Training in Transplantation Immunology

描述（由申请人提供）：本提案的实验目的是了解天然免疫和细胞运输在血管化实体器官移植中移植排斥的发病机制中的作用。在这个提议中，我们的假设是移植物中的供体树突状细胞被先天刺激激活，促进迁移到淋巴结，在那里它们呈递抗原并激活T细胞。被激活的T细胞然后迁移到发炎的移植物，并产生诱导排斥反应的效应功能。我们将在心脏移植模型中研究以下目标。为了研究Toll样受体介导的先天刺激的功能，我们将使用MyD88缺陷小鼠。缺乏MyD88与心脏移植的延迟排斥反应有关。为了研究外周淋巴结的关键功能，我们将使用淋巴结器官发生缺陷的ltβ - r缺陷小鼠。脾切除术后，ltβ - r缺陷小鼠最终排斥同种异体移植物，并伴有极长时间的动力学反应。为了追踪供体和受体树突状细胞和淋巴细胞的迁移，我们将使用组成表达绿色荧光小鼠的转基因小鼠作为供体和/或受体。在AIM 1中，我们将分析移植后供体树突状细胞myd88依赖性先天免疫激活。在AIM 2中，我们将分析移植后受体T细胞的淋巴结依赖性免疫激活。

DESCRIPTION (provided by applicant): The experimental objective of this proposal is to understand the role of innate immunity and cell trafficking in the pathogenesis of graft rejection in vascularized solid organ transplantation. In this proposal, our hypothesis is that donor dendritic cells in the graft are activated by innate stimuli promoting migration to the lymph node, where they present antigen and activate T cells. The activated T cells then migrate to the inflamed graft and produce effector functions that induce rejection. We will investigate the following Aims in a cardiac transplant model. To investigate the functions of innate stimuli mediated by Toll like receptors, we will use MyD88 deficient mice. Lack of MyD88 is associated with delayed rejection of cardiac grafts. To investigate the crucial functions of peripheral lymph nodes, we will use LTbeta-R deficient mice that have defective organogenesis of lymph nodes. After splenectomy, LTbeta-R deficient mice ultimately reject allografts with extremely prolonged kinetics. To track the migration of donor and recipient dendritic cells and lymphocytes, we will use transgenic mice that constitutively express the green fluorescent mice as donors and/or recipients. In AIM 1, we will analyze the MyD88-dependent innate immune activation of donor dendritic cells following transplantation. In AIM 2, we will analyze the lymph node dependent immune activation of recipient T cells following transplantation.