Purpose: VEGF-C/D/VEGFR-3 signaling may regulate lymphatic vessel activation and the initiation of alloimmunity after transplantation. However, the mechanisms remain unknown. We investigated the effect of perioperative intracoronary injection of synthetic VEGF-C/D inhibitor on lymphatic vessel activation, antigen-presenting cell trafficking and subsequent development of alloimmune responses in rat cardiac allografts.
Methods: We perfused the coronaries of DA donor rat hearts ex vivo with VEGF-C/D inhibitor or PBS and preserved the grafts in +4°C PBS for 4h and then transplanted the grafts to fully MHC-mismatched WF recipient rats. We analyzed ischemia-reperfusion injury, and acute and chronic rejection responses. In acute and chronic rejection models, the recipients received Cyclosporine A as immunosuppression.
Results: At 6h after the reperfusion, VEGF-C/D inhibitor did not affect the myocardial injury but reduced the number of LYVE-1+ lymphatic vessels expressing VEGFR-3, ICAM-1 and VCAM-1 in the allograft and reduced the number of dendritic cells migrating out of the allograft. VEGF-C/D inhibition enhanced allograft survival in acute rejection model. In chronic rejection model, VEGF-C/D inhibitor reduced allograft inflammation and prevented the development of cardiac fibrosis and vasculopathy.
Conclusions: Intracoronary ex vivo treatment with VEGF-C/D inhibitor prevented early activation of lymphatic endothelial cells and trapped dendritic cells into the allograft. This interfered with allorecognition resulting in reduced acute and chronic rejection responses. Our results suggest donor single-dose intracoronary treatment with VEGF-C/D inhibitor as a novel clinically feasible lymphatic vessel targeted immunomodulatory approach.
To cite this abstract in AMA style:Dashkevich A, Syrjälä S, Keränen M, Tuuminen R, Krebs R, Antti N, Alitalo K, Lemström K. Intracoronary Treatment with VEGF-C/D Inhibitor Enhances Cardiac Allograft Survival and Prevents Chronic Rejection by Regulating Lymphatic Endothelial Cell Activation [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/intracoronary-treatment-with-vegf-cd-inhibitor-enhances-cardiac-allograft-survival-and-prevents-chronic-rejection-by-regulating-lymphatic-endothelial-cell-activation/. Accessed January 24, 2020.
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