The Consequence of Impaired Lymphatic Drainage on Rejection in Cardiac Transplantation

心脏移植排斥反应中淋巴引流受损的后果

• 批准号: 10534249
• 负责人: Sydney C Ginn
• 金额: $ 4.77万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534249
• 关键词: Abdomen; Allografting; Antigens; Area; Binding; Biocompatible Materials; Blood capillaries; Blood flow; Cardiac; Cardiac health; Cause of Death; Cells; Cessation of life; Chronic; Circulation; Communities; Coronary artery; Coupled; Data; Data Collection; Development; Diagnosis; Disease; Disease model; Drainage procedure; Edema; Encapsulated; Engineering; Etiology; Excision; Family; Fibrosis; Fluid Balance; Functional disorder; Goals; Graft Rejection; Graft Survival; Growth; Heart; Heart Transplantation; Human; Hydrogels; Immune; Immune response; Immune system; Immunologics; Infiltration; Inflammation; Inflammatory; Intercellular Fluid; Knowledge; Longevity; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic function; Malignant Neoplasms; Modeling; Myocardial; Myocardial Infarction; Operative Surgical Procedures; Outcome; Pathologic; Patients; Phenotype; Process; Proliferating; Rattus; Research; Resolution; Rodent; Rodent Model; Route; Severities; Signal Transduction; Testing; Therapeutic; Time; Tissues; Transplant Recipients; Transplantation; Vascular Diseases; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factors; Vascular resistance; angiogenesis; cell motility; clinical diagnosis; combat; curative treatments; cytokine; density; ethylene glycol; experimental study; graft failure; graft function; heart function; human study; immune cell infiltrate; immune clearance; immunogenic; improved; improved outcome; insight; lymphatic circulation; lymphatic development; lymphatic drainage; lymphatic dysfunction; lymphatic malformations; lymphatic vessel; mortality; new therapeutic target; novel; novel strategies; pediatric patients; post-transplant; prevent; receptor; reconstitution; response; retransplantation; second transplant; therapeutic target; trafficking; transplant model

PROJECT SUMMARY The leading cause of chronic cardiac transplant rejection—coronary artery vasculopathy (CAV)—remains a major factor limiting long-term survival in heart transplant patients worldwide. The disease causes concentric intimal thickening along the coronary arteries leading to luminal narrowing and increased vascular resistance. CAV pathophysiology is thought to involve chronic inflammation and various immunogenic factors, implicating the lymphatic network as a potential therapeutic target. During heart transplantation, the lymphatic network is severed upon donor heart excision and not surgically reconstructed. The consequence resulting from severed lymphatic vessels in transplanted hearts is unknown. An intact lymphatic network is imperative in maintaining heart health through immune cell trafficking and tissue-fluid homeostasis. Lymphangiogenesis drives lymphatic reconstitution through the vascular endothelial growth factor (VEGF) family, where VEGF-C/VEGFR-3 signaling predominates. Previous studies have shown the beneficial effects of augmenting lymphatic growth via VEGF- C/VEGFR-3 signaling on cardiac function by simultaneously enhancing immune clearance and reducing myocardial edema and fibrosis in a disease model of myocardial infarction. We hypothesize this disruption in lymphatic drainage potentiates inflammation by impeding the egress of immune cells and pro-inflammatory cytokines out of the donor heart exacerbating transplant rejection. Preliminary results in our retrospective human study indicate significant differences in lymphatic area at earlier timepoints in an allograft’s lifespan between transplant patients with and without a clear clinical diagnosis of CAV. These data suggest modulating lymphatic development directly after cardiac transplantation may predetermine transplant outcomes by establishing critical routes of drainage earlier in the process. The long-term goal of this study is to elucidate the consequence of lymphatic dysfunction in heart transplant rejection and develop a localized, sustained lymphangiogenic-focused therapy to combat the implications of this disease. In Specific Aim 1, we will identify the effect of severed lymphatics on immune cell infiltration and rejection severity by inducing transplant acceptance and rejection in a heterotopic abdominal heart transplant rodent model. In Specific Aim 2, we will evaluate the effects of localized lymphatic augmentation on donor graft function utilizing VEGF-C encapsulated in a poly(ethylene glycol)-based hydrogel. Understanding pathologic conditions associated with lymphatic dysfunction in cardiac transplantation will provide novel therapeutic targets that enhance the longevity of donor grafts and reduce mortality among the transplant community. Optimizing cardiac function and donor graft survival is especially important for pediatric patients that require multiple heart transplants throughout their lifetime.

项目总结 慢性心脏移植排斥反应的主要原因-冠状动脉血管病变(CAV)-仍然是 限制全球心脏移植患者长期存活的主要因素。本病引起同心圆 冠状动脉内膜增厚导致管腔狭窄和血管阻力增加。 CAV的病理生理学被认为涉及慢性炎症和各种免疫原性因素，牵涉到 淋巴网络作为潜在的治疗靶点。在心脏移植期间，淋巴网络是 在供者心脏切除后被切断，而不是通过手术重建。被割断的后果 移植心脏中的淋巴管是未知的。一个完整的淋巴网络对于维持 通过免疫细胞运输和组织液平衡来维持心脏健康。淋巴管生成驱动淋巴管 通过血管内皮生长因子(VEGF)家族的重建，其中VEGF-C/VEGFR-3信号转导 占主导地位。先前的研究表明，通过血管内皮生长因子促进淋巴生长的有益效果。 C/VEGFR-3信号转导同时增强免疫清除和降低心脏功能 心肌梗死疾病模型中的心肌水肿和纤维化。我们假设这种颠覆发生在 淋巴引流通过阻碍免疫细胞和促炎细胞的外流而加剧炎症 来自供体心脏的细胞因子加剧了移植排斥反应。在我们的人类回顾性研究中的初步结果 研究表明，在同种异体移植物寿命的早期时间点， 临床诊断明确和不明确的移植患者CAV。这些数据表明调节淋巴系统 心脏移植后的直接发育可能通过建立关键的 在这一过程中，更早的排水路线。这项研究的长期目标是阐明其后果 在心脏移植排斥反应中淋巴功能障碍并发展为局部的、持续的 以淋巴管生成为重点的治疗，以对抗这种疾病的影响。在具体目标1中，我们将 通过诱导移植确定切断淋巴管对免疫细胞浸润和排斥反应严重程度的影响 异位腹部心脏移植啮齿动物模型的接受和排斥。在具体目标2中，我们将 应用血管内皮生长因子-C评价局部淋巴增强对供体移植物功能的影响 在聚乙二醇基的水凝胶中。了解与淋巴管相关的病理情况 心脏移植的功能障碍将提供新的治疗靶点，延长供者的寿命 减少移植物移植，降低移植社区的死亡率。优化心脏功能和供者移植物存活率 对于一生需要多次心脏移植的儿科患者来说，这一点尤其重要。