Leukocyte trafficking in acute renal failure

急性肾衰竭中的白细胞转运

基本信息

批准号：
8586257
负责人：
Mark Douglas Okusa
金额：
$ 34.37万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8586257
关键词：
5&apos -Nucleotidase Acute Kidney Failure Acute Renal Failure with Renal Papillary Necrosis Adenosine Adverse effects Agonist Allogenic Attenuated Autoimmune Diseases Blood Platelets Cell Therapy Cell physiology Cells Chronic Kidney Failure Cisplatin Clinical Trials Critical Illness Data Dendritic Cells Dendritic cell activation Development Economics Effectiveness End stage renal failure Exposure to FDA approved Foundations Functional disorder Funding Future Genetic Goals Grant Homeostasis Hospitalization Human Hypotension IL17 gene ITGAX gene Immune response Immune system Immunity Immunosuppression In Vitro Inflammation Inflammatory Inflammatory Response Injury Injury to Kidney Interleukin-10 Kidney Kidney Diseases Laboratories Lead Leukocyte Trafficking Longevity Malignant Neoplasms Memory Methods Modality Modeling Molecular Morbidity - disease rate Mus Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phosphoenolpyruvate Carboxylase Play Prevention Prevention therapy Process Production Public Health Reagent Regulatory T-Lymphocyte Reperfusion Injury Reporter Resistance Role Series Signal Transduction Survivors Testing Therapeutic Tissues Transgenic Mice Transplantation United States base disorder control effective therapy in vivo killer T cell mortality nephrotoxicity new therapeutic target novel novel therapeutic intervention paracrine pre-clinical preclinical study prevent public health relevance receptor renal ischemia tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): There are no FDA approved drugs for the prevention and treatment of acute kidney injury (AKI). Thus, mortality remains high and survivors of AKI suffer from significant morbidity; many develop chronic kidney disease and end stage renal disease. A precise understanding of early mechanisms of AKI is critically needed to guide development of novel therapies. Over the past two grant cycles, we identified novel therapeutic targets for the prevention and treatment of AKI. Among these, tissue resident dendritic cells (DCs) play disparate roles in tissue homeostasis - assuming a central role in the early pathogenesis of AKI, yet also playing a tolerogenic role - and in different forms of AKI, where they promote injury in ischemia-reperfusion injury (IRI) and are protective in cisplatin nephrotoxicity (CN). During the current funding cycle new information has shown that DCs can initiate immune responses following kidney IRI by activating natural killer T cells via the IL23/IL17 pathway. Abrogating this process, e.g. by adenosine 2a receptor (A2aR) agonist administration, attenuates injury. DCs express A2aRs; we demonstrate that DCs are tolerized by exposure to A2aR agonists. We propose studies to better understand the role of DC function in AKI and the role of adenosine signaling through endogenous DC A2aRs in two models of AKI (IRI and CN). These fundamental findings form the basis of a cell-based therapeutic approach, modeled after current clinical trials in cancer, autoimmune diseases, and transplantation, to tolerize DCs ex vivo with A2aR agonists for the prevention and treatment of AKI. Our preliminary data demonstrate that endogenous DC A2aRs critically control the extent of IRI, administration of A2a-tolDCs (up to 7 days before or 6 hrs after injury) protects kidneys from IRI, A2a agonists block CN, and allogenic A2a-tolDCs block IRI. Our studies will define the mechanism by which A2a agonists tolerize both murine and human DCs and the mechanism by which they prevent kidney AKI in vivo. The significance of this approach is that cell-based therapy using A2a-tolDC promotes superior tissue protection with a broad therapeutic window, avoids systemic administration of a drug (or other drugs) that could potentially have adverse side effects such as platelet dysfunction, hypotension and systemic immunosuppression, serves as a proof of concept model that tolerized DCs (from any treatment modality) may be useful in future strategies for the treatment of AKI, and promotes prolonged protection due to a lasting memory effect of A2a agonists on DCs. Using transgenic mice, selective pharmacological reagents, and novel reagents, we will test the hypotheses that (Aim 1) endogenous DC A2aRs control the extent of IRI and CN, (Aim 2) A2a-tolerized DCs are effective in prevention of AKI and treatment of established AKI, and (Aim 3) A2a-tolDCs protect kidneys by enhancing IL-10 signaling and regulatory T cells. These studies will form the basis of therapy for prevention of AKI and more broadly for transplantation and other autoimmune diseases.

描述（由申请人提供）：FDA 尚无批准用于预防和治疗急性肾损伤（AKI）的药物。因此，死亡率仍然很高，AKI 幸存者的发病率也很高；许多人患上慢性肾病和终末期肾病。为了指导新疗法的开发，迫切需要准确了解 AKI 的早期机制。在过去的两个资助周期中，我们确定了预防和治疗 AKI 的新治疗靶点。其中，组织驻留树突状细胞 (DC) 在组织稳态中发挥着不同的作用 - 在 AKI 的早期发病机制中发挥着核心作用，但也发挥着耐受性作用 - 并且在不同形式的 AKI 中，它们促进缺血再灌注损伤损伤（IRI）并对顺铂肾毒性（CN）具有保护作用。在当前的资助周期中，新信息表明 DC 可以通过 IL23/IL17 途径激活自然杀伤 T 细胞，从而在肾脏 IRI 后启动免疫反应。废除这个过程，例如通过腺苷 2a 受体 (A2aR) 激动剂给药，可减轻损伤。 DC 表达 A2aR；我们证明 DC 可以通过暴露于 A2aR 激动剂而耐受。我们提出研究以更好地了解 DC 功能在 AKI 中的作用以及通过内源 DC A2aR 的腺苷信号传导在两种 AKI 模型（IRI 和 CN）中的作用。这些基本发现构成了基于细胞的治疗方法的基础，该方法仿照当前癌症、自身免疫性疾病和移植的临床试验，使 DC 离体耐受 A2aR 激动剂，以预防和治疗 AKI。我们的初步数据表明，内源性 DC A2aR 关键控制 IRI 的程度，施用 A2a-tolDC（受伤前 7 天或受伤后 6 小时）可保护肾脏免受 IRI 影响， A2a 激动剂阻断 CN，同种异体 A2a-tolDC 阻断 IRI。我们的研究将明确 A2a 激动剂耐受小鼠和人类 DC 的机制，以及它们在体内预防肾脏 AKI 的机制。这种方法的意义在于，使用 A2a-tolDC 的细胞疗法可通过广泛的治疗窗促进卓越的组织保护，避免全身给药可能产生不良副作用（例如血小板功能障碍、低血压和全身性免疫抑制，作为概念验证模型，证明耐受的 DC（来自任何治疗方式）可能在未来治疗 AKI 的策略中有用，并由于 A2a 激动剂的持久记忆效应而促进长期保护DC。使用转基因小鼠、选择性药理学试剂和新型试剂，我们将测试以下假设：（目标 1）内源性 DC A2aR 控制 IRI 和 CN 的程度，（目标 2）A2a 耐受的 DC 可以有效预防 AKI 和治疗已建立的 AKI 和（目标 3）A2a-tolDC 通过增强 IL-10 信号传导和调节性 T 细胞来保护肾脏。这些研究将构成预防 AKI 以及更广泛的移植和其他自身免疫性疾病的治疗基础。