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

基本信息

批准号：
8774189
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
项目类别：
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/8774189
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 Health 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 receptor research study tumor growth

项目摘要

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）：顺铂和其他铂衍生物是用于治疗实体瘤的重要化学治疗剂。顺铂给药的已知并发症是急性肾脏损伤（AKI），通常需要减少剂量或退出剂量。因此，了解顺铂诱导的AKI的发病机理对于开发辅助疗法以防止AKI并减少剂量降低或抽取药物的需求。 IL-33是通过ST2受体发出信号的IL-1家族中新描述的促炎性细胞因子。我们已发表的数据表明，IL-33抑制作用减轻了CD4 T细胞浸润，肾功能衰竭和ATN，重组IL-33的给药使顺铂诱导的AKI恶化，使AKI造成了AKI，并增加了野生型CXCL1的趋化因子CXCL1，但不是CD4 - / - 小鼠和该CD4 T细胞 - 脱发是保护性的。该赠款中提出的总体假设提供了一个综合的病理生理模式，IL-33在肾脏中导致CD4 T细胞募集，从CD4 T细胞中释放CXCL1和顺铂诱导的AKI。互补研究将在用顺铂诱导的AKI，小鼠癌模型，内皮细胞和新鲜分离的近端小管中进行。特定的目标1专注于肾脏中IL-33和ST2的细胞来源。在特定目标2中，我们将确定IL-33在顺铂诱导的AKI中的有害作用。将使用IL-33或ST2抑制的免费新型药理和遗传技术。将研究IL-33，ST2和CXCL1抑制作用和CD4 T细胞基因敲除对顺铂诱导的AKI的影响，以及顺铂在小鼠癌症模型中的化学治疗疗效。特定目标3的重点是肾脏中CD4 T细胞对CXCL1的IL-33依赖性产生。将确定CXCL1抑制剂对AKI的影响。 CXCL1可以直接在体外引起细胞死亡。 CXCL1直接在体外引起近端小管损伤的作用将确定缺乏炎症。新的实验研究了CD4 T细胞耗竭对二铂诱导的AKI的影响，然后使用有或没有感兴趣的分子的CD4 T细胞的生育转移，例如将执行IL-33。这些研究与临床顺铂诱导的AKI的相关性是很大的，并且发现顺铂诱导的AKI的新型介体应该为未来的疗法提供线索。尤其如此，因为目前获得了FDA批准的抗炎药的可用性，即进入临床研究的IL-33/ST2抑制剂以及临床研究中的CXCL1抑制剂。