EXPRESSION OF TUBERCULOSIS IN THE LUNG

描述（改编自申请人摘要）：结核分枝杆菌 感染了世界上三分之一的人口，结核病是导致 发病率和死亡率由于单一的传染媒介。然而，只有5-10%的 M.无潜在免疫缺陷的结核感染受试者 在他们的一生中患上疾病。因此，保护性免疫是 在大多数受试者中诱导。了解保护的相关因素 分支杆菌需要更好地指导人类结核病的努力， 开发抗结核疫苗。PI表示， 对M. IFN γ受体阳性患者结核感染 I缺乏和IFN γ在难治性 分枝杆菌感染表明IFN γ在免疫中的重要性 对抗分枝杆菌然而，在上一个资助期间，PI发现 肺结核患者肺部IFN γ水平升高。因此 提出了关于IFN γ的有效性和/或 保护性免疫的其他因素。在目前的竞争性更新中 应用中，PI建议定义肺相关的保护性 通过比较结核病患者、健康人和健康人的几种免疫学参数， 结核病患者的家庭接触者（结核菌素皮肤试验阳性），以及 社区对照组。支气管肺泡和血液单核细胞 将使用从每例研究受试者获得的数据来表征 抗原特异性细胞因子诱导、M.结核病，CTL活性 分支杆菌结核感染的目标和介质参与这些 效应子功能（iNOS、颗粒酶、穿孔素、颗粒溶素、FasL）（特异性目的 1）。根据PI的说法，第一部分工作应确定相关因素 保护性免疫反应之间的差异（在 皮肤测试呈阳性，健康的家庭接触者）和免疫反应失败 （肺结核患者）。目标1中确定的保护相关因素应 用于评估通过以下方式诱导保护性免疫和趋化因子表达： 人类接种卡介苗。两种不同功效的卡介苗 和反应原性，以及两种疫苗给药途径（口服和 皮内）进行比较（具体目标2）。PI指出， 一项提案试图定义免疫保护的新参数， 并合理评估BCG菌株变异的影响， BCG给药途径对诱导保护性免疫的影响。

DESCRIPTION (Adapted from the Applicant's Abstract): Mycobacterium tuberculosis infects a third of the worlds' population and TB is the leading cause of morbidity and mortality due a single infectious agent. However, only 5-10% of M. tuberculosis-infected subjects without an underlying immunodeficiency develop disease during their lifetimes. Therefore protective immunity is induced in the majority of subjects. Understanding correlates of protection against M. tuberculosis in humans is needed to better direct efforts in the development of antituberculosis vaccines. The PI suggests that increased susceptibility to M. tuberculosis infection by patients with IFNgamma receptor I deficiency and successful therapeutic use of IFNgamma in refractory mycobacterial infections indicates the importance of IFNgamma in immunity against mycobacteria. However, during the previous funding period the PI found increased levels of IFNgamma in the lungs of patients with TB. Thus, the question is raised as to the effectiveness of IFNgamma and/or involvement of other factors in protective immunity. In the present competitive renewal application, the PI proposes to define pulmonary correlates of protective immunity by comparing several immunological parameters in TB patients, healthy household contacts of TB patients (tuberculin skin test positive), and community control subjects. Bronchoalveolar and blood mononuclear cells obtained from each study subject will be utilized to characterize antigen-specific cytokine induction, killing of M. tuberculosis, CTL activity against M. tuberculosis-infected targets and mediators involved in these effector functions (iNOS, granzyme, perforin, granulysin, FasL) (specific aim 1). According to the PI, this first part of the work should identify correlates of protective immunity as differences between protective immune responses (in skin-test-positive, healthy household contacts) and failed immune responses (patients with TB). Correlates of protection identified in aim #1 should then be used to assess induction of protective immunity and chemokine expression by vaccination of humans with BCG. Two strains of BCG having different efficacy and reactogenicity, and two routes of vaccine administration (oral and intracutaneous) will be compared (specific aim 2). The PI states that this proposal attempts to define new parameters of immunological protection in humans and to rationally assess the impact of BCG strain variation and the route of BCG administration on the induction of protective immunity.