The Consequence of Impaired Lymphatic Drainage on Rejection in Cardiac Transplantation

项目摘要 慢性心脏移植排斥反应的主要原因-冠状动脉血管病变（CAV）-仍然是一个 这是限制全球心脏移植患者长期生存的主要因素。这种疾病会引起同心圆 沿着冠状动脉的内膜增厚沿着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子， 淋巴网络作为一个潜在的治疗目标。在心脏移植过程中，淋巴网络 在供体心脏切除时被切断而不是手术重建由于被切断而产生的后果 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流体稳态来维持心脏健康。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 占主导地位。先前的研究已经显示了通过VEGF增强淋巴生长的有益作用， C/VEGFR-3信号传导通过同时增强免疫清除和降低免疫应答而对心脏功能的影响 在心肌梗塞疾病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细胞的流出而增强炎症 细胞因子会加剧移植排斥反应我们回顾性的人类研究的初步结果 研究表明，在同种异体移植物寿命早期， 移植患者有明确的临床诊断和没有明确的CAV。这些数据表明，调节淋巴 心脏移植后的直接发展可能通过建立关键的 在这个过程中的早期排水路线。本研究的长期目标是阐明 淋巴功能障碍的心脏移植排斥反应，并发展一个局部的，持续的 淋巴管生成为重点的治疗，以打击这种疾病的影响。具体目标1： 通过诱导移植来确定切断的血管对免疫细胞浸润和排斥严重程度的影响 在异位腹部心脏移植啮齿动物模型中的接受和排斥。在第二阶段，我们将 评估局部淋巴扩增对使用VEGF-C包裹的供体移植物功能的影响， 在基于聚（乙二醇）的水凝胶中。了解与淋巴结相关的病理状况 心脏移植中的功能障碍将提供新的治疗靶点， 移植和降低移植社区的死亡率。优化心脏功能和供体移植物存活 对于需要在其一生中进行多次心脏移植的儿科患者尤其重要。

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.