VACCINATION AGAINST MYCOBACTERIUM TUBERCULOSIS

结核分枝杆菌疫苗接种

• 批准号: 7378038
• 负责人: RICHARD F SILVER
• 金额: $ 1.76万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378038
• 关键词: VACCINATION; AGAINST; MYCOBACTERIUM; TUBERCULOSIS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tuberculosis is an international public health problem of enormous magnitude and remains the number one cause of death from an infectious disease world-wide. Tuberculosis is primarily a respiratory disease, and Mycobacterium tuberculosis (M.tb), the bacteria which causes tuberculosis, is spread via the inhalation of aerosolized droplets. We propose to utilize the technique of bronchoscopic segmental antigen challenge to elicit pulmonary immune responses to protein antigens of M.tb. This technique involves wedging the bronchoscope into specific segmental bronchi to locally instill diluted antigens. After allowing sufficient time for an immune response to develop, repeat bronchoscopy is performed with lavage of antigen-challenged and control lung segments. We will utilize the standard skin test reagent tuberculin (also known as purified protein derivative of M.tb, or PPD) as the antigen. We hypothesize that a protective recall response to antigens of M.tb can be elicited in individuals who are PPD-positive because of previous aerosol exposure to M.tb, and that this response is both quantitatively and qualitatively different from that of non-exposed individuals who have been vaccinated with BCG. We will investigate this hypothesis using the following specific aims: 1) To determine whether M.tb-specific lymphocytes can be recruited to the lung by segmental pulmonary challenge with purified protein derivative of M.tb; 2) To characterize the cellular infiltrate into alveolar segments in response to PPD challenge in terms of cell type, cytokine production, cytotoxic capacity, and ability to mediate killing of intracellular M.tb with human mononuclear phagocytes; 3) To compare the local pulmonary recall response to segmental PPD challenge in individuals with respiratory exposure to M.tb and in unexposed BCG-vaccinated subjects. Our human studies will consist of segmental pulmonary challenge of PPD-positive subjects with a history of clear exposure to M.tb or of BCG vaccination. Design of antigen challenge is adapted from studies of asthmatic subjects. Subjects will be nonsmokers age 18-50 who have no history of asthma or other chronic respiratory disease. Individuals with a history of PPD skin test response greater than 30 mm of induration, with a history of local ulceration in response to PPD testing, or with a history of systemic symptoms (such as fever, chills, and myalgias) in response to skin testing will be excluded from the study. We will perform an initial bronchoscopy to instill PPD, and a repeat procedure 48 hours later. In the initial bronchoscopy, PPD diluted in warmed sterile saline will be instilled into the lingular bronchus of the left lung, and the same volume of saline alone will be instilled into the right middle lobe bronchus. No bronchoalveolar lavage will be performed. The second bronchoscopy, performed 48 hours after the PPD challenge, will consist of the performance of bronchoalveolar lavage of both the challenge and control segments. In some studies, blood samples will also be obtained to allow for determination of the specificity of the pulmonary immune response elicited PPD by comparison to responses of unsorted blood lymphocytes. Initial studies will be aimed at determining the minimal dose of PPD needed to induce influx of lymphocytes into the challenged bronchial segment.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。结核病是一个严重的国际公共卫生问题，并且仍然是全世界传染病死亡的头号原因。结核病主要是一种呼吸道疾病，结核分枝杆菌（M.tb）是引起结核病的细菌，通过吸入雾化液滴传播。我们建议利用支气管镜节段抗原激发技术来引发针对结核分枝杆菌蛋白抗原的肺部免疫反应。该技术涉及将支气管镜楔入特定的节段支气管以局部滴注稀释的抗原。在有足够的时间让免疫反应发生后，重复支气管镜检查，并对抗原激发的肺段和对照肺段进行灌洗。我们将使用标准皮试试剂结核菌素（也称为 M.tb 的纯化蛋白衍生物，或 PPD）作为抗原。我们假设，由于之前接触过 M.tb 的气溶胶，PPD 阳性的个体可以引发对 M.tb 抗原的保护性回忆反应，并且这种反应在数量和质量上都与未接触过 M.tb 的个体不同。已接种卡介苗疫苗的人。我们将使用以下具体目标来研究这一假设： 1) 确定 M.tb 特异性淋巴细胞是否可以通过用 M.tb 的纯化蛋白衍生物进行分段肺部攻击而招募到肺部； 2) 从细胞类型、细胞因子产生、细胞毒性能力以及介导人单核吞噬细胞杀死细胞内 M.tb 的能力等方面来表征响应 PPD 攻击而进入肺泡节段的细胞浸润； 3) 比较呼吸道暴露于 M.tb 的个体和未接种 BCG 疫苗的受试者对节段性 PPD 挑战的局部肺部回忆反应。我们的人体研究将包括对有明确结核分枝杆菌暴露史或卡介苗接种史的 PPD 阳性受试者进行分段肺部攻击。抗原激发的设计改编自哮喘受试者的研究。受试者为 18-50 岁的不吸烟者，无哮喘或其他慢性呼吸道疾病史。有 PPD 皮试反应史、硬结超过 30 毫米、有 PPD 测试反应史的个体、或有皮试反应史的全身症状（如发热、寒战和肌痛）的个体将被排除在研究之外。我们将进行初始支气管镜检查以灌输 PPD，并在 48 小时后重复手术。初次支气管镜检查时，将用温热无菌生理盐水稀释的PPD滴入左肺舌支气管，将等体积的生理盐水单独滴入右中叶支气管。不会进行支气管肺泡灌洗。第二次支气管镜检查在 PPD 激发后 48 小时进行，包括对激发段和对照段进行支气管肺泡灌洗。在一些研究中，还将获得血液样本，以便通过与未分选的血液淋巴细胞的反应进行比较来确定 PPD 引发的肺部免疫反应的特异性。初步研究旨在确定诱导淋巴细胞流入受攻击支气管段所需的 PPD 最小剂量。