Reduced human platelet uptake by pig livers deficient in the asialoglycoprotein receptor 1 protein

Paris, Leela L.; Estrada, José L.; Li, Ping; Blankenship, Ross L.; Sidner, Richard A.; Reyes, Luz M.; Montgomery, Jessica B.; Burlak, Christopher; Butler, James; Downey, Susan M.; Wang, Zheng Yu; Tector, Matthew; Tector, A. Joseph

doi:10.1111/xen.12164

Cited by 45 publications

(50 citation statements)

References 18 publications

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“…Recently, gene silencing has been used to limit this thrombocytopenia. As described by Paris et al, 7 removing the asialoglycoprotein receptor 1 protein from the porcine livers significantly reduces the amount of human platelet uptake. Although carbohydrate reductions have proved essential to limiting AMR in a pig-to-human model, little attention has been afforded to the effect that these modifications may have on hepatic platelet consumption.…”

Section: Introductionmentioning

confidence: 93%

Silencing Porcine CMAH and GGTA1 Genes Significantly Reduces Xenogeneic Consumption of Human Platelets by Porcine Livers

et al. 2016

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Background A profound thrombocytopenia limits hepatic xenotransplantation in the pig-to-primate model. Porcine livers also have shown the ability to phagocytose human platelets in the absence of immune-mediate injury. Recently, inactivation of the porcine ASGR1 gene has been shown to decrease this phenomenon. Inactivating GGTA1 and CMAH genes has reduced the antibody-mediated barrier to xenotransplantation; herein we describe the effect that these modifications have on xenogeneic consumption of human platelets in the absence of immune-mediated graft injury. Methods WT, ASGR1−/−, GGTA1−/−, and GGTA1−/−CMAH−/− knockout pigs were compared for their xenogeneic hepatic consumption of human platelets. An in vitro assay was established to measure the association of human platelets with liver sinusoidal endothelial cells (LSECs) by immunohistochemistry. Perfusion models were used to measure human platelet uptake in livers from WT, ASGR1−/−, GGTA1−/−, and GGTA1−/− CMAH−/− pigs. Results GGTA1−/−, CMAH−/− LSECs exhibited reduced levels of human platelet binding in vitro, when compared to GGTA1−/− and WT LSECs. In a continuous perfusion model, GGTA1−/− CMAH−/− livers consumed fewer human platelets than GGTA1−/− and WT livers. GGTA1−/− CMAH−/− livers also consumed fewer human platelets than ASGR1−/− livers in a single pass model. Conclusions Silencing the porcine carbohydrate genes necessary to avoid antibody-mediated rejection in a pig-to-human model also reduces the xenogeneic consumption of human platelets by the porcine liver. The combination of these genetic modifications may be an effective strategy to limit the thrombocytopenia associated with pig-to-human hepatic xenotransplantation.

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Section: Introductionmentioning

confidence: 93%

Silencing Porcine CMAH and GGTA1 Genes Significantly Reduces Xenogeneic Consumption of Human Platelets by Porcine Livers

et al. 2016

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“…Two additional classes of donor genetics have been reported, transgenes expressing human regulators of hemostasis (CD39 and hTM) and pigs with further genetic deletions to depleted additional xenogeneic carbohydrate antigens [52]. Anticoagulation genes are primarily expected to rectify well documented molecular incompatibilities in porcine thrombomodulin which may enhance the thrombogenic potential of transplanted pig organs.…”

Section: Genetic Modifications Of Donorsmentioning

confidence: 99%

“…Pig with deletions in the enzymes required to produce Neu5Gc modified glycans and an SDa related GalNAc antigen show the lowest level of antibody reactivity to human and nonhuman primate antibody [52]. There has been no transplant experience with antigen reduced donor pigs.…”

Section: Genetic Modifications Of Donorsmentioning

confidence: 99%

Current status of pig heart xenotransplantation

Mohiuddin

Reichart

Byrne

et al. 2015

International Journal of Surgery

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Significant progress in understanding and overcoming cardiac xenograft rejection using a clinically relevant large animal pig-to-baboon model has accelerated in recent years. This advancement is based on improved immune suppression, which attained more effective regulation of B lymphocytes and possibly newer donor genetics. These improvements have enhanced heterotopic cardiac xenograft survival from a few weeks to over 2 years, achieved intrathoracic heterotopic cardiac xenograft survival of 50 days and orthotopic survival of 57 days. This encouraging progress has rekindled interest in xenotransplantation research and refocused efforts on preclinical orthotopic cardiac xenotransplantation.

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“…Unfortunately, there was no data on immunosuppressive regimen and any major bleeding due to thrombocytopenia [19]. [21,22], (ii) differences in human and porcine platelet oligosaccharides influencing platelet phagocytosis by LSECs in vitro [23], and (iii) involvement of CD18 receptor in platelet phagocytosis by porcine Kupffer cells [24]. They also confirmed previous finding of interspecies incompatibilities in CD47/Signal Regulatory Protein M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 9 alpha (SIRPα) self-signaling impacting human platelet uptake by pig LSECs (Figure 5) [25,26].…”

Section: Progress With Genetically-engineered Pigsmentioning

confidence: 99%

Current status of pig liver xenotransplantation

Ekser

Markmann

Tector

2015

International Journal of Surgery

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The shortage of organs from deceased human donors is a major problem limiting the number of organs transplanted each year and results in the death of thousands of patients on the waiting list. Pigs are currently the preferred species for clinical organ xenotransplantation. Progress in genetically-engineered (GE) pig liver xenotransplantation increased graft and recipient survival from hours with unmodified pig livers to up to 9 days with normal to near-normal liver function. Deletion of genes such as GGTA1 (Gal-knockout pigs) or adding genes such as human complement regulatory proteins (hCD55, hCD46 expressing pigs) enabled hyperacute rejection to be overcome. Although survival up to 9 days was recorded, extended pig graft survival was not achieved due to lethal thrombocytopenia. The current status of GE pig liver xenotransplantation with world experience, potential factors causing thrombocytopenia, new targets on pig endothelial cells, and novel GE pigs with more genes deletion to avoid remaining antibody response, such as beta1,4-N-acetyl galactosaminyl transferase 2 (β4GalNT2), are discussed.

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Reduced human platelet uptake by pig livers deficient in the asialoglycoprotein receptor 1 protein

Cited by 45 publications

References 18 publications

Silencing Porcine CMAH and GGTA1 Genes Significantly Reduces Xenogeneic Consumption of Human Platelets by Porcine Livers

Silencing Porcine CMAH and GGTA1 Genes Significantly Reduces Xenogeneic Consumption of Human Platelets by Porcine Livers

Current status of pig heart xenotransplantation

Current status of pig liver xenotransplantation

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