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: 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
• 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

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）： 顺铂和其它铂衍生物是用于治疗实体瘤的重要化疗剂。顺铂给药的一种已知并发症是急性肾损伤（阿基），通常需要减少剂量或停药。因此，了解顺铂诱导的阿基的发病机制对于开发预防阿基和减少剂量减少或停药的需要的预防性治疗是重要的。IL-33是IL-1家族中新描述的促炎细胞因子，其通过ST 2受体发出信号。我们发表的数据表明，IL-33抑制减弱CD 4 T细胞浸润，肾衰竭和ATN，重组IL-33的施用抑制顺铂诱导的阿基，并增加野生型但非CD 4-/-小鼠中的趋化因子CXCL 1，并且CD 4 T细胞耗竭具有保护作用。本授权中提出的总体假设提供了一个综合的病理生理学模式，其中IL-33导致肾脏中的CD 4 T细胞募集、CXCL 1从CD 4 T细胞释放和顺铂诱导的阿基。将在顺铂诱导的阿基、小鼠癌症模型、内皮细胞和新鲜分离的近端小管中进行补充研究。具体目标1关注肾脏中IL-33和ST 2的细胞来源。 在具体目标2中，我们将确定IL-33在顺铂诱导的阿基中的损伤作用。将使用IL-33或ST 2抑制的补充新药理学和遗传学技术。将研究IL-33、ST 2和CXCL 1抑制和CD 4 T细胞敲除对顺铂诱导的阿基的影响以及顺铂在小鼠癌症模型中的化疗功效。具体目标3关注肾脏中CD 4 T细胞的IL-33依赖性CXCL 1产生。将确定CXCL 1抑制剂对阿基的影响。CXCL 1在体外可直接导致细胞死亡。CXCL 1在体外直接致大鼠近曲小管损伤中的作用 将确定是否存在炎症。将进行新的实验，研究通过CD 4 T细胞耗竭，然后在有或没有目标分子（例如IL-33）的情况下过继转移CD 4 T细胞，对顺铂诱导的阿基的保护作用。这些研究与临床顺铂诱导的阿基的相关性是实质性的，并且顺铂诱导的阿基的新介质的发现应该为未来的治疗提供线索。由于目前已有FDA批准的抗炎药、正在进入临床研究的IL-33/ST 2抑制剂和正在临床研究的CXCL 1抑制剂，因此这一点尤其如此。