ROLE OF T CELLS IN RENAL ISCHEMIC REPERFUSION INJURY

描述：缺血性急性肾功能衰竭是天然和慢性肾功能衰竭的主要原因。 移植肾受损。没有特定的治疗方法，潜在的 缺血再灌注损伤(IRI)的机制尚不完全清楚。 我们的目标是阐明肾脏IRI的潜在机制，以便 开发新的治疗方法。来自多个小组的实验研究，包括 我们自己的，已经显示出在炎症和白细胞在肾脏中的重要作用 IRI。尽管大部分焦点都集中在中性粒细胞上，但新的证据表明 发挥淋巴细胞的作用。我们有一个小鼠模型的初步数据 细胞迁移到缺血后肾脏。此外，T细胞缺陷的小鼠 能显著减少肾脏损伤和中性粒细胞的浸润。我们 因此，假设T淋巴细胞在肾脏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脏IRI小鼠模型， 包括敏感的菊粉清除量来测量肾小球滤过率 费率。我们将通过以下方式评估不同T细胞群体的直接作用 利用在选择T细胞和消耗T细胞方面存在遗传缺陷的小鼠 在正常小鼠身上。新数据证明了我们操纵T细胞的能力 使用枯竭和收养转移技术的种群。其他输入 将进行活体研究，以比较中性粒细胞和 肾脏IRI中的T细胞。阐明T细胞与T细胞相互作用的机制 肾小管上皮细胞(RTEC)在IRI中，我们将检测T细胞黏附 在模拟脑缺血后遗症的条件下进行RTEC培养 活着。我们将测量暴露于RTEC的T细胞黏附 缺氧-复氧、化学缺氧和自由基生成系统；以及 确定哪些黏附分子对T细胞负责-RTEC 互动。初步数据表明，这些刺激可以显著 上调T细胞与RTEC的黏附。我们还将比较T细胞黏附与 RTEC对中性粒细胞和巨噬细胞的作用。我们的研究可能会导致 关于IRI本质的重要新发现。此外，由于专注于T 细胞和平移设计的实验，我们的数据可以带来新的 肾脏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.