Alveolar macrophage and mycobacteria

肺泡巨噬细胞和分枝杆菌

• 批准号: 6803128
• 负责人: William J Martin
• 金额: $ 34.54万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-22 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803128
• 关键词: Mycobacterium avium; Mycobacterium tuberculosis; alveolar macrophages; bactericidal immunity; gene therapy; host organism interaction; immunodeficiency; interferon gamma; laboratory mouse; leukocyte activation /transformation; nonhuman therapy evaluation; respiratory infections; tuberculosis; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Profound immunosuppression as occurs in HIV-infected subjects is frequently associated with complicating mycobacterial infections. Mycobacterium tuberculosis is a worldwide pathogen and is a major cause of morbidity and mortality in both normal and immunosuppressed subjects. Non-tuberculous mycobacteria such as M. avium can be opportunistic infections that infect immunosuppressed individuals or subjects with underlying disorders such as pulmonary silicosis. Regardless of whether mycobacteria are acting as pathogens or opportunistic infectious organisms, mycobacteria in the lung first infect alveolar macrophages (AMs), the resident inflammatory cell of the alveolar spaces. AMs must be primed and activated by cytokines such as IFN-gamma or TNF-alpha to maximally respond to infectious organisms such as mycobacteria. Although it is recognized that AMs are central to the pathogenesis of mycobacterial disease, there are few studies that have examined the role of AMs in vivo in response to mycobacterial infection. We have developed a novel approach to "reconstitute" normal and activated AMs into the lungs of immunodeficient animals. We will use this new approach to test the hypothesis Deficiencies in the response of AMs to mycobacteria such as MAC or M. tuberculosis permit initial lung infection and subsequent dissemination during immunosuppression; conversely, correction of these AM deficiencies will restore alveolar immunity, control lung infection and prevent dissemination. We will examine the underlying mechanisms by which AMs respond in vivo to mycobacterial infection and will then use a variety of strategies to activate AMs for reconstitution to see if alveolar host defense is restored and infection eradicated. This will also test whether AMs activated by pro-inflammatory cytokines such as IFN-gamma mediate alveolar host defense to mycobacteria by AM-derived TNF-alpha. These Specific Aims include: 1) to determine the mechanisms by which normal AMs reconstituted into the lungs of immunodeficient mice restore alveolar host defense to mycobacteria and prevent dissemination, 2) to determine if proinflammatory cytokines such as IFN-gamma are essential for alveolar host defense to mycobacteria and to prevent dissemination, 3) to determine if ex vivo gene therapy to reconstituted macrophages results in persistent overexpression of pro-inflammatory cytokines such as IFN-gamma in vivo and improves alveolar host defenses to mycobacteria and prevents dissemination, and 4) to determine if the effects of pro-inflammatory cytokines such as IFN-? on alveolar host defenses to mycobacteria are mediated by AM-derived TNF-alpha. This proposal will test hypotheses in vivo not possible by other means and will determine whether reconstitution of normal or activated AMs is sufficient to restore alveolar host defense to mycobacterial disease despite the presence of ongoing systemic immunosuppression.

描述（由申请人提供）：在感染HIV感染的受试者中发生的深刻免疫抑制与分枝杆菌感染复杂化有关。结核分枝杆菌是一种全球病原体，是正常和免疫抑制受试者发病率和死亡率的主要原因。诸如鸟杆菌等无结核分枝杆菌可能是机会性感染，可感染免疫抑制的个体或患有肺病等潜在疾病的受试者。不管分枝杆菌是病原体还是机会性传染性生物，肺首次感染肺泡巨噬细胞（AMS），肺泡空间的炎性细胞。 AMS必须由IFN-Gamma或TNF-Alpha等细胞因子启动和激活，以最大程度地反应感染性生物，例如分枝杆菌。尽管人们认识到AMS对于分枝杆菌疾病的发病机理是核心，但很少有研究检查了AMS在体内对分枝杆菌感染的作用。我们已经开发了一种新颖的方法来“重建”正常的AM和激活的AM中的免疫缺陷动物的肺。我们将使用这种新方法来测试AMS对分枝杆菌的反应中的假设缺陷，例如MAC或M.结核病。允许在免疫抑制期间初始肺部感染以及随后的传播；相反，对这些AM缺陷的校正将恢复肺泡免疫，控制肺部感染并防止传播。我们将研究AMS在体内对分枝杆菌感染的反应的潜在机制，然后使用多种策略激活AMS以重新建立，以查看是否恢复了肺泡宿主防御，并消除了感染。这还将测试AMS是否被促炎性细胞因子（例如IFN-gamma）介导肺泡宿主防御的AM衍生TNF-Alpha介导肺泡宿主防御。 These Specific Aims include: 1) to determine the mechanisms by which normal AMs reconstituted into the lungs of immunodeficient mice restore alveolar host defense to mycobacteria and prevent dissemination, 2) to determine if proinflammatory cytokines such as IFN-gamma are essential for alveolar host defense to mycobacteria and to prevent dissemination, 3) to determine if ex vivo gene therapy to reconstituted巨噬细胞导致促炎性细胞因子（例如IFN-gamma in vivo）的持续过表达，并改善了肺泡宿主防御性分枝杆菌并防止传播，以及4），以确定促炎细胞因子（例如IFN-）的影响？在肺泡的宿主防御上，分枝杆菌是由AM衍生的TNF-Alpha介导的。该建议将通过其他方式在体内检验假设，并确定正常或激活的AMS是否足以恢复肺泡宿主防御分生不清，尽管存在持续的系统性免疫抑制。