T cell modulation of renal ischemia reperfusion injury.

肾缺血再灌注损伤(IRI)是引起急性肾功能衰竭(ARF)的主要原因 同种异体肾移植我们和其他人已经在实验中证明了细胞的重要调节作用 肾功能衰竭。下一阶段是了解潜在的作用机制！肾IRI中的细胞。我们 假设I细胞通过转运到缺血肾脏，通过激活来调节肾脏IRI 通过T细胞受体(TCR)-主要组织相容性复合体(MHC)的抗原特异性相互作用，以及 产生炎症介质，与其他特定的淋巴细胞协同工作。具体目标1：我们 TCR-MHC复合体通过抗原特异性介导I细胞参与肾IRI的假说 回应。我们有初步数据表明，TCR受体和MHC II类分子直接影响 肾IRI的转归。我们将使用已建立的小鼠肾脏IRI模型和具有特异性的小鼠 基因敲除，评估肾脏、分子和细胞反应。我们还将进行T细胞领养 转移研究并使用骨髓嵌合体。我们将使用CD4TCR转基因小鼠来探讨其作用 IRI的抗原特异性和T细胞活化。具体目标2：我们假设早期的T细胞贩运， 细胞因子的激活和产生介导了肾脏IRI后的后续损伤。我们将使用我们的新产品 开发了淋巴细胞分离技术以评估T细胞向缺血后肾脏的转运。我们会 比较T细胞与其他白细胞的转运，并从以下方面描述体外肾T细胞的特征 促炎症细胞因子在蛋白质和mRNA水平的激活状态和产生。领养 转移技术将用于直接测试这些T细胞细胞因子的功能作用。具体目标3： 我们假设，在IRI后，T细胞与NKT和B细胞相互作用，以充分表达肾脏损伤。我们会 利用NKT和B细胞功能缺陷的小鼠，进行过继转移研究。我们将表演 在野生型小鼠中使用新的激动剂、阻滞剂和耗竭剂进行补充实验 开发的工具以前限制了这些研究。这是一个新的方向，将带来新的见解 进入启动缺血后肾脏炎症的非常早期的细胞步骤。长期目标将是 识别促进肾缺血再灌注损伤过程的抗原和分子途径，并发展 ARF的靶向免疫治疗。

Kidney ischemia reperfusion injury (IRI) is a major cause of acute renal failure (ARF) in both native and allograft kidney. We and others have demonstrated an important modulatory role forI cells inexperimental kidney ARF. The next stage is to understand the mechanisms underlying the role for! cells in renal IRI. We hypothesize that I cells modulate renal IRI by trafficking into ischemic kidney, becoming activated through antigen specific interactions through the T cell receptor (TCR)-major histocompatibility complex (MHC), and produce inflammatory mediators that work in concert with other specific lymphocytes. Specific Aim 1: We hypothesize that the TCR-MHC complex mediates I cell participation in renal IRI through antigen specific responses. We have preliminary data that TCR receptors, as well as MHC class II directly influence outcome of renal IRI. We will use an established mouse model of renal IRI and mice with specific knockouts, and evaluate renal, molecular and cellular responses. We will also perform T cell adoptive transfer studies and use bone marrow chimeras. We will use CD4 TCR transgenic mice to probe the role of antigen specificity and T cell activation in IRI. Specific Aim 2: We hypothesize that early T cell trafficking, activation and production of cytokines mediates subsequent injury following renal IRI. We will use our new developed lymphocyte isolation technique to evaluate trafficking of T cells into postischemic kidney. We will compare T cell trafficking with that of other leukocytes, and characterize the renal T cells ex vivo in terms of activation status and production of proinflammatory cytokines at the protein and mRNA level. Adoptive transfer techniques will be used to directly test the functional role of these T cell cytokines. Specific Aim 3: We hypothesize that T cells interact with NKTand B cells for full expression of renal injury after IRI. We will use mice deficient in NKT and B cell function, and perform adoptive transfer studies. We will perform complementary experiments with agonists, blockers and depleting agents in wild type mice using new developed tools that previously limited these studies. This is a novel direction that will lead to new insights into the very early cellular steps that initiate postischemic kidney inflammation. The long term goal will be to identify the antigens and molecular pathways that fuel the injury processes in renal IRI, and develop targeted immune therapies for ARF.