Acute Kidney Injury and Double Negative T Cells

急性肾损伤和双阴性 T 细胞

• 批准号: 8416321
• 负责人: Abdel Rahim Hamad
• 金额: $ 20.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416321
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adoptive Transfer; Age; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Biological Assay; Brain; CD3 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Therapy; Cells; Characteristics; Colitis; Complex; Cues; Data; Databases; Epithelial Cells; Etiology; Family; Foundations; Health Care Costs; Heart; Homeostasis; Hypoxia; Immune; Immune response; Immune system; Immunology; In Vitro; Individual; Inflammation; Injury; Ischemia; Kidney; Kidney Transplantation; Lead; Link; Mediating; Modeling; Morbidity - disease rate; Mus; Myocardial Ischemia; Organ; Pathogenesis; Phenotype; Population; Process; Production; Recovery; Recruitment Activity; Reperfusion Injury; Research Personnel; Resistance; Role; Spleen; Stimulus; Stroke; System; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Tubular formation; Tumor Necrosis Factor Ligand Superfamily Member 6; Work; cell type; cytokine; immune function; injury and repair; innovation; kidney cell; loss of function mutation; lymph nodes; member; mortality; mouse model; novel; novel therapeutics; prevent; renal ischemia; repaired; research study

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is associated with a high mortality, morbidity, and increased health care cost. Among the most common etiologies of AKI in both native and transplanted kidneys is ischemia-reperfusion injury (IRI), which has no specific therapy. IRI is also a major process underlying myocardial ischemia and stroke. Mechanisms of early injury and recovery from IRI are complex and remain incompletely understood. IRI involves diverse cell types of the innate and adaptive immune systems, some of which cause damage while others promote injury repair. Efforts to understand the individual and collaborative roles of the different immune cells that reside in the kidney in the steady state or recruited after injury are important for laying the foundation for developing effective strategies o ameliorate renal damage associated with IRI. We have novel data that a fairly newly identified and poorly understood cell type that belong to the TCR¿¿+CD4-CD8- double negative (DN) T cell subset, preferentially localizes in large numbers in the normal kidney and changes with age and ischemia. These cells can be anti-inflammatory and genetically modified mice with large quantities of DN T cells are protected from IRI. We hypothesize that DN T cells mediate unique immune functions that are necessary for maintaining local immune responses and renal tubular epithelial cell homeostasis in the steady state, while also protecting from injury and enhancing recovery after IRI. We will begin to test this novel hypothesis through the following specific Aims: In Aim 1, we will test the hypothesis that local DN T cells maintain immune homeostasis by suppression of activated conventional T cells. We will also study effects on renal tubular epithelial cells (RTECs), which make up the bulk of the kidney cells. In Aim 2, we will test the hypothesis that DN T cells directly protect from early injury and accelerate repair after IRI. We will also elucidate mechanisms of action. Results will provide novel information on this newly identified kidney cell and has the potential to harness a novel cell for cell therapy directed to ischemia reperfusion injury.

描述（由申请方提供）：急性肾损伤（阿基）与高死亡率、发病率和医疗保健成本增加相关。自体肾和移植肾中阿基的最常见病因是缺血再灌注损伤（IRI），目前尚无特异性治疗方法。IRI也是心肌缺血和卒中的主要基础过程。IRI的早期损伤和恢复机制是复杂的，仍然不完全清楚。IRI涉及先天性和适应性免疫系统的多种细胞类型，其中一些引起损伤，而另一些促进损伤修复。努力了解不同免疫细胞的个体和协作作用，这些免疫细胞在稳态下驻留在肾脏中或在损伤后招募，这对于为开发改善与IRI相关的肾损伤的有效策略奠定基础是重要的。我们有新的数据表明，一种相当新发现的和知之甚少的细胞类型，属于TCR + CD 4-CD 8-双阴性（DN）T细胞亚群，优先大量定位于正常肾脏，并随年龄变化， 缺血这些细胞可以是抗炎的，并且具有大量DN T细胞的遗传修饰小鼠被保护免受IRI。我们假设DN T细胞介导独特的免疫功能，这些免疫功能是维持局部免疫应答和稳定状态下肾小管上皮细胞稳态所必需的，同时还保护免受损伤并促进IRI后的恢复。我们将开始通过以下具体目标来检验这一新的假设：在目标1中，我们将检验局部DN T细胞通过抑制活化的常规T细胞来维持免疫稳态的假设。我们还将研究对肾小管上皮细胞（RTEC）的影响，RTEC构成了肾细胞的主体。在目标2中，我们将检验DN T细胞直接保护早期损伤并加速IRI后修复的假设。我们还将阐明作用机制。结果将提供关于这种新鉴定的肾细胞的新信息，并有可能利用一种新的细胞用于针对缺血再灌注损伤的细胞治疗。