Mycobacteria interactions and vaccine efficacy

描述（由申请人提供）： 接触“非典型”或“环境”分枝杆菌 [EM] 被认为是导致世界许多地区 BCG 疫苗抗结核病功效降低的主要机制。然而迄今为止，EM 干扰疫苗接种后保护性免疫发展的确切机制仍然未知。据推测，持续暴露于交叉反应抗原可以将特定细胞隔离在体内的其他部位，或者针对环境分枝杆菌产生的免疫反应足以在卡介苗获得保护作用之前控制卡介苗。然而，文献中记录的研究使用了几种不同的暴露方案，使得结果的解释非常困难。该应用程序旨在使用标准化暴露协议进行分析研究。我们建议在卡介苗接种前（以确定环境暴露是否干扰疫苗免疫力的产生）或卡介苗接种后（以确定环境暴露是否影响卡介苗的长期功效）施用环境分枝杆菌。在整个研究过程中，我们将从引流淋巴结和肺部分离免疫细胞，并确定细胞是否在环境暴露部位被隔离，对分枝杆菌抗原反应高度激活，或从淋巴细胞池中删除。使用这些方法，我们的目的是确定 EM 和 BCG 之间微生物相互作用的基础，这种相互作用是疫苗无法预防结核分枝杆菌感染的原因。此外，我们建议进行初步蛋白质组学研究，以确定 EM 中不存在的结核分枝杆菌关键抗原，这些抗原可以纳入亚单位疫苗中。

DESCRIPTION (provided by applicant): Exposure to "atypical" or "environmental" mycobacteria [EM] is believed to be the primary mechanism thought to be responsible for the reduced efficacy of the BCG vaccine against tuberculosis in many parts of the world. To date however, the exact mechanism by which EM interfere with the development of protective immunity in response to vaccination still remains unknown. It has been hypothesized that constant exposure to cross-reactive antigens can sequester specific cells at alternative sites in the body, or that the immune response generated against environmental mycobacteria is strong enough to control BCG before its protective effect can be acquired. The studies documented in the literature however have used several different exposure protocols making interpretation of the results very difficult. This application seeks to carry out an analytical study using standardized exposure protocols. We propose to administer environmental mycobacteria either before BCG vaccination (to determine whether environmental exposure interferes with the generation of immunity against the vaccine) or following BCG vaccination (to determine whether environmental exposure influences the long-term efficacy of BCG). Throughout the study we will isolate immune cells from the draining lymph nodes and lungs and determine whether cells become sequestered at the site of environmental exposure, become highly activated in response to mycobacterial antigens, or become deleted from the lymphocyte pool. Using these methods we aim to determine the basis of the microbial interactions between EM and BCG that underlies the failure of the vaccine to protect against infection with M. tuberculosis. In addition, we propose to carry out a preliminary proteomics study to identify key antigens from M. tuberculosis that are absent from EM that could be incorporated into a sub-unit vaccine.