Pro-Apoptotic Tuberculosis Vaccine

描述：（由申请人提供）开发的主要障碍 针对巨噬细胞内病原体的有效疫苗，包括 结核分枝杆菌，是如何提供外源性抗原的方式， 刺激保护性细胞免疫反应。最近的调查 包括M的反义突变体。结核病H37Rv已经减少， 生产超氧化物歧化酶（SOD），并表现出有前途的活性， 疫苗原型表明，疫苗效力的机制可能是 结核病相关的微生物抗原向CD8+的交叉呈递 淋巴细胞通过MHC I类途径。目前提案的目标是 第一，表征所观察到的肺中的细胞和细胞因子反应， 感染SOD减少的M.结核病，如快速肺 出现间质浸润，单核细胞发生凋亡 是SOD减少菌株所特有的过程， 在感染M.结核病或目前的疫苗 结核菌株，卡介苗。这应界定在何种条件下， 抗原交叉呈递发生在体内，产生的信息可能是 可用于多种疫苗。第二个目标是构建非还原 通过替换野生型SOD等位基因的H37Rv和BCG的SOD减弱突变体 突变等位基因，其中一些编码酶效率较低的突变体 的SOD。这应该会产生一种稳定且 第三个目标是确定 最佳水平的SOD生产最大的疫苗效力和免疫 保护的相关性。减少生产要素的生产， 抑制巨噬细胞凋亡的细胞内病原体是 制造新的疫苗，实现MHC I类抗原呈递。这应该 不仅对肺结核也对其他传染病有影响 其中CD8+ T细胞应答是保护性免疫的关键组成部分， 反应

DESCRIPTION: (Provided by Applicant) A major hurdle in the development of effective vaccines against pathogens that reside within macrophages, including Mycobacterium tuberculosis, is how to deliver exogenous antigens in a manner that stimulates a protective cellular immune response. Recent investigations involving antisense mutants of M. tuberculosis H37Rv that have diminished production of superoxide dismutase (SOD) and exhibit promising activity as a vaccine prototype suggest that the mechanism of vaccine efficacy may be apoptosis-associated cross-presentation of microbial antigens to CD8+ lymphocytes via MHC Class I pathways. The goals of the current proposal are first, to characterize the cellular and cytokine responses in the lung observed early after infection with SOD-diminished M. tuberculosis, as rapid pulmonary interstitial infiltration with mononuclear cells undergoing apoptosis appears to be a process unique to the SOD-diminished strains that is not observed during infection with either virulent M. tuberculosis or the current vaccine strain for tuberculosis, BCG. This should define the conditions under which antigen cross-presentation occurs in vivo, yielding information that may be useful for a variety of vaccines. The second goal is to construct non-reverting SOD-diminished mutants of H37Rv and BCG by replacing the wild-type SOD allele with mutant alleles, some of which encode enzymatically less efficient mutants of SOD. This should yield a SOD-diminished vaccine candidate that is stable and safe enough for administration to man. The third goal is to determine the optimal level of SOD production for maximum vaccine efficacy and the immune correlates of protection. Diminishing the production of factors produced by intracellular pathogens that inhibit macrophage apoptosis is a strategy for making new vaccines that achieve MHC Class I antigen presentation. This should have implications not only for tuberculosis but for other infectious diseases in which CD8+ T-cell responses are a critical component of a protective immune response.