IMMUNE RESPONSE TO LEISHMANIA MAJOR

在宿主感染大利什曼原虫(Lm， 皮肤利什曼病的病原体，巨噬细胞 感染了这种寄生虫，就会激发出针对LM的T细胞。在 CL、LM特异性Th1细胞保护小鼠免受感染模型的建立 而LM特异性的Th2细胞则会加重疾病。要设计一种有效的 CL疫苗(即不会诱导Th2型T细胞的疫苗)， LM特异性Th1和Th2细胞被激活的机制必须 完全理解。这样的研究将扩大我们对 CL的发病机制应加深对其认识 免疫调节总体而言。 此应用程序将探索在LM和之间发生的交互 抗原提呈细胞(APC)以及感染的APC和 寄生虫特异性T细胞，目的是识别因子[APC 功能，细胞因子，寄生虫抗原(Ag)]，决定Th1 或者刺激Th2寄生虫特异性T细胞。三种方法将 被带走： 1)建立了一种小鼠辐射嵌合体系统。 观察到来自耐药小鼠的T细胞无法调节 在敏感环境中运行时的保护，而T细胞来自 易受感染的小鼠在 抵抗能力强的环境。对这些结果的最简单解释 是APC决定了保护性T细胞还是加重T细胞 激活了。因此，将对这一辐射嵌合体系统进行分析 此外，通过构建嵌合体，其中动物在 B细胞或巨噬细胞的水平来确定这两者中的任何一种 细胞负责Th1或Th2细胞的选择性激活。 2)进一步分析T细胞与APC之间的相互作用 在CL中，建立了针对LM的初步体外反应(PIV)。 该分析将被用来分析导致 通过改变用于刺激的APC来激活LM特异性T细胞 应答、APC可获得的寄生虫Ag和细胞因子 在响应的生成过程中出现。 3)最后，最近的实验揭示了感染的巨噬细胞 与未感染相比，APC可更有效地诱导T细胞活化 巨噬细胞。由于这些观察和因为LM是必修课 巨噬细胞的胞内寄生虫，重要的是要确定 肺炎衣原体感染对巨噬细胞APC功能的影响 因此，巨噬细胞会感染LM，并出现以下情况 巨噬细胞的APC功能将被检测：银的加工、生产 T细胞共刺激信号的表达及表面蛋白的表达 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.