The Consequence of Impaired Lymphatic Drainage on Rejection in Cardiac Transplantation

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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.