EXPRESSION OF TUBERCULOSIS IN THE LUNG

描述(改编自申请者摘要)：结核分枝杆菌 感染了世界上三分之一的人口，而结核病是导致 单一感染源造成的发病率和死亡率。然而，只有5%-10%的人 无潜在免疫缺陷的结核分枝杆菌感染者 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发。了解保护的关联性 在人类中对抗结核分枝杆菌是需要更好地指导努力 抗结核疫苗的开发。PI表明增加了 携带干扰素-γ受体患者对结核分枝杆菌感染的易感性 I缺乏与干扰素-γ在难治性疾病治疗中的成功应用 分枝杆菌感染提示干扰素-γ在免疫中的重要性 抗分枝杆菌。然而，在前一个资助期内，PI发现 肺结核患者肺组织中的干扰素-γ水平升高。因此， 有人对IFNGamma的效力和/或参与提出了疑问 保护性免疫中的其他因素。在当前的竞争更新中 应用，PI建议定义肺保护性相关因素 几种免疫学指标在结核病患者免疫中的比较 与结核病患者有家庭接触者(皮肤结核试验呈阳性)；以及 社区控制对象。支气管肺泡和血单个核细胞 从每个研究对象获得的信息将被用来表征 抗原特异性细胞因子诱导、杀伤结核分枝杆菌、CTL活性 针对结核分枝杆菌感染目标和参与这些活动的媒介 效应器功能(iNOS、颗粒酶、穿孔素、颗粒溶素、FasL)(特定目标 1)。根据PI，这项工作的第一部分应该确定相关因素 保护性免疫作为保护性免疫反应之间的差异(在 皮肤测试阳性、健康的家庭接触者)和免疫反应失败 (结核病患者)。然后，目标1中确定的保护相关因素应该 被用来评估保护性免疫和趋化因子的诱导 为人类接种卡介苗。疗效不同的两种卡介苗 和反应性，以及两种疫苗接种途径(口服和 皮内)将进行比较(特定目标2)。公安党表示，这是 一项提案试图定义免疫保护的新参数 并理性地评估卡介苗菌株变异和 卡介苗给药途径对保护性免疫的诱导作用。

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.