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. 2020 Oct 16;10(1):17531.
doi: 10.1038/s41598-020-73150-9.

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

Joachim Denner  1 , Matthias Längin  2   3 , Bruno Reichart  3 , Luise Krüger  4 , Uwe Fiebig  4 , Maren Mokelke  3 , Julia Radan  3 , Tanja Mayr  2 , Anastasia Milusev  5 , Fabian Luther  5 , Nicoletta Sorvillo  5 , Robert Rieben  5 , Paolo Brenner  6 , Christoph Walz  7 , Eckhard Wolf  8 , Berit Roshani  9 , Christiane Stahl-Hennig  9 , Jan-Michael Abicht  2   3
Affiliations

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

Joachim Denner et al. Sci Rep. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Viral load (copies per 100 ng DNA) in different organs of baboon P after explantation of the pig heart, in PBMCs and different organs of the donor pig and in the pig heart after explantation as measured by real-time PCR.
Figure 2
Figure 2
Kinetics of the IL-6 amount in the blood of transplanted baboons as measured by ELISA. The baboon recipients of the treatment group III are indicated (N, O, P, Q).
Figure 3
Figure 3
Increased IL-6 and TNF serum levels in baboons with PCMV/PRV-positive hearts. BD CBA Non-human primate Th1/Th2 kit was used to measure plasma levels of (A) IL-6, (B) TNF, (C) IFN γ, (D) IL-2, (E) IL-4 and (F) IL-5 one week before transplantation (day -7) and during the experiment (day 13, 26, 180 and 194, respectively) in baboons N, O, P and Q. Dotted lines indicate lowest standard concentration.
Figure 4
Figure 4
A Histopathologic evaluation of the explanted pig hearts from baboons N to Q. Arrowheads mark perivascular and arrows moderate edema in otherwise unremarkable myocardial tissue in all specimens. Scale bars indicate 250 μm. B. Histopathologic evaluation revealed perivascular (arrowhead) and interstitial (arrow) edema in otherwise unremarkable myocardial tissue in all specimens. In particular, no morphologic signs of cellular or antibody-mediated transplant reaction was found. Scale bars indicate 100 µm.
Figure 5
Figure 5
Measurement of tPA-PAI-1 complexes in the blood of baboons J65-Q74.
See this image and copyright information in PMC

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