Platelets and complement in antibody-mediated rejection

抗体介导的排斥反应中的血小板和补体

• 批准号: 9086203
• 负责人: William M Baldwin
• 金额: $ 39.02万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086203
• 关键词: Acute; Allografting; Antibodies; Antigens; Apoptosis; Autoantigens; Binding; Biological Markers; Biopsy; Blood Platelets; Blood Vessels; Characteristics; Chemotaxis; Chronic; Cleaved cell; Clinical Research; Complement; Complement Inactivators; Data; Endothelial Cells; Epitopes; Extracellular Matrix Proteins; Fibrosis; Figs - dietary; Functional disorder; Funding; Glycosaminoglycans; Goals; Human; Hyaluronan; Hyaluronidase; IL8 gene; Impairment; In Vitro; Inflammation; Inflammatory; Injury; Kidney Transplantation; Lesion; Leukocytes; Lupus; Mediating; Mediator of activation protein; Modeling; P-Selectin; Pathologic; Patients; Platelet Activation; Platelet Factor 4; Properdin; Protocols documentation; RANTES; Recruitment Activity; Reporting; Rheumatoid Arthritis; Role; Serotonin; Signal Transduction; Site; Staging; Testing; Therapeutic Intervention; Toll-like receptors; Vascular Diseases; Vascular Endothelium; Vascular Permeabilities; abstracting; base; chemokine; clinically relevant; in vivo Model; inhibitor/antagonist; kidney allograft; macrophage; monocyte; mouse model; response; von Willebrand Factor

Project Summary / Abstract Antibodies are a major cause of acute and chronic rejection in renal transplants. Some pathologic manifestations of acute antibody-mediated rejection (AMR) that has progressed to graft dysfunction have been defined. However, it is evident that not all of the mediators of AMR have been identified. The potentially reversible stages that precede graft impairment are difficult to resolve in clinical studies even with protocol biopsies because of uncontrollable variables inherent among patients. We have used in vitro and in vivo models to demonstrate that antibodies stimulate endothelial cells to exocytose von Willebrand factor and P- selectin. We propose that activated platelets have critical functions in early AMR and greatly expand inflammation by interacting with endothelial cells and leukocytes. We reported that platelet factor 4 and serotonin accumulated in renal allografts at 100- to 1000-fold higher concentrations compared with other platelet-transported mediators. The localization of large quantities of platelet factor 4 in the allograft has multiple consequences on macrophage function. These interactions are particularly relevant because macrophage infiltrates in human biopsies are a characteristic of AMR. Release of serotonin from platelets also has potential to recruit leukocytes to renal transplants. In addition, platelets can stimulate monocytes and macrophages indirectly at sites of inflammation where endothelial cells release increased amounts of the extracellular matrix protein hyaluronan. Hyaluronidase 2 expressed by activated platelets cleaves HA into fragments that act as danger signals to stimulate macrophages through toll like receptors. The potential beneficial effects of modulating platelet activation in AMR have not been tested fully. In addition to blocking specific platelet mediators, we have found that clinically relevant complement inhibitors are one approach to decrease platelet localization in allografts. We propose the hypothesis that antibodies initiate platelet and endothelial responses that augment leukocyte interactions with blood vessels in renal transplants during AMR. We will test this hypothesis in 3 specific aims: 1) Test the role of platelet-derived mediators in directly causing injury to renal transplants; 2) Test the multiple effects of C1 inhibitor on recruitment and activation of platelets and macrophages; and 3) Test the role of hyaluronan released by vascular endothelium and cleaved by platelets in augmenting inflammation and contributing to fibrosis in renal transplants. To accomplish these specific aims, we will use mouse models of AMR in renal transplants that have been developed by Drs. Fairchild and Valujskikh in Projects 1 and 3 in the previous funding period as well as the passive transfer models developed in our Project 2. Our goals for each specific aim are to understand mechanisms by which platelets contribute to AMR, identify biomarkers of platelet-induced injury and test potential therapeutic interventions.

项目摘要 /摘要 抗体是肾移植中急性和慢性排斥反应的主要原因。一些病理 已发展为移植功能障碍的急性抗体介导的排斥反应（AMR）的表现已 定义。但是，很明显，并非已经确定了AMR的所有调解人。潜在的 在临床研究中，在临床研究中也难以解决移植物损伤之前的可逆阶段 活检是由于患者固有的不可控制的变量。我们已经在体外和体内使用 模型证明抗体会刺激对胞外剂量von willebrand因子和p-的内皮细胞 selectin。我们建议活化的血小板在早期AMR中具有关键功能，并且大大扩展 通过与内皮细胞和白细胞相互作用来炎症。我们报道了血小板因子4和 与其他 血小板传输的介体。同种异体移植中大量血小板因子4的定位具有 对巨噬细胞功能的多重后果。这些互动特别重要，因为 人类活检中的巨噬细胞浸润是AMR的特征。血小板也释放5-羟色胺 有可能将白细胞募集到肾移植。此外，血小板可以刺激单核细胞和 巨噬细胞在炎症部位间接地释放内皮细胞增加了数量 细胞外基质蛋白透明质酸。透明质酸2由激活的血小板裂解 充当危险信号的碎片通过像受体一样的收费刺激巨噬细胞。潜力 在AMR中调节血小板激活的有益作用尚未完全测试。除了阻止 特定的血小板介质，我们发现临床相关补体抑制剂是一种方法 减少同种异体移植物中的血小板定位。我们提出了以下假设：抗体启动血小板和 内皮反应增加了白细胞与肾移植中血管的相互作用 在AMR期间。我们将在3个特定目的中检验这一假设：1）测试血小板衍生的介体在 直接导致肾脏移植受伤； 2）测试C1抑制剂对招募和 血小板和巨噬细胞的激活； 3）测试血管内皮释放的透明质酸的作用 并被血小板裂解，以增加炎症并导致肾移植的纤维化。到 完成这些特定目的，我们将在已经 由Drs开发。在上一个资金期间，项目1和3中的Fairchild和Valujskikh以及 在我们的项目2中开发的被动转移模型。我们针对每个特定目标的目标是了解 血小板有助于AMR的机制，鉴定血小板诱导的损伤的生物标志物和 测试潜在的治疗干预措施。