IMMUNE ESCAPE MECHANISMS IN LEISHMANASIS

描述（由申请方提供）：在世界许多地区，原生动物寄生虫大型利什曼原虫感染导致显著的发病率。L.主要感染被认为是研究体内极化的Th 1/Th 2细胞因子应答的范例，其中IL-4驱动的Th 2应答作为对L.严重感染与此良好建立的模型相反，在缺乏IL-4受体α链（IL-4 R α-/-）的遗传纯BALB/c小鼠中，感染L.主要亚株LV 39引起高度进行性疾病;与易感BALB/c小鼠相似，而L.主要亚株IR 173被高度控制。这些结果表明，IL-4以外的因子能够抑制IFN γ激活的细胞内L.主要寄生虫IL- 10已被确定为导致L. IL-4 R α-/-小鼠中的主要LV 39。在用中和性抗IL-10受体抗体处理的IL-4 R α-/-小鼠和IL-4 R α和IL-10基因缺陷的BALB/c小鼠中，主要的LV 39感染逆转为愈合表型。这个提议利用了L.主要的LV 39和IR 173感染，以评估细胞因子调节、IL-10分泌性Treg细胞的作用、巨噬细胞和树突状细胞在引导针对L.主要感染，以及L.大疫苗。这些研究的长期目标是确定参与L。主要的免疫逃逸机制，这是完全揭示了在IL-4/IL- 13信号转导的情况下。这些研究对开发针对利什曼原虫感染的疗法和疫苗以及体内调节Th 1/Th 2细胞因子发育的机制具有意义。

DESCRIPTION (provided by the applicant): Infection with the protozoan parasite Leishmania major causes significant morbidity in many parts of the world. The mouse model of L. major infection has been considered the paradigm to study polarized Th1/Th2 cytokine responses in vivo, with IL-4-driven Th2 responses as a determinant of susceptibility to L. major infection. Contrary to this well-established model, in genetically pure BALB/c mice deficient for IL-4 receptor alpha chain (IL-4Ralpha-/-), infection with L. major sub-strain LV39 causes highly progressive disease; similar to susceptible BALB/c mice, while the L. major sub-strain IR173 is highly controlled. These results suggest that factors other than IL-4 are capable of suppressing IFNgamma activated killing of intracellular L. major parasites. IL- 10 has been identified as the factor, which causes susceptibility to L. major LV39 in IL-4Ralpha-/- mice. In IL-4Ralpha-/- mice treated with neutralizing anti-IL-10 receptor antibody and in BALB/c mice genetically deficient for both IL-4Ralpha and IL-10, the disease to L. major LV39 infection was reversed to a healing phenotype. This proposal exploits the disparate outcomes of L. major LV39 and IR173 infections to assess cytokine regulation, the role of IL-10-secreting Treg cells, the roles of macrophages and dendritic cells in directing T cell immune responses to L. major infection, and the efficacy and mechanisms of protection by L. major vaccines. The long-term goal of these studies is to identify the cellular processes and antigens involved in L. major immune escape mechanisms, which are fully revealed in the absence of IL-4/IL- 13 signaling. These studies have implications for the development of therapies and vaccines directed toward Leishmania infections as well as the mechanisms that regulate Th1/Th2 cytokine development in vivo.