Anti-tuberculosis vaccination: The role of macrophages

描述（由申请人提供）：结核病是世界主要疾病。由耐多药结核分枝杆菌（Mtb）菌株引起的结核病病例发病率不断上升，这突出表明需要一种有效的抗结核疫苗。尽管最近在这方面投入了大量的努力，但大多数最近设计的疫苗已被证明对小鼠和豚鼠的结核分枝杆菌攻击感染的保护作用并不比它们设计取代的卡介苗强。在几乎所有情况下，接种疫苗使小鼠将Mtb攻击感染的能力降低约1个对数。现已确定，对结核分枝杆菌感染的免疫是由Th1细胞介导的，大多数抗结核分枝杆菌疫苗的设计目的是使宿主能够产生更多的结核分枝杆菌特异性CD4和CD8 Th1细胞。然而，需要记住的是，尽管由Th1细胞介导，但免疫是由巨噬细胞表达的，而结核分枝杆菌在整个感染过程中都存在于巨噬细胞中。因此，有必要了解易感宿主（5-10%的人类、所有小鼠和豚鼠）无法解决Mtb感染是由于Th1细胞数量不足，还是巨噬细胞功能的内在缺陷。作为开始研究抗Mtb Th1反应的巨噬细胞成分的一种方法，拟议的研究将使用接种过Mtb疫苗的小鼠和通过空气传播途径感染Mtb的幼年小鼠来验证接种疫苗提供的1 log保护不是(a)每个病变和每个巨噬细胞更多的Th1细胞，(b)更高水平的巨噬细胞激活，或(c)每个巨噬细胞更低的Mtb负荷的结果。相反，这完全是由于Th1细胞的早期生成导致巨噬细胞的早期激活。与人类疾病的相关性：拟议的研究涉及巨噬细胞在结核病免疫表达中的作用，结核病是每年导致200多万人死亡的世界主要疾病。

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.