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: 10490963
• 负责人: Sydney C Ginn
• 金额: $ 4.68万
• 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/10490963
• 关键词: Abdomen; Allografting; Antigens; Area; Binding; Biocompatible Materials; Blood Circulation; Blood capillaries; Blood flow; Cardiac; Cardiac health; Cause of Death; Cells; Cessation of life; Chronic; 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; Light; Longevity; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic function; Malignant Neoplasms; Modeling; Myocardial; Myocardial Infarction; Operative Surgical Procedures; Outcome; Pathologic; Patients; Phenotype; Process; 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; base; cell motility; clinical diagnosis; combat; curative treatments; cytokine; density; ethylene glycol; experimental study; graft failure; graft function; heart function; human study; 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; 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.

项目摘要 慢性心脏移植排斥反应的主要原因 - 冠状动脉血管病（CAV） 全球心脏移植患者长期生存的主要因素。疾病引起同心 沿冠状动脉的内膜增厚，导致管腔狭窄并增加血管耐药性。 CAV病理生理学被认为涉及慢性炎症和各种免疫原性因素，隐含 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 因捐助者的心脏而切断了惊喜，没有手术重建。被切断的结果 移植心脏中的淋巴管尚不清楚。完整的淋巴网络必须维持 通过免疫细胞贩运和组织流体稳态的心脏健康。淋巴管生成驱动淋巴 通过血管内皮生长因子（VEGF）家族重建，其中VEGF-C/VEGFR-3信号传导 主要。先前的研究表明，通过VEGF-增加淋巴生长的有益作用 C/VEGFR-3关于心脏功能的信号传导，通过简单地增强免疫通量和减少 心肌梗死模型中的心肌水肿和纤维化。我们假设这种破坏 淋巴引流通过阻碍免疫细胞和促炎性的出口来增强炎症 供体心脏的细胞因子加剧了移植排斥。我们的回顾性人类的初步结果 研究表明，在同种异体移植寿命的早期时间点上淋巴面积有显着差异 具有和没有明确临床诊断的CAV的移植患者。这些数据表明调节淋巴管 心脏移植后直接发育可以通过建立关键 在此过程的早期排水路线。这项研究的长期目标是阐明后果 心脏移植排斥反应中淋巴功能障碍并发展出局部的持续 以淋巴管为中心的疗法应对这种疾病的影响。在特定目标1中，我们将 通过诱导移植来确定严重淋巴机对免疫细胞浸润和抑制严重程度的影响 在异位腹部心脏移植啮齿动物模型中接受和排斥。在特定的目标2中，我们将 评估使用VEGF-C封装的局部淋巴增强对供体移植功能的影响 在聚（乙二醇）基于水凝胶中。了解与淋巴相关的病理状况 心脏移植功能障碍将提供新的热目标，以提高供体的寿命 移植和减少移植社区的死亡率。优化心脏功能和供体移植生存 对于需要多次心脏移植的儿科患者尤其重要。