Molecular And Gene Therapy For Organ Transplantation: Targeting Of Lymph Angiogenesis As a New Immunomodulatory Approach In Heart Transplantation
Final Report Abstract
Cardiac allograft injury occurs with ischemia, infection, and rejection. Ischemia-reperfusion injury releases a series of DAMPs or damage-associated molecular pattern molecules that activate innate immune cells, e.g., dendritic and other antigen presenting cells. The traffic of these cells to secondary lymphoid organs occurs via the afferent lymphatics and enables antigen-presentation to T cells. The cross-talk between innate and adaptive immune responses may further promote alloimmune activation and have significant effect on primary graft failure and the development of cardiac fibrosis and allograft vasculopathy, which is the main survival-limiting complication in heart transplant patients in the long run. In this project, we set out to define the impact of tissue injury during organ preservation and ischemia-reperfusion injury on the activation of lymphatic endothelium and its consequences for the development of alloimmune responses. Specifically, we demonstrate that VEGF-C–VEGFR-3 axis is central in the ischemia-reperfusion–induced early lymphatic endothelial cell activation. It enables danger messaging towards the secondary lymphoid organs, and promotes alloimmune response in cardiac allografts. We further suggest a clinically feasible and successful manipulation of the donor organ with VEGF-C inhibition with long-term beneficial effects in rat and mouse cardiac allografts. This is the first study to demonstrate that ischemia-reperfusion injury induces VEGF-C–mediated lymphatic endothelial cell activation in cardiac allografts. We provide evidence that donor heart manipulation with VEGF-C inhibition preventes the lymphatic endothelial cell activation and dendritic cell maturation in cardiac allografts. The resulting trapping of dendritic cells into the cardiac allografts prevents the innate danger messaging mechanisms, ameliorates the activation of adaptive immunity and robustly prevents acute rejection and the development of cardiac fibrosis and allograft vasculopathy. We therefore suggest that the rapid and long-lasting effects of therapeutic perioperative targeting of VEGF-C may have important practical implications as a novel immunomodulatory approach.
Publications
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VEGF Receptor Signaling in the Cardiac Lymphatics. “The Cardiac Lymphatic System. An Overview”, 2013; edited by G. Karunami. Springer Verlag, ISBN 978-1-4614-6773-1
Dashkevich A, Lemström KB, Nykänen A
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Angiopoietin-2 Inhibition Prevents Transplant Ischemia-Reperfusion Injury and Chronic Rejection in Rat Cardiac Allografts. Am J Transplant 13-01582, 2014. Epub ahead of print
Syrjala S, Tuuminen R, Raissadati A, Keranen M, Dashkevich A, Arnaudova R, Krebs R, Leow C, Saharinen P, Nykanen A, Alitalo K, Lemström K
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Ischemia–Reperfusion Injury Enhances Lymphatic Endothelial VEGFR3 and Rejection in Cardiac Allografts. American Journal of Transplantation 2016; 16: 1160–1172. First published: 21 December 2015
A. Dashkevich, A. Raissadati, S. O. Syrjälä G. Zarkada, M. A. I. Keränen, R. Tuuminen, R. Krebs, A. Anisimov, M. Jeltsch, V.‐M. Leppänen, K. Alitalo, A. I. Nykänen, K. B. Lemström
