Anti-tuberculosis vaccination: The role of macrophages

描述(申请人提供)：结核病是一种主要的世界性疾病。结核分枝杆菌耐多药菌株(Mtb)引起的结核病病例的发病率不断增加，这突出表明需要一种有效的抗结核疫苗。尽管最近对这一事业投入了大量努力，但事实证明，大多数最近设计的疫苗在小鼠和豚鼠身上对结核分枝杆菌挑战感染的保护作用并不比卡介苗更好，卡介苗是它们设计的替代品。在几乎所有的情况下，接种疫苗使小鼠能够将结核分枝杆菌的挑战感染保持在大约1log低水平。现已证实，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为宿主提供产生大量结核分枝杆菌特异性CD4和CD8 Th1细胞的能力。然而，需要记住的是，尽管免疫是由Th1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，有必要了解易感宿主(5%-10%的人，以及所有小鼠和豚鼠)未能解决结核分枝杆菌感染是由于Th1细胞数量不足，还是由于巨噬细胞功能的固有缺陷。作为开始研究抗结核分枝杆菌Th1反应的巨噬细胞成分的一种方式，拟议的研究将使用通过空气途径感染结核分枝杆菌的接种和未接种的小鼠来检验这样的假设，即接种疫苗提供的1log保护不是由于(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结核分枝杆菌载量。相反，它完全是由于Th1细胞的早期生成而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免疫表达中的作用，与结核病有关，结核病是一种主要的世界性疾病，每年导致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.