T cell modulation of renal ischemia reperfusion injury.

肾缺血再灌注损伤（IRI）是急性肾功能衰竭（ARF）的主要原因， 同种异体移植肾我们和其他人已经证明了一个重要的调节作用，为I细胞在实验中 肾ARF。下一个阶段是了解角色的潜在机制！肾IRI细胞。我们 假设I细胞通过运输到缺血肾中， 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，和 产生与其他特定淋巴细胞协同作用的炎症介质。具体目标1：我们 假设TCR-MHC复合物通过抗原特异性介导I细胞参与肾IRI， 应答我们有初步的数据表明TCR受体，以及MHC II类直接影响 肾IRI的结果。我们将使用已建立的肾IRI小鼠模型和具有特异性抗体的小鼠。 敲除，并评估肾、分子和细胞应答。我们还将进行T细胞过继 转移研究和使用骨髓嵌合体。我们将使用CD 4 TCR转基因小鼠来探讨 IRI中的抗原特异性和T细胞活化。具体目标2：我们假设早期T细胞运输， 细胞因子的活化和产生介导肾IRI后的后续损伤。我们将使用新的 开发了淋巴细胞分离技术，以评估T细胞向缺血后肾脏的运输。我们将 比较T细胞与其他白细胞的运输，并在体外表征肾T细胞， 在蛋白质和mRNA水平上的促炎细胞因子的活化状态和产生。养父 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： 我们推测IRI后T细胞与NK细胞和B细胞相互作用，充分表达了肾损伤。我们将 使用NKT和B细胞功能缺陷的小鼠，并进行过继转移研究。我们将执行 在野生型小鼠中使用新的激动剂、阻断剂和消耗剂的补充实验 开发了以前限制这些研究的工具。这是一个新颖的方向，将导致新的见解 进入引发缺血后肾脏炎症的早期细胞步骤。长期目标是 确定在肾IRI中促进损伤过程的抗原和分子途径， 针对ARF的靶向免疫疗法。

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.