Regulatory T Cells in Acute Kidney Injury

急性肾损伤中的调节性 T 细胞

基本信息

批准号：
9029397
负责人：
Gilbert R Kinsey
金额：
$ 35.55万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-15 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9029397
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Adoptive Transfer Anti-Inflammatory Agents Anti-inflammatory Antibodies Apoptosis Binding Blocking Antibodies Blood Vessels Bone Marrow Cardiac Surgery procedures Cell Death Cell Line Cell Surface Proteins Cell Surface Receptors Cell surface Cells Cessation of life Chronic Kidney Failure Cisplatin Clinical Research Clinical Trials Data Development Diphtheria Toxin Disease Endothelial Cells Epithelial Cells Equilibrium Foundations Functional disorder Future Genetic Genus Hippocampus Glucose Health Healthcare Systems Hospital Costs Hospitalization Human IL2RA gene Immune Immunologics Immunosuppression Inflammation Inflammation Mediators Inflammatory Injection of therapeutic agent Injury Interleukin-10 Interleukin-2 Investigation Kidney Knockout Mice Knowledge Length of Stay Ligands Literature Lymphocyte Measures Mediating Mitochondria Modeling Morbidity - disease rate Mus Myelogenous Nephrotoxic Oxidative Phosphorylation PDCD1LG1 gene Palmitates Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Production Property Publishing Recovery Regulatory T-Lymphocyte Renal function Reperfusion Injury Reperfusion Therapy Resistance Role Signal Transduction Speed Supportive care Testing Therapeutic Time Transgenic Mice Tubular formation Vascular Endothelial Cell Work base cytokine experience extracellular in vivo interleukin-10 receptor kidney cell kidney vascular structure macrophage monocyte mortality mouse model nephrotoxicity neutrophil new therapeutic target novel overexpression oxidation pre-clinical preclinical study prevent programs protective effect public health relevance receptor renal ischemia trafficking

项目摘要

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) complicates at least 5% of all hospitalizations and up to 30% of cardiac surgeries, increasing mortality and progressing to chronic renal disease in a significant number of patients. Ischemia- reperfusion injury (IRI) is a major pathogenic factor in the development of AKI. Inflammation contributes significantly to the loss of renal function and kidney cell death. CD4+FoxP3+ regulatory T cells (Tregs) are renal-protective lymphocytes that raise the threshold of experimental AKI (i.e. mice with reduced Treg numbers are highly susceptible to short ischemic times). In addition, augmenting Treg numbers by IV injection (adoptive transfer) of isolated Tregs to naïve mice prior to severe kidney IRI offers marked protection from injury and dysfunction. Our investigation into the mechanism of action for Tregs has revealed that expression of both the cytokine interleukin 10 (IL-10) and the cell surface protein programmed death 1 (PD-1) by Tregs are required. IL-10 suppresses trafficking and inflammatory mediator production by myeloid immune cells through binding the IL-10 receptor (IL-10R). The consequences of PD-1 on Tregs binding with its ligand PD-L1 expressed on other cells are not currently known. Information from the literature and from our own studies suggest that PD-1 activation would enhance oxidative phosphorylation, CD25 (an important cell surface receptor that promotes Treg function and survival) and IL-10 expression in Tregs. These intracellular consequences of PD-1 activation and their role in protection from kidney IRI will be determined using mouse and human Tregs in Aim 1. Preliminary data demonstrate that antibody-mediated blockade of PD-L1 or the IL-10R in recipient mice, prior to Treg adoptive transfer, negates their protective action in IRI. The cells that must express PD-L1 and the IL-10R to interact with and respond to Tregs and protect the kidney are not known. PD-L1 is expressed on kidney vascular endothelial cells and our preliminary data reveal preferential intraluminal Treg accumulation in the peritubular vasculature during reperfusion. We hypothesize that Treg-mediated protection from AKI requires the expression of PD-L1 on endothelial cells that line the inside of blood vessels, and the IL-10 receptor on myeloid immune cells. We will use mouse models that lack PD-L1 (Aim 2) or the IL-10R (Aim 3) in vascular endothelial cells and myeloid immune cells, respectively, to zero in on the cells interact with Tregs and respond to IL-10 produced by Tregs in a way that is protective to the kidney. These mechanistic studies in mice will provide a platform for future pre-clinical and clinical studies of the therapeutic utility of Tregs and Treg-associated mechanisms in AKI.

描述（由适用提供）：急性肾脏损伤（AKI）使至少5％的住院和心脏手术的30％复杂化，增加了死亡率并发展为大量患者的慢性肾脏疾病。缺血再灌注损伤（IRI）是AKI发展的主要致病因素。炎症对肾功能和肾细胞死亡的丧失显着贡献。 CD4+ FOXP3+调节性T细胞（TREG）是肾脏保护淋巴细胞，可提高实验性AKI的阈值（即Treg数量降低的小鼠非常容易受到短暂性缺血时代的极敏感）。此外，在严重的肾脏IRI之前，通过静脉注射（收养转移）向幼稚的小鼠增加Treg数字，可明显保护受伤和功能障碍。我们对Tregs作用机理的投资表明，需要Tregs的细胞因子白介素10（IL-10）和细胞表面蛋白编程死亡1（PD-1）的表达。 IL-10通过结合IL-10受体（IL-10R）来抑制髓样免疫细胞的运输和炎症介质产生。当前尚不清楚PD-1对在其他细胞上表达的配体PD-L1结合的Tregs的后果。来自文献和我们自己的研究的信息表明，PD-1激活将增强氧化磷酸化，CD25（促进Treg功能和存活的重要细胞表面受体）和Treg中的IL-10表达。 PD-1激活的这些细胞内后果及其在AIM 1中使用小鼠和人treg在肾脏IRI的保护中的作用。初步数据表明，在TREG发电之前，抗体介导的PD-L1或受体中IL-10R的封锁或IL-10R在TREG发电之前，在IRI中否定了其受保护的动作。不知道必须表达PD-L1和IL-10R的细胞与Tregs相互作用并响应并保护肾脏。 PD-L1在肾脏血管内皮细胞上表达，我们的初步数据揭示了再灌注过程中周围脉管系统中首选的Treg积累。我们假设Treg介导的AKI的保护需要在血管内部的内皮细胞上表达PD-L1，以及在血管内部的细胞，以及在髓样免疫球上的IL-10受体。我们将使用缺乏PD-L1（AIM 2）或血管内皮细胞和髓样免疫细胞中缺乏PD-L1或IL-10R（AIM 3）的小鼠模型，以在细胞上与Tregs相互作用，并响应Treg所产生的IL-10，以对肾脏受到保护的方式。这些小鼠的机械研究将为将来的临床前和临床研究提供一个平台 AKI中Tregs和Treg相关机制的治疗效用。