Environmental mycobacteria and BCG interference

环境分枝杆菌和卡介苗干扰

• 批准号: 8776922
• 负责人: IAN M ORME
• 金额: $ 22.31万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8776922
• 关键词: Animals; Area; Atypical Mycobacteria; BCG Vaccine; CD4 Positive T Lymphocytes; Cells; Data; Event; Exposure to; Failure; Flow Cytometry; Genus Mycobacterium; Health; High Prevalence; Immunity; Immunosuppressive Agents; India; Infection; Injection of therapeutic agent; Interleukin-10; Intravenous; Knock-in Mouse; Knockout Mice; Laboratories; Life; Lung; Masks; Measures; Modeling; Monitor; Mus; Mycobacterium tuberculosis; Necrosis; Paper; Plant Roots; Population; Reaction; Regulatory T-Lymphocyte; Resistance; Staining method; Stains; Students; Subcutaneous Injections; Surface; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tuberculosis; Vaccinated; Vaccination; Vaccines; Virulent; base; cytokine; mouse model; prevent; protective effect; protective efficacy; research study; response; vaccination against tuberculosis; vaccine trial

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.

描述（由申请人提供）：本 R21 申请的目的是测试以下假设：环境分枝杆菌 [EM] 干扰先前 BCG 疫苗接种功效的能力的基础是由于 CD4 T 子集的诱导细胞称为调节性 T 细胞。我们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六个月，然后表明，如果动物随后受到结核分枝杆菌的攻击，抵抗力会被消除或大幅减弱。我们的初步研究现在表明，这可能是由于 EM 诱导调节性 T 细胞的能力所致，因此为了检验这一假设，我们将测量攻击后这些细胞在肺部的积累，耗尽它们，看看这是否会恢复抵抗力，并确定其分泌的细胞因子IL-10是否是干扰的关键依据。最后，我们将在现实条件下测试这一假设，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，因为基于卡介苗的新型疫苗即将在已知存在电磁暴露且存在大量毒力 W-Beijing 菌株的人群中进行测试。