Defining the Correlates of Bactericidal Immunity in Tuberculosis

描述（申请人提供）：结核病仍然是全球传染病发病率和死亡率最重要的原因之一，并且尚未发现用于控制结核分枝杆菌（Mtb）的有效疫苗。并且免疫系统能够实现针对该生物体的高水平的杀菌免疫仍有待证明。沿着我们在爱因斯坦的结核病研究小组的同事，我们最近已经生产并鉴定了一种快速生长的非致病性M.在小鼠中可诱导针对Mtb的非凡和前所未有的保护性免疫水平的丝霉亲和素。初步研究表明，用这种M.我们将其命名为IKE+的耻垢病菌株可以快速诱导高水平的杀菌免疫来应答毒性Mtb的攻击。这与组织细菌水平的前所未有的降低有关，在某些情况下，甚至组织完全灭菌，结核病明显治愈。初步的过继转移研究表明，这种免疫力依赖于记忆性CD4+ T细胞群，它们能够将显著水平的杀菌反应转移给新生动物。此外，该CD4+ T细胞群的诱导似乎依赖于免疫环境中B细胞的存在。这些发现定义了一个新的实验系统，在其中寻找针对M.结核病，我们将使用它来确定能够诱导显着的抗分枝杆菌反应的特定T细胞群的特征。在这个为期两年的项目中，我们建议确定相关T细胞群体的表型和抗原特异性，并广泛表征其在关键细胞因子和其他效应分子产生方面的功能活性。这些研究可能揭示免疫系统控制和消除结核分枝杆菌的机制，并对结核病疫苗的开发具有潜在的重大意义。 公共卫生相关性：结核病仍然是全球传染病发病和死亡的最重要原因之一。该提案是一个计划的一个组成部分，该计划旨在更详细地了解免疫系统在使用新型实验疫苗进行特异性免疫后识别和杀死结核分枝杆菌的机制。这项研究的目标是建立原则，使设计和建设更好的疫苗，以预防结核病。

DESCRIPTION (provided by applicant): Tuberculosis remains one of the most significant global causes of morbidity and mortality from infectious disease, and an effective vaccine for controlling Mycobacterium tuberculosis (Mtb) has yet to be found. Well established correlates of vaccine induced protection against Mtb have not been established, and it remains to be shown that the immune system is capable of achieving high levels of bactericidal immunity against this organism. Along with our colleagues in the tuberculosis research group at Einstein, we have recently produced and characterized a genetically engineered form of the rapidly growing nonpathogenic M. smegmatis that can induce an extraordinary and unprecedented level of protective immunity in mice against Mtb. Initial studies show that mice immunized with this M. smegmatis strain, which we designate IKE+, can respond to challenges by virulent Mtb with rapid induction of a high level of bactericidal immunity. This is associated with unprecendented reductions in tissue bacterial levels, and in some cases even complete sterilization of tissues with apparent cure of tuberculosis. Preliminary adoptive transfer studies show that this immunity is dependent on a population of memory CD4+ T cells, which are able to transfer a significant level of the bactericidal response to naove animals. Furthermore, the induction of this population of CD4+ T cells appears to be dependent on the presence of B cells in the immunizing environment. These findings define a new experimental system in which to seek correlates of bactericidal immunity against M. tuberculosis, which we will use to identify the characteristics of the specific T cell populations that are capable of inducing the remarkable anti-mycobacterial responses. In this two year project, we propose to identify the phenotype and antigen specificities of the relevant T cell populations, and extensively characterize their functional activities with respect to production of key cytokines and other effector molecules. These studies are likely to reveal previously unexplored mechanisms by which the immune system can control and eliminate Mtb, and have potentially major implications for development of tuberculosis vaccines. PUBLIC HEALTH RELEVANCE: Tuberculosis remains one of the most important global causes of morbidity and mortality from infectious disease. This proposal is an integral component of a program that aims to understand in greater detail the mechanisms by which the immune system can be made to recognize and kill Mycobacterium tuberculosis following specific immunization with novel experimental vaccines. The goal of the research is to establish principles that will enable the design and construction of better vaccines for the prevention of tuberculosis.