Immune Mechanisms in Kidney Ischemic Preconditioning

肾脏缺血预处理中的免疫机制

• 批准号: 8044719
• 负责人: Gilbert R Kinsey
• 金额: $ 0.93万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-23 至 2010-08-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044719
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Arts; Attenuated; Blood flow; Cells; Clinical; FDA approved; Immune; Immune response; Immune system; Immunosuppressive Agents; Inflammatory; Ischemia; Ischemic Preconditioning; Kidney; Laboratories; Leukocytes; Mediating; Mediator of activation protein; Methods; Modeling; Morbidity - disease rate; Neutrophil Infiltration; Organ; Patients; Production; Property; Regulatory T-Lymphocyte; Reperfusion Injury; Reperfusion Therapy; Role; Signal Transduction; Stimulus; T cell anergy; Testing; anergy; cytokine; high risk; killer T cell; mortality; new therapeutic target; prevent; protective effect; renal ischemia

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) induced by ischemia (loss of blood flow) is a significant clinical problem associated with high morbidity and mortality. Currently there are no FDA approved treatments for AKI. Increased accumulation and activation of immune system cells in the kidney after ischemia-reperfusion injury (IRI) are major mediators of AKI. Ischemic preconditioning (IPC) is a phenomenon induced by brief ischemia and reperfusion that renders an organ tolerant to subsequent prolonged ischemia. Several recent studies have demonstrated that renal IPC is in part mediated by cells of the immune system, but the precise mechanisms of the immune-mediated protection are not currently known. Preliminary studies in our laboratory have revealed that there are significant changes in kidney leukocytes induced by IPC, including a decrease in the number and activation of invariant natural killer T (iNKT) cells in the kidney after IRI. These iNKT cells have recently been shown to mediate kidney IRI through the early production of inflammatory cytokines and recruitment of neutrophils. Importantly, studies in other models have demonstrated that iNKT cells become anergic after initial stimulation; unable to respond to subsequent stimulus signals. In addition, we observed an increase in the number of resident regulatory T cells (Tregs) induced by IRI. Tregs have immunosuppressive properties and prevent excessive immune responses. The roles of iNKT cell anergy and Tregs in IPC have never been investigated. Thus we hypothesize IRI-induced iNKT cell anergy and/or accumulation of Tregs in the kidney mediate the protection afforded by IPC and propose to investigate this hypothesis through the following specific aims: 1) Test the hypothesis that kidney IPC induces phenotypic and quantitative changes in renal leukocytes, 2) Test the hypothesis that ischemia-reperfusion induced iNKT cell anergy mediates kidney IPC, 3) Test the hypothesis that regulatory T cells mediate the protective effects of kidney IPC. Relevance: Through the use of state of the art immunological methods we hope to harness immunological concepts that undergird renal IPC and identify potential novel therapeutic targets to prevent or attenuate the occurrence of AKI in high-risk patients. These strategies will likely be generalizable to IPC of other organs.

描述（由申请人提供）：缺血（血流损失）引起的急性肾脏损伤（AKI）是与高发病率和死亡率相关的重大临床问题。目前尚无FDA批准的AKI治疗方法。缺血再灌注损伤（IRI）后，肾脏中免疫系统细胞的积累和激活增加是AKI的主要介体。缺血性预处理（IPC）是短暂缺血和再灌注引起的一种现象，它可耐有器官，可耐受随后的延长缺血。最近的一些研究表明，肾脏IPC部分是由免疫系统细胞介导的，但是当前尚不清楚免疫介导的保护的确切机制。我们实验室的初步研究表明，IPC引起的肾脏白细胞有很大变化，包括IRI后肾脏中不变的天然杀伤剂（Inkt）细胞的数量和激活减少。最近，这些INKT细胞通过早期产生炎症细胞因子和中性粒细胞的募集来介导肾脏IRI。重要的是，其他模型中的研究表明，初始刺激后inkt细胞变得厌食。无法响应随后的刺激信号。此外，我们观察到IRI诱导的居民调节T细胞（TREG）数量增加。 Treg具有免疫抑制特性，并防止过度免疫反应。从未研究过Inkt Cell Anergy和Tregs在IPC中的作用。因此，我们假设肾脏在肾脏中引起的iNINV细胞消极和/或积累介导了IPC提供的保护，并建议通过以下具体目的通过以下特定目的研究这一假设：1）测试肾脏IPC在肾脏中诱导表型和定量变化的假设，该假说在肾脏中含量启发肾脏含量，2）均启发了静脉曲张的静脉曲张。 IPC，3）测试调节T细胞介导肾脏IPC的保护作用的假设。相关性：通过使用最先进的免疫学方法，我们希望利用肾脏IPC的免疫学概念，并确定潜在的新型治疗靶标，以预防或减轻高危患者中AKI的发生。这些策略可能会推广到其他器官的IPC。