Anti-tuberculosis vaccination: The role of macrophages

结核病是一种主要的世界性疾病。多重耐药引起的结核病发病率上升 结核分枝杆菌菌株(Mtb)强调了有效的抗结核病疫苗的必要性。 尽管最近对这一事业投入了大量的努力，但最近设计的大多数疫苗 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强， 他们被设计用来替代的疫苗。在几乎所有情况下，接种疫苗都能为小鼠提供 将结核分枝杆菌挑战感染控制在大约1对数的低水平。已经确定对结核分枝杆菌感染的免疫力是 由Th1细胞介导，大多数抗结核分枝杆菌疫苗旨在为宿主提供一种能力 产生更多数量的结核分枝杆菌特异性CD4和CDS Th1细胞。然而，需要记住的是， 虽然免疫是由Th1细胞介导的，但免疫是由结核分枝杆菌贯穿其中的巨噬细胞表达的。 感染的过程。因此，需要了解易受影响的主机(5%-10%)是否发生故障 人，以及所有的小鼠和豚鼠)，解决结核分枝杆菌感染是由于世代不足 Th1细胞的数量，或巨噬细胞功能的固有缺陷。作为开始调查 巨噬细胞成分的抗结核分枝杆菌Th1反应，建议研究将使用疫苗和NATve 通过空气传播途径感染结核分枝杆菌的小鼠，以测试1log提供的保护的假设 接种疫苗不是因为(A)每个皮损和每个巨噬细胞有更多的Th1细胞，(B)更高水平的 巨噬细胞激活，或(C)每个巨噬细胞的结核分枝杆菌载量较低。相反，这完全是由于早先 由于Th1细胞的早期生成，巨噬细胞被激活。 与人类疾病的相关性：拟议的研究涉及巨噬细胞在表达 对结核病的免疫力，这是一种每年导致200多万人死亡的主要世界性疾病。

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 CDS 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 naTve 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.