Pro-Apoptotic Tuberculosis Vaccine

描述（由申请人提供）：开发针对巨噬细胞内病原体（包括结核分枝杆菌）的有效疫苗的主要障碍是如何以刺激保护性细胞免疫应答的方式递送抗原。最近的研究涉及M.具有减少的铁辅因子超氧化物歧化酶（SOD）产生的结核病的疫苗显示它们是减毒的，在小鼠中诱导强的CD4+和CD8+ T细胞应答，并且表现出作为疫苗原型的有希望的活性。这些效应似乎与通常被SOD抑制的先天免疫反应的暴露有关，SOD是M.结核病和其他致病分枝杆菌。增强的先天宿主免疫应答可能允许结核病相关的微生物抗原通过MHC I类途径交叉呈递，以诱导强适应性CD4+和CD8+ T细胞应答，与目前的结核病疫苗BCG相反，BCG表现出主要的CD4+ T细胞应答和最小的CD8+ T细胞应答。目前的建议的目标是，首先，表征感染SOD减少的M后早期观察到的肺中的细胞和细胞因子反应。结核病，因为经历凋亡的单核细胞的快速肺间质浸润似乎是SOD减少的菌株所特有的过程，这在用任一毒性M.结核病或卡介苗。这应该定义抗原在体内交叉呈递发生的条件，产生可能对各种疫苗有用的信息。第二个目标是通过用突变等位基因替换野生型SOD等位基因来构建H37Rv和BCG的非回复SOD减少突变体，其中一些突变等位基因编码酶促效率较低的SOD突变体。这将产生一个SOD减少疫苗候选人，是稳定和安全的管理人。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相关的保护。减少由细胞内病原体产生的抑制巨噬细胞凋亡的因子的产生是制造实现MHC I类抗原呈递的新疫苗的策略。这不仅对结核病有意义，而且对其他传染病也有意义，在这些传染病中，CD8+ T细胞反应是保护性免疫反应的关键组成部分。

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 antigens in a manner that stimulates a protective cellular immune response. Recent investigations involving antisense mutants of M. tuberculosis that have diminished production of iron-cofactored superoxide dismutase (SOD) show that they are attenuated, induce strong CD4+ and CD8+ T-cell responses in mice, and exhibit promising activity as a vaccine prototype. These effects appear to be related to an unmasking of the innate immune responses normally inhibited by SOD, which is a prominent extracellular enzyme of M. tuberculosis and other pathogenic mycobacteria. The enhanced innate host immune responses presumably permit apoptosis-associated cross-presentation of microbial antigens via MHC Class I pathways to induce strong adaptive CD4+ and CD8+ T-cell responses, in contrast to the current vaccine for tuberculosis, BCG, which exhibits a predominant CD4+ T-cell response and minimal CD8+ T-cell responses. 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 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 maximal 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 also for other infectious diseases in which CD8+ T-cell responses are a critical component of a protective immune response.