Training in Transplantation Immunology

描述(申请人提供)：这项建议的实验目标是了解先天免疫和细胞运输在血管化实体器官移植中移植物排斥反应发病机制中的作用。在这个方案中，我们的假设是移植物中的供者树突状细胞被促进向淋巴结迁移的先天刺激激活，在那里它们呈递抗原并激活T细胞。然后，激活的T细胞迁移到发炎的移植物上，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。MyD88的缺乏与心脏移植物的延迟排斥反应有关。为了研究外周淋巴结的重要功能，我们将使用LTbeta-R缺陷小鼠，这些小鼠具有淋巴组织发生缺陷。脾切除后，LTbeta-R缺陷小鼠最终以极长的动力学时间排斥同种异体移植。为了跟踪供体和受体树突状细胞和淋巴细胞的迁移，我们将使用构成表达绿色荧光小鼠的转基因小鼠作为供体和/或受体。在目的1中，我们将分析供者树突状细胞移植后MyD88依赖的先天免疫激活。在AIM 2中，我们将分析受者T细胞移植后的淋巴依赖免疫激活。

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.