Acute Kidney Injury and Double Negative T Cells

急性肾损伤和双阴性 T 细胞

• 批准号: 10360589
• 负责人: Abdel Rahim Hamad
• 金额: $ 49.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360589
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adoptive Transfer; Allografting; Apoptotic; Bone Marrow; Cell Communication; Cell Culture System; Cells; Chimera organism; Coculture Techniques; Data; Elements; Epithelial Cells; Etiology; Goals; Health; Health Care Costs; Hematopoietic; Homeostasis; Human; Immune; Immune checkpoint inhibitor; In Vitro; Injury; Intervention; Ischemia; Kidney; Kidney Transplantation; Lead; Ligands; MHC Class I Genes; Mediating; Mus; Nephrectomy; Outcome; PD-1 blockade; Pathogenicity; Phenotype; Play; Process; Publishing; Renal function; Reperfusion Injury; Research Personnel; Role; Sampling; Suppressor-Effector T-Lymphocytes; System; T-Lymphocyte; Testing; Tissues; Transplantation; Tubular formation; base; cancer immunotherapy; cell type; clinically relevant; cytokine; immunoregulation; improved; injury recovery; insight; mortality; mouse model; novel; novel therapeutics; peripheral lymphoid organ; preclinical study; prevent; programmed cell death ligand 1; programmed cell death protein 1; repaired; response; side effect; single-cell RNA sequencing; transcriptome; translational study

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.

项目摘要 急性肾损伤（阿基）与自体肾的高死亡率、移植肾的移植物存活率降低有关。 器官移植和高昂的医疗费用。阿基最常见的病因包括： 移植肾缺血再灌注损伤（IRI）。目前没有针对阿基的特异性疗法， 恢复过程不完全清楚。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细胞参与引起阿基，而其他T细胞参与防止组织损伤。 损坏和改善修复。我们的团队专注于描述和理解双重的作用， 在健康肾脏和阿基期间，观察到阴性（DN）的人外周血T细胞。DN T细胞是最不了解的T细胞之一， 类型，因为它们缺乏外周淋巴器官，因此相对被忽视。然而，在这方面， 我们最近发现DNT细胞是肾脏αβT细胞（以下简称KDNT）的主要组成部分 细胞）。KDNT细胞的重要性通过它们在体外被证实的抑制功能而得到强调， 在实验阿基期间的免疫调节保护功能。本次更新申请基于强大的 最近发表和未发表的初步数据显示KDNT细胞分为两种（PD-1+和PD-2+）， NK 1.1+）亚群。小鼠PD-1+ DNT细胞在稳态下活跃分裂 这是伴随着增殖爆发响应实验IRI的机制， 受已知的经典或非经典MHC I和II分子限制。非分裂的NK1.1+子集是 在小鼠中，由MHC 2 m依赖性非经典MHC I类调节。本次续约申请的主要目标 本研究旨在探讨PD-1分子的调控作用，KDNT细胞与肾小管上皮细胞的关系， 细胞（RTEC）在健康和阿基中的作用，以及使用人肾将我们的小鼠发现转化为人类 样本和被丢弃的已故捐赠者。我们的具体目的：验证PD-1/PD-L系统 调节健康和阿基中肾脏DN T细胞的稳态和效应子功能。2)测试的假设 肾脏DN和TREC在健康和阿基期间通过双向回路相互调节。3)检验这一假设 人KDNT细胞是在健康和阿基期间调节RTEC稳态的抑制细胞。我们 拥有实现这些目标的所有关键要素，包括体外KDNT/RTEC培养系统， 获得缺血前后（来自肾切除术）和丢弃的死者肾脏样本的唯一途径 捐赠肾脏，以及具有既定合作记录的研究者协同团队， 取得成功所需的补充专业知识。