Inhibition of platelet-leukocyte interactions to treat TRALI

抑制血小板-白细胞相互作用来治疗 TRALI

• 批准号: 7933939
• 负责人: Paul S Frenette
• 金额: $ 45.15万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933939
• 关键词: A Mouse; Acute Lung Injury; Address; Adhesions; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Area; Biological; Biological Assay; Biological Markers; Blood; Blood Cells; Blood Platelets; Blood Transfusion; Blood Vessels; Cell Adhesion Molecules; Cell Communication; Clinical; Clinical Research; Clinical Trials; Complex; Detection; Disease; E-Selectin; Endothelium; Erythrocytes; Etiology; Event; Fluorescence; Functional disorder; Future; Generations; Heart; Hematological Disease; Hematopoietic; Hour; Human; Image; Inflammatory; Injection of therapeutic agent; Injury; Integrins; Interleukin 2 Receptor Gamma; Lead; Leukocytes; Ligands; Lipids; Lung; Macrophage-1 Antigen; Mediating; Medicine; Methods; Modeling; Morbidity - disease rate; Mus; NOD/SCID mouse; Nature; Organ; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Preparation; Prevention; Production; Publishing; Rattus; Reactive Oxygen Species; Reporting; Resolution; Role; Selectins; Sickle Cell Anemia; Signal Transduction; Speed; Stem cells; Syndrome; System; Testing; Therapeutic; Transfusion; Umbilical Cord Blood Transplantation; base; cellular imaging; clinically relevant; design; in vivo; leukocyte activation; lung injury; lung vascular injury; meetings; mortality; mouse model; neutrophil; novel; preclinical study; prevent; public health relevance; safety testing; stem; tool; translational study

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (04) Clinical Research, and the specific Challenge Topic 04-HL-103 Assess the role of leukocyte interaction with platelets, erythrocytes, and endothelium in the pathogenesis of heart, lung, and blood diseases. Transfusion-related acute lung injury (TRALI), the main cause of transfusion-related morbidity and mortality reported to the FDA, is a clinical syndrome in which acute lung injury occurs within 6 hours of a blood transfusion. Although its pathophysiology remains unclear, antibodies and/or bioactive lipids activating polymorphonuclear neutrophils (PMNs) have been suggested to initiate the syndrome in patients with a predisposing pro-inflammatory event. Our preliminary studies suggest that platelet-leukocyte interactions play a key role in the disease. More specifically, endothelial signals emerging from the engagement of E- selectin with E-selectin ligand-1 (ESL-1) expressed on PMNs, induced the activation of the integrin Mac-1 at the leading edge of crawling PMNs, allowing the capture of platelets which, in turn, led to injury through the production of reactive oxygen species (ROS). The present challenge is to conduct pre-clinical studies and develop novel methods to assay this type of delayed PMN activation. The proposed translational studies will lead to a clinical trial testing the safety and efficacy of novel antagonists against adhesion molecules involved in TRALI. In Specific Aim 1, we evaluate the efficacy of GMI-1070, novel selectin antagonist, in an established mouse model of TRALI. In Specific Aim 2, we will develop a humanized model of TRALI in which mice harbor circulating human PMNs by transplantation of cord blood-derived hematopoietic stem and progenitor cells in immunodeficient NOD/SCID mice deficient in the IL-2r common gamma chain. We will induce TRALI by injection of an anti-HNA-2a, which was previously shown to produce lung injury in a rat ex vivo model. We will evaluate using multichannel fluorescence intravital microcopy (MFIM) whether the administration of this antibody induces platelet-leukocyte interactions and ROS generation. We will determine the effect of GMI-1070 administration on lung injury, and platelet-leukocyte interactions by MFIM. In Specific Aim 3, we will develop a clinically relevant biological marker of the secondary wave of PMN activation using flow-based imaging of platelet complexes with the polarized leading edge of PMNs. This assay will provide a novel biological end-point to assess PMN activation and the efficacy of anti-inflammatory drugs in clinical trials. PUBLIC HEALTH RELEVANCE: Preliminary studies suggest that platelet-leukocyte interactions play a key role in the pathogenesis of TRALI. In this proposal, we will perform translational studies and develop new tools in preparation of a clinical trial to treat and/or prevent TRALI.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (04) 临床研究，以及具体的挑战主题 04-HL-103 评估白细胞与血小板、红细胞和内皮细胞相互作用在心、肺、心肺疾病发病机制中的作用。和血液疾病。 输血相关急性肺损伤（TRALI）是向 FDA 报告的输血相关发病和死亡的主要原因，是一种在输血后 6 小时内发生急性肺损伤的临床综合征。尽管其病理生理学尚不清楚，但已表明激活多形核中性粒细胞 (PMN) 的抗体和/或生物活性脂质可在具有诱发促炎事件的患者中引发该综合征。我们的初步研究表明血小板-白细胞相互作用在该疾病中发挥关键作用。更具体地说，E-选择素与 PMN 上表达的 E-选择素配体-1 (ESL-1) 结合产生的内皮信号，诱导爬行 PMN 前缘整合素 Mac-1 的激活，从而捕获血小板，进而通过产生活性氧（ROS）导致损伤。目前的挑战是进行临床前研究并开发新方法来检测这种类型的延迟性 PMN 激活。拟议的转化研究将进行一项临床试验，测试针对 TRALI 中涉及的粘附分子的新型拮抗剂的安全性和有效性。在具体目标 1 中，我们评估了新型选择素拮抗剂 GMI-1070 在已建立的 TRALI 小鼠模型中的功效。在具体目标 2 中，我们将开发 TRALI 人源化模型，其中通过将脐带血来源的造血干细胞和祖细胞移植到缺乏 IL-2r 共同伽玛链的免疫缺陷 NOD/SCID 小鼠中，使小鼠体内含有循环的人类 PMN。我们将通过注射抗 HNA-2a 来诱导 TRALI，此前已证明该抗 HNA-2a 在大鼠离体模型中会产生肺损伤。我们将使用多通道荧光活体显微镜 (MFIM) 评估施用该抗体是否会诱导血小板-白细胞相互作用和 ROS 生成。我们将通过 MFIM 确定 GMI-1070 给药对肺损伤和血小板-白细胞相互作用的影响。在具体目标 3 中，我们将使用具有 PMN 偏振前缘的血小板复合物的基于流的成像来开发 PMN 激活二次波的临床相关生物标记。该测定将为临床试验中评估 PMN 激活和抗炎药物的功效提供一个新的生物学终点。 公共卫生相关性：初步研究表明血小板-白细胞相互作用在 TRALI 的发病机制中发挥着关键作用。在本提案中，我们将进行转化研究并开发新工具，以准备治疗和/或预防 TRALI 的临床试验。