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资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。结核病是一个巨大的国际公共卫生问题，并且仍然是世界范围内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）是导致结核病的细菌，通过吸入雾化液滴传播。我们建议利用支气管镜节段性抗原激发技术，以引起肺结核蛋白抗原的免疫反应。这项技术包括将支气管镜楔入特定的段支气管，以局部滴注稀释的抗原。在允许足够的时间来发展免疫应答后，重复进行支气管镜检查，灌洗抗原激发的肺段和对照肺段。我们将使用标准皮试试剂结核菌素（也称为结核分枝杆菌纯化蛋白衍生物或PPD）作为抗原。我们假设，结核分枝杆菌抗原的保护性回忆反应，可以引起个人PPD阳性，因为以前的气溶胶暴露于结核分枝杆菌，这种反应是定量和定性的不同，从未暴露的个人谁已经接种了卡介苗。我们将通过以下具体目的来研究这一假说：1）确定结核分枝杆菌特异性淋巴细胞是否可以通过用结核分枝杆菌纯化蛋白衍生物进行肺段性激发而募集到肺中; 2）在细胞类型、细胞因子产生、细胞毒性能力方面表征响应于PPD攻击的细胞浸润到肺泡段中，以及用人单核吞噬细胞介导杀死细胞内结核分枝杆菌的能力; 3）比较呼吸道暴露于结核分枝杆菌的个体和未暴露的BCG疫苗接种受试者对节段性PPD激发的局部肺回忆反应。我们的人体研究将包括PPD阳性受试者的肺段性激发，这些受试者有明确的结核分枝杆菌暴露史或卡介苗接种史。抗原激发的设计改编自哮喘受试者的研究。受试者为年龄18-50岁的非吸烟者，无哮喘或其他慢性呼吸道疾病史。PPD皮试反应史大于30 mm硬结、PPD试验反应有局部溃疡史或皮试反应有全身症状史（如发热、寒战和肌痛）的个体将从研究中排除。我们将进行初始支气管镜检查以灌输PPD，并在48小时后重复该程序。在初始支气管镜检查中，将用温热无菌盐水稀释的PPD滴入左肺的舌支气管，并将相同体积的盐水单独滴入右中叶支气管。不进行支气管肺泡灌洗。PPD激发后48小时进行的第二次支气管镜检查将包括激发和对照节段的支气管肺泡灌洗。在一些研究中，还将获得血液样本，以允许通过与未分选的血液淋巴细胞的反应进行比较来确定PPD引起的肺免疫反应的特异性。初步研究旨在确定诱导淋巴细胞流入激发支气管段所需的PPD最小剂量。