EXPRESSION OF MTB ANTIGENS BY INFECTED MACROPHAGES

结核病是世界上导致死亡的主要原因， 单一的传染源肺结核的发病率正在上升 对传统抗生素耐药的菌株 治疗方法已经出现。虽然接种卡介苗菌株， 牛分枝杆菌可能有助于降低 儿童结核病，这种疫苗接种提供很少，如果有的话， 保护成年人。制定替代战略来对抗 结核病的过程中，更好地了解的机制， 发病机制和对结核分枝杆菌（M. 结核病）是必需的.特别是M. TB.衍生 由受感染的巨噬细胞表达的抗原， 因此，需要新的和改进的疫苗， 上调T细胞对M的应答。结核病，可以被开发。一些 以前的研究集中在II类限制性反应介导的 CD 4 + T细胞对M. TB.抗原具有 如果有的话，也很糟糕。小鼠模型中的最新证据 分枝TB.感染表明l类限制性反应介导了 通过CD 8 + T细胞的免疫可能是重要的保护性免疫。研究 将确定是否有任何蛋白质 由M. TB.当在培养物中生长时，有助于抗原性 M.感染的巨噬细胞上I类分子的表位。TB.在 此外，无论含有N-甲酰基-甲硫氨酸的肽是否结合到 较少多态性的Ib类分子和引发的反应性T细胞将 测定证据表明，M。TB.肽表位可以通过 来自许多个体的lb类分子可能提供 有价值的候选人M。TB.疫苗。 实验方法包括体外再刺激T细胞， 来自感染M. TB.和 测定I类限制性，M. TB.特异性反应性 小鼠T 对特定M具有确定特异性的细胞克隆。TB.蛋白将 检测它们赋予过继免疫的保护性免疫力的能力， 转移到用雾化M. TB.分离 I类限制性M. TB.反应性T细胞不仅能识别 T细胞疫苗的潜在候选者，但也将促进 分析了M. TB.来自 不同的组织位置和暴露于不同的细胞因子。

Tuberculosis is the leading cause of death in the world attributable to a single infectious agent. The incidence of tuberculosis is increasing in the United States and strains resistant to conventional antibiotic therapy(s) have emerged. Although vaccination with the BCG strain of Mycobacterium bovis may be beneficial in lowering the incidence of tuberculosis in children, such vaccination provides little, if any, protection for adults. To develop alternate strategies to combat the course of tuberculosis, a better understanding of the mechanisms of pathogenesis and the immune response to Mycobacterium tuberculosis (M. tb.) is required. In particular, identification of the M. tb. derived antigens that are expressed by infected macrophages and elicit T cell responses is required so that new and improved vaccines, designed to upregulate the T cell response to M. tb., can be developed. A number of previous studies have focused on class II restricted responses mediated by CD4+ T cells and the response of CD8+ T cells to M. tb. antigens has been poorly, if at all, characterized. Recent evidence in the mouse model of M. tb. infection suggests that class l restricted responses mediated by CD8+ T cells may be important for protective immunity. The studies described in this proposal will establish whether any of the proteins secreted from M. tb. when grown in culture, contribute to antigenic epitopes in class I molecules on macrophages infected with M. tb. In addition, whether N-formyl-Methionine containing peptides bind to the less polymorphic class lb molecules and elicit reactive T cells will be determined. Evidence that M. tb. peptide epitopes could be presented by class lb molecules from many individuals would provide potentially valuable candidates for M. tb. vaccines. The experimental approach will involve the in vitro restimulation of T cells from both human patients, as well as mice, infected with M. tb. and assayed for class l restricted, M. tb. specific, reactivity. Murine T cell clones with defined specificity for a particular M. tb. protein will be assayed for their ability to confer protective immunity upon adoptive transfer to mice challenged with aerosolized M. tb. The isolation of class I restricted M. tb. reactive T cells will not only identify potential candidates for T cell vaccines, but will also facilitate an analysis of the processing of M. tb. antigens in macrophages from different tissue locations and following exposure to different cytokines.