Environmental mycobacteria and BCG interference

描述（由申请方提供）：本R21申请的目的是检验以下假设：环境分枝杆菌[EM]干扰既往BCG疫苗接种有效性的能力的基础是诱导称为调节性T细胞的CD 4 T细胞亚群。我们已经建立了一个高度可重复的模型，其中小鼠接种卡介苗，然后暴露于死亡的鸟分枝杆菌6个月，然后已经表明，如果动物然后用结核分枝杆菌攻击，则抵抗力被消除或基本上减弱。我们的初步研究现在表明，这可能是由于EM诱导调节性T细胞的能力，因此为了验证这一假设，我们将在挑战后测量这些细胞在肺中的积累，耗尽它们以观察这是否恢复抵抗力，并确定它们分泌的细胞因子IL-10是否是干扰的关键基础。最后，我们将在现实条件下测试这一假设，通过用新出现的W-北京菌株挑战小鼠，这些菌株本身是调节性T细胞的强效诱导剂。这些研究具有重要的实践基础，因为新的基于BCG的疫苗即将在已知存在EM暴露的人群中进行测试，并且那里有大量的毒力W-北京菌株。

DESCRIPTION (provided by applicant): The purpose of this R21 application is to test the hypothesis that the basis of the capacity of environmental mycobacteria [EM] to interfere with the efficacy of prior BCG vaccination is due to the induction of a subset of CD4 T cells called regulatory T cells. We have established a highly reproducible model in which mice are vaccinated with BCG, then exposed for six months to dead M.avium, then have shown that resistance is ablated or substantially diminished if the animal is then challenged with M.tuberculosis. Our preliminary studies now suggest that this may be due to the capacity of the EM to induce regulatory T cells, and so to test this hypothesis we will measure the accumulation of these cells in the lungs after challenge, deplete them to see if this restores resistance, and determine if their secretion of the cytokine IL-10 is the key basis of interference. Finally, we wil test this hypothesis under realistic conditions, by challenging mice with new emerging W-Beijing strains that are themselves potent inducers of regulatory T cells. These studies have an important practical basis, given that new BCG based vaccines are about to be tested in people in which EM exposure is known to exist, and where virulent W-Beijing strains abound.