The IL-33/CD4 T cell/CXCL1 System in Acute Kidney Injury

IL-33/CD4 T 细胞/CXCL1 系统在急性肾损伤中的作用

• 批准号: 8624518
• 负责人: CHARLES Louis EDELSTEIN
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624518
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adoptive Transfer; Adverse effects; Anti-Inflammatory Agents; Antibodies; Antineoplastic Agents; Applications Grants; Attenuated; Binding; Blood Vessels; CD4 Positive T Lymphocytes; CXCL1 gene; Cancer Model; Cancer Patient; Cardiovascular Diseases; Cause of Death; Cell Death; Cells; Chemotactic Factors; Chronic Kidney Failure; Cisplatin; Clinical; Clinical Research; Complication; Data; Dendritic Cells; Development; Diabetes Mellitus; Dose; Dose-Limiting; Endothelial Cells; FDA approved; Family; Family member; Functional disorder; Future; Genetic Techniques; Grant; IL8RB gene; ITGAX gene; In Situ Hybridization; In Vitro; Infiltration; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Interleukin-1; Interleukin-18; Interleukin-8B Receptor; Kidney; Kidney Failure; Knock-out; Malignant Neoplasms; Malignant neoplasm of lung; Mediator of activation protein; Methods; Mus; Pathogenesis; Platinum; Play; Population; Production; Proteins; Protocols documentation; Publishing; Recombinants; Risk Factors; Role; Signal Transduction; Smooth Muscle Myocytes; Solid Neoplasm; Source; Staining method; Stains; System; T-Cell Depletion; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Transgenic Organisms; Tubular formation; Veterans; Withdrawal; chemokine; chemotherapeutic agent; cytokine; drug withdrawal; improved; inhibitor/antagonist; interest; macrophage; nephrotoxicity; neutrophil; novel; novel therapeutics; prevent; public health relevance; receptor; research study; tumor growth

DESCRIPTION (provided by applicant): Cisplatin and other platinum derivatives are important chemotherapeutic agents used to treat solid tumors. A known complication of cisplatin administration is acute kidney injury (AKI) which often necessitates dose reduction or withdrawal. Therefore, an understanding of the pathogenesis of cisplatin-induced AKI is important for the development of adjunctive therapies to prevent AKI and to lessen the need for dose decrease or drug withdrawal. IL-33 is a newly described pro-inflammatory cytokine in the IL-1 family that signals via the ST2 receptor. Our published data demonstrate that IL-33 inhibition attenuates CD4 T cell infiltration, renal failure and ATN, that administration of recombinant IL-33 worsens cisplatin-induced AKI and increases the chemokine CXCL1 in wild type but not CD4 -/- mice and that CD4 T cell-depletion is protective. The overall hypothesis presented in this grant provides an integrated pathophysiological schema whereby IL-33 results in CD4 T cell recruitment in the kidney, release of CXCL1 from CD4 T cells and cisplatin-induced AKI. Complementary studies will be performed in mice with cisplatin-induced AKI, mouse cancer models, endothelial cells and freshly isolated proximal tubules. Specific Aim 1 focuses on the cellular source of IL-33 and ST2 in the kidney. In Specific Aim 2, we shall determine the injurious role of IL-33 in cisplatin-induced AKI. Complimentary novel pharmacological and genetic techniques of IL-33 or ST2 inhibition will be used. The effect of IL-33, ST2 and CXCL1 inhibition and CD4 T cell knockout on cisplatin-induced AKI and the chemotherapeutic efficacy of cisplatin in mouse cancer models will be studied. Specific Aim 3 focuses on the IL-33-dependent production of CXCL1 by CD4 T cells in the kidney. The effect of CXCL1 inhibitors on AKI will be determined. CXCL1 can directly cause cell death in vitro. The effect of CXCL1 to directly cause proximal tubule injury in vitro in the absence of inflammation, will be determined. Novel experiments investigating the effect on protection against cisplatin-induced AKI by CD4 T cell depletion followed by adoptive transfer of CD4 T cells with or without the molecule of interest e.g. IL-33 will be performed. The relevance of these studies to clinical cisplatin-induced AKI is substantial and the discovery of novel mediators of cisplatin-induced AKI should provide clues to future therapies. This is particularly true because of the current availability of anti-inflammatory agents that are FDA- approved, IL-33/ST2 inhibitors that are entering clinical studies and CXCL1 inhibitors that are in clinical studies.

描述(由申请人提供)： 顺铂等铂类化合物是治疗实体瘤的重要化疗药物。顺铂治疗的一个已知并发症是急性肾损伤(AKI)，通常需要减少剂量或停药。因此，了解顺铂诱导AKI的发病机制对于开发预防AKI的辅助治疗和减少减少剂量或停药的需要具有重要意义。IL-33是IL-1家族中的一种新近发现的促炎细胞因子，它通过ST2受体传递信号。我们发表的数据表明，抑制IL-33可以减少CD4T细胞的渗透、肾功能衰竭和ATN，重组IL-33的应用可以恶化顺铂诱导的AKI，并增加野生型但不是CD4-/-小鼠的趋化因子CXCL1，并且CD4T细胞耗尽具有保护作用。这项资助中提出的总体假设提供了一个综合的病理生理学方案，根据该方案，IL-33导致CD4T细胞在肾脏中的募集，从CD4T细胞中释放CXCL1，以及顺铂诱导的AKI。补充研究将在顺铂诱导的AKI小鼠、小鼠癌症模型、内皮细胞和新鲜分离的近端小管上进行。具体目标1重点研究肾脏中IL-33和ST2的细胞来源。在特定的目标2中，我们将确定IL-33在顺铂诱导的AKI中的损伤作用。将使用IL-33或ST2抑制的免费新药理和遗传技术。我们将研究IL-33、ST2和CXCL1的抑制以及CD4T细胞敲除对顺铂诱导的AKI的影响以及顺铂对小鼠肿瘤模型的化疗效果。具体目标3集中在肾脏中CD4T细胞产生依赖于IL-33的CXCL1。CXCL1抑制剂对AKI的影响将被确定。CXCL1在体外可直接导致细胞死亡。CXCL1直接致近端小管损伤的体外实验研究 是否没有炎症，将被确定。将进行新的实验，研究通过去除CD4T细胞，然后过继转移带有或不带有感兴趣分子(如IL-33)的CD4T细胞来保护顺铂诱导的AKI的效果。这些研究与顺铂诱导的AKI的临床相关性很大，顺铂诱导的AKI的新介质的发现应该为未来的治疗提供线索。这一点尤其正确，因为目前有FDA批准的抗炎药、正在进入临床研究的IL-33/ST2抑制剂和正在进行临床研究的CXCL1抑制剂。