Impact of porcine cytomegalovirus on long-term orthotopic cardiac xenotransplant survival

Joachim Denner,Tanja Mayr,Jan-Michael Abicht,Matthias Längin,Berit Roshani,Paolo Brenner,Anastasia Milusev,Christoph Walz,Uwe Fiebig,Nicoletta Sorvillo,Robert Rieben,Eckhard Wolf,Christiane Stahl-Hennig,Luise Krüger,Bruno Reichart,Julia Radan,Fabian Luther,Maren Mokelke

doi:10.1038/s41598-020-73150-9

Abstract

Xenotransplantation using pig organs has achieved survival times up to 195 days in pig orthotopic heart transplantation into baboons. Here we demonstrate that in addition to an improved immunosuppressive regimen, non-ischaemic preservation with continuous perfusion and control of post-transplantation growth of the transplant, prevention of transmission of the porcine cytomegalovirus (PCMV) plays an important role in achieving long survival times. For the first time we demonstrate that PCMV transmission in orthotopic pig heart xenotransplantation was associated with a reduced survival time of the transplant and increased levels of IL-6 and TNFα were found in the transplanted baboon. Furthermore, high levels of tPA-PAI-1 complexes were found, suggesting a complete loss of the pro-fibrinolytic properties of the endothelial cells. These data show that PCMV has an important impact on transplant survival and call for elimination of PCMV from donor pigs.

Highlights

Xenotransplantation using pig organs has achieved survival times up to 195 days in pig orthotopic heart transplantation into baboons
We show that other porcine viruses, which could potentially impact xenotransplant survival, including porcine endogenous retroviruses (PERVs), hepatitis E virus (HEV), three porcine lymphotropic herpesviruses (PLHV) and the porcine circoviruses (PCV) 1 and 2, had not been transmitted
For the first time, we show that the use of organs from porcine cytomegalovirus (PCMV)/PRV-positive pigs in this lifesupporting model is associated with a reduction of the transplant survival time

Summary

Introduction

Xenotransplantation using pig organs has achieved survival times up to 195 days in pig orthotopic heart transplantation into baboons. In that study hearts from α1,3-galactosyltransferase-knockout (GTKO) pigs that express human membrane cofactor protein (CD46) and human thrombomodulin (hTM) had been transplanted into baboons and survival times up to 195 days were achieved. This is a milestone on the way to clinical cardiac xenotransplantation which is urgently needed: The supply of human organs does not match the needs and many patients with terminal cardiac failure die while being on the waiting list. HHV-6 was found to promote cancer development[19] and accelerate acquired immunodeficiency syndrome (AIDS) in humans and m onkeys[20,21], possibly by its immunosuppressive p roperty[21,22,23,24,25]

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Results

Conclusion