Leukocyte trafficking in acute renal failure

急性肾衰竭中的白细胞转运

• 批准号: 8984301
• 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
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8984301
• 关键词: 5' -Nucleotidase; ADORA2A gene; 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; Health; 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; Knockout Mice; 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; novel therapeutics; paracrine; pre-clinical; preclinical study; prevent; receptor; renal ischemia; tool; treatment strategy; 5' -Nucleotidase; ADORA2A gene; 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; Health; 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; Knockout Mice; 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; novel therapeutics; paracrine; pre-clinical; preclinical study; prevent; receptor; renal ischemia; tool; treatment strategy

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）：没有FDA批准的药物用于预防和治疗急性肾脏损伤（AKI）。因此，死亡率仍然很高，AKI的幸存者遭受了明显的发病率。许多人患有慢性肾脏疾病和终阶段肾脏疾病。需要对AKI的早期机制进行确切的理解，以指导新型疗法的发展。在过去的两个赠款周期中，我们确定了预防和治疗AKI的新型治疗靶标。 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).在当前的融资周期中，新信息表明，DC可以通过IL23/IL17途径激活自然杀伤剂T细胞来引发肾脏IRI后的免疫反应。废除此过程，例如通过腺苷2A受体（A2AR）激动剂给药，减轻了损伤。 DCS表达A2AR；我们证明了DC通过暴露于A2AR激动剂的耐受性。我们提出的研究以更好地了解DC功能在AKI中的作用以及通过内源性DC A2AR在AKI模型（IRI和CN）中通过内源性DC A2AR的作用。这些基本发现构成了基于细胞的治疗方法的基础，该方法以癌症，自身免疫性疾病和移植的当前临床试验为基础，以耐用A2AR激动剂来预防和治疗AKI。我们的初步数据表明，内源性DC A2AR批判性地控制IRI的范围，施用A2A-TOLDC（在受伤前长达7天或6小时）可以保护肾脏免受IRI的影响， A2A激动剂阻止CN和同种异体A2A-TOLDCS阻止IRI。我们的研究将定义A2a激动剂耐鼠和人类DC的机制以及它们阻止体内肾脏Aki的机制。这种方法的意义在于，使用A2A-TOLDC的基于细胞的治疗可以通过广泛的治疗窗口促进优质的组织保护，避免系统地给药（或其他药物），这些药物（或其他药物）可能会产生不良副作用的不良副作用，例如血小板功能障碍，低血压和全身性免疫抑制作用，可用于对任何概念的证明，以适用于dc的策略（可用于策略），以适用于任何有效的治疗方法，并且是有效的，该策略是有效的，并且是由有效的方法进行治疗，并且可以使其适用。由于A2A激动剂对DCS的持久记忆效应，促进了长时间的保护。使用转基因小鼠，选择性的药理试剂和新试剂，我们将测试（目标1）内源性DC A2AR控制IRI和CN的程度（AIM 2）A2A含量的DC有效预防AKI的AKI和AIM 3），（AIM 3）A2A-TOLDCS SINDULS and SIGNULS SIGNNEDS NESTIND STHENNE，该假设是有效的。这些研究将构成预防AKI的治疗基础，并更广泛地移植和其他自身免疫性疾病。