ROLE OF T CELLS IN RENAL ISCHEMIC REPERFUSION INJURY

描述：缺血性急性肾衰竭是原发性和继发性肾功能衰竭的主要原因。 移植肾损伤没有特定的治疗方法， 缺血再灌注损伤（IRI）的机制仅被部分理解。 我们的目标是阐明肾脏IRI的潜在机制， 开发新的疗法来自多个小组的实验研究，包括 我们自己的，已经显示出炎症和白色细胞在肾脏中的重要作用， IRI。虽然大多数的焦点都集中在中性粒细胞上，但新的证据表明， 淋巴细胞的作用。我们有一个小鼠模型的初步数据， 细胞迁移到缺血后的肾脏。此外，缺乏T细胞的小鼠 显著减少肾损伤和中性粒细胞浸润。我们 因此推测T淋巴细胞在肾IRI中起重要作用。 为了验证这一假设，我们将使用我们建立的肾IRI小鼠模型， 包括敏感的菊糖清除率来测量肾小球滤过 率我们将评估不同T细胞群的直接作用， 使用遗传上缺乏选择性T细胞以及耗尽T细胞的小鼠， 在正常小鼠中。新数据表明我们有能力操纵T细胞 人口使用耗竭和过继转移技术。附加的 将进行体内研究以比较中性粒细胞与 肾IRI中T细胞。为了阐明T细胞相互作用的机制， 肾小管上皮细胞（RTEC）在IRI，我们将检查T细胞粘附 在模拟缺血后后遗症的条件下培养RTEC， vivo.我们将测量T细胞粘附到暴露于 缺氧-复氧、化学缺氧和自由基生成系统，以及 确定哪些粘附分子负责T细胞-RTEC 交互.初步数据表明，这些刺激可以显着 上调T细胞-RTEC粘附。我们还将比较T细胞粘附与 嗜中性粒细胞和巨噬细胞。我们的研究可能会导致 关于IRI性质的重要新发现。此外，由于专注于T 细胞和实验的平移设计，我们的数据可以导致新的 肾IRI的治疗试验。

DESCRIPTION: Ischemic acute renal failure is a major cause of native and transplant kidney damage. There is no specific therapy and the underlying mechanisms of ischemic reperfusion injury (IRI) are only partially understood. Our goal is to elucidate the mechanisms underlying renal IRI in order to develop new therapy. Experimental studies from a number of groups, including our own, have shown an important role for inflammation and white cells in renal IRI. Though most of the focus has been on neutrophils, new evidence points toward a role for lymphocytes. We have preliminary data in a mouse model that T cells migrate into postischemic kidney. Furthermore, mice deficient in T cells have significantly reduced renal injury and neutrophil infiltration. We therefore hypothesize that T lymphocytes play an important role in renal IRI. To test this hypothesis, we will use our established mouse model of renal IRI, which includes sensitive inulin clearances to measure glomerular filtration rate. We will evaluate the direct roles of different T cell populations by using mice genetically deficient in select T cells as well as depleting T cells in normal mice. New data demonstrates our ability to manipulate T cell populations using depletion and adoptive transfer techniques. Additional in vivo studies will be performed to compare the role of the neutrophil to that of the T cell in renal IRI. To elucidate the mechanisms of T cell interaction with renal tubular epithelial cells (RTEC) in IRI, we will examine T cell adhesion to RTEC in culture under conditions designed to mimic postischemic sequelae in vivo. We will measure T cell adhesion to RTEC exposed to hypoxia-reoxygenation, chemical anoxia and free-radical generating systems, and determine which adhesion molecules are responsible for T cell-RTEC interactions. Preliminary data demonstrate that these stimuli can significant up-regulate T cell-RTEC adhesion. We will also compare T cell adhesion with RTEC to neutrophils and macrophages. Our studies will potentially lead to important novel findings on the nature of IRI. In addition, due to focus on T cells and translational design of experiments, our data can lead to new therapeutic trials for renal IRI.