Transgenic Expression of Human CD46 on Porcine Endothelium

Bongoni, Anjan K.; Kiermeir, David; Schnider, Jonas; Jenni, Hansjörg; Garimella, Pavan; Bähr, Andrea; Klymiuk, Nikolai; Wolf, Eckhard; Ayares, David; Voegelin, Esther; Constantinescu, Mihai A.; Rieben, Robert

doi:10.1097/tp.0000000000000746

Cited by 11 publications

(2 citation statements)

References 66 publications

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“…To analyse whether animals infected with PCMV/PRV could present alteration in the coagulation system, tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 complexes (tPA-PAI-1) were measured in plasma samples by an ELISA 31 . Interestingly, we observed that baboons P and Q, which presented clear pathological alterations, also had very high levels of tPA-PAI-1 complexes (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Denner

Längin

Reichart

et al. 2020

Sci Rep

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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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Section: Resultsmentioning

confidence: 99%

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

Denner

Längin

Reichart

et al. 2020

Sci Rep

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“…The full requirements for clinically effective xenotransplantation will become evident as transplant studies continue and salient aspects of delayed xenograft rejection are revealed. Although CD46 affects coagulation and fibrinolytic cascades 54 further transgenes may be required to combat coagulation dysregulation and thrombotic microangiopathy associated with endothelial activation. Candidate transgenes for future inclusion thus include human anticoagulant thrombomodulin 55 , the endothelium protein C receptor 56 and CD39 57 .…”

Section: Discussionmentioning

confidence: 99%

Efficient production of multi-modified pigs for xenotransplantation by ‘combineering’, gene stacking and gene editing

Fischer

Kraner-Scheiber

Petersen³

et al. 2016

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Xenotransplantation from pigs could alleviate the shortage of human tissues and organs for transplantation. Means have been identified to overcome hyperacute rejection and acute vascular rejection mechanisms mounted by the recipient. The challenge is to combine multiple genetic modifications to enable normal animal breeding and meet the demand for transplants. We used two methods to colocate xenoprotective transgenes at one locus, sequential targeted transgene placement - ‘gene stacking’, and cointegration of multiple engineered large vectors - ‘combineering’, to generate pigs carrying modifications considered necessary to inhibit short to mid-term xenograft rejection. Pigs were generated by serial nuclear transfer and analysed at intermediate stages. Human complement inhibitors CD46, CD55 and CD59 were abundantly expressed in all tissues examined, human HO1 and human A20 were widely expressed. ZFN or CRISPR/Cas9 mediated homozygous GGTA1 and CMAH knockout abolished α-Gal and Neu5Gc epitopes. Cells from multi-transgenic piglets showed complete protection against human complement-mediated lysis, even before GGTA1 knockout. Blockade of endothelial activation reduced TNFα-induced E-selectin expression, IFNγ-induced MHC class-II upregulation and TNFα/cycloheximide caspase induction. Microbial analysis found no PERV-C, PCMV or 13 other infectious agents. These animals are a major advance towards clinical porcine xenotransplantation and demonstrate that livestock engineering has come of age.

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Cell-Based Assays for Modeling Xenogeneic Immune Responses

Casós

Sommaggio

Pérez-Cruz

et al. 2020

Xenotransplantation

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Transgenic Expression of Human CD46 on Porcine Endothelium

Abstract: In this human-to-pig xenoperfusion model, complement inhibition by transgenic hCD46 expression led to a significant inhibition of procoagulant and antifibrinolytic pathways.

Cited by 11 publications

References 66 publications

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

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

Efficient production of multi-modified pigs for xenotransplantation by ‘combineering’, gene stacking and gene editing

Cell-Based Assays for Modeling Xenogeneic Immune Responses

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