞增生李斯特菌的实验性充气感染，导致暴露于DEP的啮齿动物的肺部细菌负担增加。 [段落]我们有新的初步数据，表明人类血液吞噬细胞同时占M.TB和DEP。在同时添加DEP和M.TB期间，M.TB诱导的外周血细胞的细胞因子产生（IFN-GAMMA，TNF-ALPHA，IL-6，IL-6降低，IL-10降低，IL-10增加），以DEP剂量依赖性方式改变。在M.TB感染之前20小时接触DEP，废除了M.TB诱导的IL-6和IL-10产生，可能表明与内毒素耐受性类似，对随后的刺激的细胞无反应/耐受性具有DEP诱导的状态。 DEP吸入暴露后，我们对健康志愿者的独特初步研究表明，M.TB诱导的IFN-GAMMA增加，并降低了M.TB诱导的IL-6和IL-10释放。 DEP在体外添加和体内暴露研究都表明，DEP降低了血液细胞在体外控制M.TB生长的能力。 [段落]该赠款中提出的研究与以前的DEP（PM）效应研究不同。将研究（1）对患有和没有病原体（M.TB）特异性记忆免疫的人类对公共卫生重要性（M.TB）的病原体的免疫力（M.TB），以及（3）在体外和体内受感染的原发性人体血细胞中。我们建议扩大对DEP暴露的剂量和时间动力学作用的研究。将评估抗原特异性细胞因子产生，M.TB诱导的细胞增殖，M.TB和TH1和TH2的生长控制以及收费受体（TLR）基因表达及其信号传导途径。 [段落]我们假设PM（DEP）和M.TB对人宿主的综合作用可能会改变抗霉菌的免疫反应，从而增加对M.TB感染和TB疾病的易感性，并可能对人群水平产生潜在的公共健康影响。公共卫生相关性：空气污染与结核病（TB）在全球范围内提出了对肺部健康的公共卫生挑战。该赠款将解决空气污染物是否可以严重改变人体防御性结核病。我们将研究柴油排气颗粒和结核病对人体的结合如何影响人类的免疫反应，从而增加对结核病感染和结核病疾病的脆弱性，这可能会影响人口水平的公共卫生。