Environmental mycobacteria and BCG interference

描述（由申请人提供）：本R21申请的目的是验证以下假设，即环境分枝杆菌[EM]干扰先前卡介苗接种效果的能力的基础是由于诱导CD4 T细胞亚群称为调节性T细胞。我们已经建立了一种高度可重复的模型，在该模型中，小鼠接种卡介苗，然后暴露于死亡的M.avium 6个月，然后表明，如果动物随后受到M.tuberculosis的攻击，抗性会被消除或大大减少。我们现在的初步研究表明，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，我们将测量这些细胞在挑战后在肺部的积累，消耗它们以查看这是否恢复抵抗力，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验证这一假设，用新出现的W-Beijing菌株挑战小鼠，这些菌株本身就是调节性T细胞的有效诱导剂。这些研究具有重要的实践基础，因为新的卡介苗疫苗即将在已知存在EM暴露的人群中进行测试，并且有毒的W-Beijing菌株大量存在。

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.