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

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.

Porcine Endogenous Retroviruses and Xenotransplantation, 2021

“…In this study, it was shown that no PERV was transmitted to the transplant recipient, although the donor pigs were positive for PERV-A, PERV-B, and PERV-C. PERV-A/C were not found in the donor pigs. In cases where PCMV was transmitted to the baboon recipient, and the survival time of the transplant was significantly reduced, PERV transmission also was not observed [105].…”

“…Concerning the preclinical trials, in recent studies transplanting islet cell in marmosets [103] and cynomolgus monkeys [104], no PERV transmission was observed (Table 2). No PERV transmission was observed in a preclinical trial transplanting pig hearts from genetically modified pigs to baboons, with survival times of 182 and 195 days [26,105] (Table 2). These long survival times were achieved because in addition to an improved immunosuppressive regimen, non-ischaemic preservation with continuous perfusion, and control of post-transplantation growth of the transplant, the transmission of the porcine cytomegalovirus (PCMV) was prevented [105].…”

“…No PERV transmission was observed in a preclinical trial transplanting pig hearts from genetically modified pigs to baboons, with survival times of 182 and 195 days [26,105] (Table 2). These long survival times were achieved because in addition to an improved immunosuppressive regimen, non-ischaemic preservation with continuous perfusion, and control of post-transplantation growth of the transplant, the transmission of the porcine cytomegalovirus (PCMV) was prevented [105]. In this study, it was shown that no PERV was transmitted to the transplant recipient, although the donor pigs were positive for PERV-A, PERV-B, and PERV-C. PERV-A/C were not found in the donor pigs.…”

Recent progress and remaining hurdles toward clinical xenotransplantation

“…In a recent publication, the Münich team in Europe reported a significantly increased survival of pig‐to‐NHP cardiac xenografts up to 195 days 17 . This was achieved using GAT, CD46, and TBM transgenic pig hearts, ensuring a non‐ischemic preservation with continuous cold perfusion, strict post‐transplant blood pressure control to achieve “porcine‐like” hemodynamics 48 and therefore prevent xenoheart overgrowth, 17 and porcine cytomegalovirus (PCMV)‐free pigs 49 . Their immunosuppressive regimen was composed of “classic agents” including rituximab anti‐CD20 antibody, anti‐thymocyte‐globulin, anti‐CD40 mAb, steroids, and mycophenolate mofetil.…”

Xenogeneic and Stem Cell-Based Therapy for Cardiovascular Diseases: Genetic Engineering of Porcine Cells and Their Applications in Heart Regeneration

“…The influence of PCMV on human transplant recipients is unclear. However, in baboons, PCMV transmission in orthotopic pig heart xenotransplantation was recently found to be associated with a shorter survival time of the transplant [ 64 ].…”