Acute Kidney Injury and Double Negative T Cells

项目摘要 急性肾损伤(AKI)与天然肾脏的高死亡率、移植肾存活率降低有关 移植，以及非常高的医疗保健费用。AKI的最常见病因包括原发病和 移植肾为缺血再灌注损伤(IRI)。目前还没有针对AKI和 对恢复过程的了解还不完全。一个主要的未知数是每种T细胞类型的确切作用。这是 重要的是，一些T细胞参与引起AKI，而其他T细胞则参与预防组织 损坏和改进修复。我们的团队正专注于描述和理解Double的角色 正常肾脏和急性肾损伤时T细胞阴性(DN)。糖尿病肾病T细胞是人类最不了解的T细胞之一 类型由于其在外周淋巴器官中的稀少而被相对忽视。然而， 我们最近发现DNT细胞是肾脏αβT细胞(以下简称KDNT)的重要组成部分 单元格)。KDNT细胞的重要性被它们在体外和体外被证实的抑制功能所强调。 实验性AKI过程中的免疫调节保护作用。此续订申请基于Strong 最近发表和未发表的初步数据显示，KDNT细胞分为两个(PD-1+和 NK1.1+)在小鼠和人肾中的表达。小鼠PD-1+DNT细胞在稳定状态下活跃分裂 伴随着对实验性IRI反应的增殖性猝发，机制不是 受到已知经典或非经典MHC I和II分子的限制。不可除NK1.1+子集为 受2M依赖的非经典MHCI类分子在小鼠体内的调节。此续订申请的主要目标是 目的是探讨PD-1分子的调节作用、肾小管上皮细胞与肾小管上皮细胞的关系 健康和AKI中的细胞(RTEC)，以及使用人类肾脏将我们的小鼠发现翻译到人类 样本和被遗弃的已故捐赠者。我们的具体目标：检验PD-1/PD-L系统的假设 调节健康和急性肾损伤患者肾脏DNT细胞的动态平衡和效应功能。2)检验假设 在健康和AKI期间，肾脏DN和TREC通过双向环路相互调节。3)检验假设 人类KDNT细胞是抑制细胞，在健康和AKI期间调节RTEC的动态平衡。我们 具备实现这些目标的所有关键要素，包括体外KDNT/RTEC培养系统， 独一无二地获取缺血前后的人类肾脏样本(来自肾切除术)和被丢弃的死者 捐赠者肾脏，以及一个具有既定合作记录和 成功取得成果所需的补充专业知识。

Project Summary Acute kidney injury (AKI) is associated with high mortality in native kidneys, decreased allograft survival in transplants, and very high health care cost. Among the most common etiologies of AKI in both native and transplanted kidneys is ischemia-reperfusion injury (IRI). There is currently no specific therapy for AKI and the recovery process is incompletely understood. A major unknown is precise roles of each T cell type. This is important as some T cells are involved in causing AKI, whereas others are involved in preventing tissue damage and improving repair. Our team is focusing on characterizing and understanding the role of double negative (DN)  T cells in healthy kidney and during AKI. DN T cells are one of the least understood T cell types because of their paucity in peripheral lymphoid organs and thus have been relatively ignored. However, we recently discovered DNT cells as a large constituent of kidney αβT cells (hereafter referred to as KDNT cells). Significance of KDNT cells is underscored by their proven suppressive functions in vitro and immunoregulatory protective function during experimental AKI. This renewal application is based on strong recently published and unpublished preliminary data showing that KDNT cells are divided into two (PD-1+ and NK1.1+) subsets in murine and human kidney. Murine PD-1+ DNT cells are actively dividing in the steady state that is accompanied by a proliferative burst in response to experimental IRI by mechanisms that are not restricted by known classical or non-classical MHC I and II molecules. The non-dividing NK1.1+ subset is regulated by 2m-dependent non-classical MHC class I in mice. The major goals of this renewal application are to investigate the regulatory role of PD-1 molecule, relationship of KDNT cells and renal tubular epithelial cells (RTEC) in health and AKI, and translational of our murine findings to humans using human kidney samples and from discarded deceased donors. Our specific Aims: Test the hypothesis that PD-1/PD-L system regulates homeostasis and effector function of kidney DN T cells in health and AKI. 2) Test the hypothesis that kidney DN and TREC regulate each other via a bidirectional loop during health and AKI. 3) Test the hypothesis that human KDNT cells are suppresser cells that regulate homeostasis of RTEC during health and AKI. We have all the key critical elements to achieve these goals that include an in vitro KDNT/RTEC culture system, unique access to human kidney samples pre and post ischemia (from nephrectomies) and discarded deceased donor kidneys, and a synergistic team of investigators with an established collaborative track record and complementary expertise needed for successful outcome.