IMMUNE RESPONSE TO LEISHMANIA MAJOR

在用硕大利什曼原虫（Lm， 皮肤利什曼病的病原体，CL），巨噬细胞成为 感染寄生虫并引发Lm特异性T细胞。 在 CL小鼠模型，Lm特异性Th1细胞保护小鼠免受感染 而Lm特异性Th2细胞加重疾病。 设计有效的 针对CL的疫苗（即，一种不会诱导Th2型T细胞）， Lm特异性Th1和Th2细胞被激活的机制必须是 完全理解 这些研究将扩大我们对 CL的发病机制，并应增加我们对 一般免疫调节。 这个应用程序将探索Lm和 抗原呈递细胞（APC）之间以及感染的APC和 寄生虫特异性T细胞，其目标是识别因子[APC 功能，细胞因子，寄生虫抗原（Ag）]，决定是否Th1 或刺激Th2寄生虫特异性T细胞。 三种方法将 采取： 1)开发了一种小鼠辐射嵌合体系统， 观察到来自抗性小鼠的T细胞不能介导 当在易感环境中工作时， 易感小鼠能够介导保护作用， 一个抗拒的环境。 对这些结果最简单的解释 是APC决定了保护性还是恶化性T细胞 激活 因此，将分析这种辐射嵌合体系统 进一步通过构建嵌合体，其中所述动物在 水平的B细胞或巨噬细胞，以确定是否这些 细胞负责选择性激活Th1或Th2细胞。 2)为了进一步分析T细胞和APC之间的相互作用， 在CL中，开发了Lm特异性的主要体外（PIV）应答。 该试验将用于分析导致以下结果的参数 通过改变用于刺激Lm特异性T细胞的APC来活化Lm特异性T细胞 反应、APC可用的寄生虫抗原和细胞因子 在生成响应的过程中。 3)最后，最近的实验表明，受感染的巨噬细胞 作为比未感染者更有效的APC诱导T细胞活化 巨噬细胞 由于这些观察，因为Lm是一个专性的 巨噬细胞的细胞内寄生虫，重要的是要确定 Lm感染对巨噬细胞APC功能的影响。 因此，巨噬细胞将感染Lm， 巨噬细胞APC功能将被检查：Ag加工，生产 T细胞的共刺激信号，以及表面的表达， 与APC功能相关的分子。

Following infection of the host with Leishmania major (Lm, the etiological agent of cutaneous leishmaniasis, CL), macrophages become infected with the parasite and Lm-specific T cells are elicited. In the murine model for CL, Lm-specific Th1 cells protect mice from infection whereas Lm-specific Th2 cells exacerbate disease. To design an effective vaccine against CL (i.e., one that will not induce Th2-type T cells), the mechanisms by which Lm-specific Th1 and Th2 cells are activated must be fully understood. Such studies would expand our knowledge regarding the pathogenesis of CL and should add to our understanding of immunoregulation in general. This application will explore the interactions that occur between Lm and antigen presenting cells (APC) as well as between infected APC and parasite-specific T cells with the goal of identifying the factors [APC functions, cytokines, parasite antigens (Ag)] that determine whether Th1 or Th2 parasite-specific T cells are stimulated. Three approaches will be taken: 1) A mouse radiation chimera system was developed in which it was observed that T cells from resistant mice are unable to mediate protection when operating in a susceptible environment while T cells from susceptible mice are capable of mediating protection when operating in a resistant environment. The simplest interpretation of these results is that APC dictate whether protective or exacerbative T cells are activated. Therefore, this radiation chimera system will be analyzed further by constructing chimeras in which the animals are chimeric at the level of the B cell or macrophages to determine whether either of these cells is responsible for selective activation of Th1 or Th2 cells. 2) To further analyze the interactions that occur between T cells and APC in CL, a primary in vitro (PIV) response specific for Lm was developed. The assay will be utilized to analyze the parameters leading to activation of Lm-specific T cells by varying the APC used to stimulate the response, the parasite Ag available to the APC and the cytokines present during the generation of the response. 3) Finally, recent experiments are revealing that infected macrophages act as more efficient APC for inducing T cell activation than uninfected macrophages. Because of these observations and because Lm is an obligate intracellular parasite of macrophages, it is important to determine the effects that infection with Lm has on macrophages APC functions. Therefore, macrophages will be infected with Lm, and the following macrophages APC functions will be examined: Ag processing, the production of costimulatory signals for T cells, and the expression of surface molecules relevant to APC function.