Thalidomide treatment prevents chronic graft rejection after aortic transplantation in rats – an experimental study |
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| Authors: | Katharine K Miller Dong Wang Xiaomeng Hu Xiaoqin Hua Tobias Deuse Evgenios Neofytou Thomas Renne Joachim Velden Hermann Reichenspurner Sonja Schrepfer Daniel Bernstein |
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| Institution: | 1. Transplant and Stem Cell Immunobiology (TSI)‐Lab, University Heart Center Hamburg, Hamburg, Germany;2. Department of Surgery, Transplant and Stem Cell Immunobiology (TSI)‐Lab, University California San Francisco (UCSF), San Francisco, CA, USA;3. Cardiovascular Research Center (CVRC), University Medical Center Hamburg‐Eppendorf, Hamburg, Germany;4. German Centre for Cardiovascular Research (DZHK) e.V., University Medical Center Hamburg‐Eppendorf, Hamburg, Germany;5. Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany;6. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA;7. Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA;8. Department of Clinical Chemistry, University Medical Center Hamburg, Hamburg, Germany;9. Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden;10. Evotec AG, Hamburg, Germany;11. Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, GermanyShared last authorship. |
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| Abstract: | Cardiac allograft vasculopathy (CAV) affects approximately 30% of cardiac transplant patients at 5 years post‐transplantation. To date, there are few CAV treatment or prevention options, none of which are highly effective. The aim of the study was to investigate the effect of thalidomide on the development of CAV. The effect of thalidomide treatment on chronic rejection was assessed in rat orthotopic aortic transplants in allogeneic F344 or syngeneic Lew rats (n = 6 per group). Animals were left untreated or received thalidomide for 30 days post‐transplant, and evidence of graft CAV was determined by histology (trichrome and immunohistochemistry) and intragraft cytokine measurements. Animals that received thalidomide treatment post‐transplant showed markedly reduced luminal obliteration, with concomitant rescue of smooth muscle cells (SMCs) in the aortic media of grafts. Thalidomide counteracted neointimal hyperplasia by preventing dedifferentiation of vascular SMCs. Measurement of intragraft cytokine levels after thalidomide treatment revealed downregulation of matrix metalloproteinase 8 and monocyte chemotactic protein 1, cytokines involved in tissue remodelling and inflammation, respectively. Importantly, no negative side effects of thalidomide were observed. Thalidomide treatment prevents CAV development in a rodent model and is therefore potentially useful in clinical applications to prevent post‐transplant heart rejection. |
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| Keywords: | cardiac allograft vasculopathy rats thalidomide |
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