Anti-tuberculosis vaccination: The role of macrophages

描述（由申请人提供）：结核病是一种主要的世界性疾病。由结核分枝杆菌（Mtb）的多药耐药菌株引起的结核病病例的发病率不断增加，突出了对有效抗结核疫苗的需求。尽管最近在这方面做了很多努力，但大多数最近设计的疫苗在小鼠和豚鼠中对Mtb攻击感染的保护性并不比BCG更强，BCG是它们被设计用来取代的疫苗。在几乎所有情况下，疫苗接种为小鼠提供了将Mtb攻击感染保持在约1 log低水平的能力。已经确定，对Mtb感染的免疫是由Th 1细胞介导的，并且大多数抗Mtb疫苗的设计是为了向宿主提供产生大量Mtb特异性CD 4和CD 8 Th 1细胞的能力。然而，需要记住的是，尽管免疫是由Th 1细胞介导的，但免疫是由Mtb在整个感染过程中驻留的巨噬细胞表达的。因此，有必要知道易感宿主（5-10%的人，以及所有小鼠和豚鼠）未能解决Mtb感染是由于产生的Th 1细胞数量不足，还是由于巨噬细胞功能的内在缺陷。作为开始研究抗Mt B Th 1应答的巨噬细胞成分的一种方法，拟议的研究将使用经空气传播途径感染Mt B的接种和未接种小鼠来检验以下假设，即疫苗接种提供的1 log保护不是（a）每个病变和每个巨噬细胞更多Th 1细胞，（B）更高水平的巨噬细胞活化，或（c）每个巨噬细胞更低的Mt B负荷的结果。相反，这完全是由于Th 1细胞的早期产生导致巨噬细胞的早期激活。与人类疾病的相关性：这项拟议中的研究涉及巨噬细胞在表达对结核病的免疫力中的作用，结核病是一种主要的世界性疾病，每年造成200多万人死亡。

DESCRIPTION (provided by applicant): Tuberculosis is a major world disease. The increasing incidence of TB cases caused by multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) underscores the need for an efficacious anti-TB vaccine. Although much effort has recently been devoted to this cause, the majority of recently designed vaccines have proved no more protective against an Mtb challenge infection in mice and guinea pigs than BCG, the vaccine that they were designed to replace. In almost all cases vaccination provides mice the capacity to hold an Mtb challenge infection at about a 1 log lower level. It is established that immunity to Mtb infection is mediated by Th1 cell, and most anti-Mtb vaccines are designed with view to providing the host a capacity to generate larger numbers of Mtb-specific CD4 and CD8 Th1 cells. It needs to be kept in mind, however, that although mediated by Th1 cells, immunity is expressed by macrophages in which Mtb resides throughout the course of infection. Therefore, there is a need to know whether failure of susceptible hosts (5-10% of humans, and all mice and guinea pigs) to resolve Mtb infection is due to the generation of an inadequate number of Th1 cells, or to an intrinsic deficiency in macrophage function. As a way to begin investigating the macrophage component of the anti-Mtb Th1 response, the proposed research will use vaccinated and naive mice infected with Mtb via the airborne route to test the hypothesis that the 1 log protection afforded by vaccination is not the result of (a) more Th1 cells per lesion and per macrophage, (b) a higher level of macrophages activation, or (c) a lower Mtb load per macrophage. Instead, it is due entirely to earlier activation of macrophages because of earlier generation of Th1 cells. Relevance to human disease: The proposed study deals with the role of macrophages in the expression of immunity, to tuberculosis, a major world disease that kills over 2 million people annually.