Acute Kidney Injury and Double Negative T Cells

急性肾损伤和双阴性 T 细胞

• 批准号: 8843185
• 负责人: Abdel Rahim Hamad
• 金额: $ 37.25万
• 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 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843185
• 关键词: Activities of Daily Living; Acute Renal Failure with Renal Papillary Necrosis; Adoptive Transfer; Allografting; Antigen-Presenting Cells; Automobile Driving; Biological Assay; CD28 gene; CD3 Antigens; CD8B1 gene; Caring; Cells; Cessation of life; Cytokine Signaling; Data; Epithelial Cells; Equilibrium; Etiology; Experimental Animal Model; Frequencies; Genes; Goals; Health Care Costs; Homeostasis; Hour; Human; Immune; Immunology; In Vitro; Inflammation; Injury; Ischemia; Kidney; Kidney Transplantation; Lead; Light; Medical; Morbidity - disease rate; Mus; Natural regeneration; Pathogenesis; Pathway interactions; Phenotype; Play; Population; Property; Protocols documentation; Recovery; Reperfusion Injury; Reperfusion Therapy; Role; Signal Transduction; T cell response; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; TNFSF5 gene; Testing; Tissues; Transplantation; Tubular formation; Work; base; cell type; clinically relevant; cytokine; immunoreactivity; improved; in vivo; insight; interest; loss of function; mortality; novel; novel therapeutics; prevent; programs; renal ischemia; repaired; research study; response; trafficking

Project Summary Acute kidney injury (AKI) is associated with a high mortality in native kidneys, decreased allograft survival in transplants, and very high health care costs. Among the most common etiologies of AKI in both native and transplanted kidneys is ischemia-reperfusion injury (IRI). Despite advances in medical care, the mortality and morbidity associated with AKI after IRI remain high, with no specific therapy. A major unknown is the role of different T cell types in either causing/preventing tissue damage or improving/worsening repair. Detailed understanding of the roles of different T cell types holds great promise in both elucidating mechanisms underlying IRI and also in devising new strategies to ameliorate AKI. One such strategy is to shift the T cell balance in favor of protective T cell types and away from pathogenic ones. Therefore, it is important to study different T cell types residing and trafficking to the kidney and investigate their roles in the steady state and IR conditions. Our team has had a long-standing interest in studying immune cells in AKI using experimental animal models with translational potential. We recently discovered a unique population of CD4-CD8- double negative (DN) CD3+TCRab+ T cells that occupies a large niche of the ab T cell compartment in the normal mouse kidney and undergoes marked changes during AKI. However, their functions in the normal kidney and AKI pathogenesis remain relatively unknown. Based on strong preliminary data on DN cells, our overarching hypothesis is that kidney DN T cells play a major and unique role in regulating renal immune cell homeostasis in the steady state and after AKI. Our specific Aims are: 1) Investigate mechanisms and significance of steady state proliferation of kidney DN T cells. 2) Investigate immunoreactivity of DN T cells to IRI induced AKI. 3) Test the ability of DN T cells to prevent AKI and/or accelerate repair using gain and loss-of-function strategies. Establishing a functional role for this previously unappreciated cell type in the kidney will substantially advance our understanding of the kidney immunology and could lead to paradigm shifting scientific concepts.

项目摘要 急性肾损伤（阿基）与天然肾的高死亡率相关， 移植中的同种异体移植物存活率以及非常高的医疗保健费用。最常见的 自体和移植肾中阿基的病因是缺血-再灌注损伤（IRI）。 尽管医疗保健取得了进步，但IRI后阿基相关的死亡率和发病率仍高于其他疾病。 仍然很高，没有具体的治疗。一个主要的未知数是不同类型的T细胞在 导致/防止组织损伤或改善/恶化修复。详细了解 不同类型T细胞的作用在阐明这两种机制方面都有很大的希望， 潜在的IRI以及制定改善阿基的新策略。其中一个战略是 改变T细胞平衡，有利于保护性T细胞类型，远离致病性T细胞类型。 因此，重要的是研究不同类型的T细胞驻留和运输到淋巴细胞。 肾脏，并研究其在稳态和IR条件下的作用。我们的团队 长期以来，人们一直对使用实验动物模型研究阿基中的免疫细胞感兴趣， 平移势我们最近发现了一个独特的CD 4-CD 8-双 阴性（DN）CD 3 +TCRab+ T细胞，其占据了ab T细胞区室的大生态位， 正常小鼠肾脏，并在阿基期间发生显著变化。然而，其功能 在正常肾脏和阿基发病机制仍然相对未知。基于强 关于DN细胞的初步数据，我们的总体假设是肾脏DN T细胞在DN细胞中起着重要作用。 在稳态下调节肾免疫细胞稳态中的主要和独特作用 阿基之后本研究的具体目的是：1）探讨稳定性的机制和意义 肾脏DN T细胞增殖状态。2)探讨DN T细胞对IRI的免疫反应性 诱发阿基。3)测试DN T细胞预防阿基和/或使用增益加速修复的能力 和功能丧失策略。为这个以前不被重视的人建立一个职能角色 肾脏中的细胞类型将大大促进我们对肾脏免疫学的理解 并可能导致范式转变的科学概念。