Protective Effects of Transgenic Human Endothelial Protein C Receptor Expression in Murine Models of Transplantation

Lee, K. F. E.; Lü, Bo; Roussel, J; Murray‐Segal, Lisa; Salvaris, Evelyn; Hodgkinson, S.; Hall, Bruce M.; d’Apice, Anthony J.F.; Cowan, Peter J.; Gock, Hilton

doi:10.1111/j.1600-6143.2012.04122.x

Cited by 15 publications

(10 citation statements)

References 48 publications

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“…Transgenic mice expressing human endothelial protein C receptor (hEPCR) were protected against warm renal ischemia reperfusion injury. Hearts from these mice survived longer after heterotropic transplantation in C6-deficient rats showing less edema and hemorrhage (Lee et al 2012 ). Platelet aggregation plays a key role in the development of thrombotic microangiopathy in primate recipients of pig xenografts.…”

Section: Solid Xenoorgansmentioning

confidence: 99%

The current state of xenotransplantation

2014

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Pigs as a source of grafts for xenotransplantation can help to overcome the rapidly growing shortage of human donors. However, in the case of pig-to-human transplantation, the antibody-xenoantigen complexes lead to the complement activation and immediate hyperacute rejection. Methods eliminating hyperacute rejection (HAR) include α1,3-galactosyltransferase (GGTA1) inactivation, regulation of the complement system and modification of the oligosaccharide structure of surface proteins. The humoral immune response control and reduction of the risk of coagulation disorders are the priority tasks in attempts to overcome acute humoral xenograft rejection that may occur after the elimination of HAR. The primary targets for research are connected with the identification of obstacles and development of strategies to tackle them. Because of the magnitude of factors involved in the immune, genetic engineers face a serious problem of producing multitransgenic animals in the shortest possible time.

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Section: Solid Xenoorgansmentioning

confidence: 99%

The current state of xenotransplantation

2014

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“…Heterotopic cardiac xenografts from human EPCR‐transgenic mice showed a significant prolongation of survival in rat recipients and resistance to collagen‐induced thrombosis . Although human EPCR expression in mice/rat transplants is different from pig/baboon transplantation, this model evaluates the effect of transgenic expression of human EPCR in different species as well as the relevant function of human EPCR.…”

Section: Therapeutic Options To Inhibit Platelet Activation And/or Agmentioning

confidence: 99%

The role of platelets in coagulation dysfunction in xenotransplantation, and therapeutic options

Iwase

Ezzelarab

Ekser

et al. 2014

Xenotransplantation

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Xenotransplantation could resolve the increasing discrepancy between the availability of deceased human donor organs and the demand for transplantation. Most advances in this field have resulted from the introduction of genetically engineered pigs, e.g., α1,3-galactosyltransferase gene-knockout (GTKO) pigs transgenic for one or more human complement-regulatory proteins (e.g., CD55, CD46, CD59). Failure of these grafts has not been associated with the classical features of acute humoral xenograft rejection, but with the development of thrombotic microangiopathy in the graft and/or consumptive coagulopathy in the recipient. Although the precise mechanisms of coagulation dysregulation remain unclear, molecular incompatibilities between primate coagulation factors and pig natural anticoagulants exacerbate the thrombotic state within the xenograft vasculature. Platelets play a crucial role in thrombosis and contribute to the coagulation disorder in xenotransplantation. They are therefore important targets if this barrier is to be overcome. Further genetic manipulation of the organ-source pigs, such as pigs that express one or more coagulation-regulatory genes (e.g., thrombomodulin, endothelial protein C receptor, tissue factor pathway inhibitor, CD39), is anticipated to inhibit platelet activation and the generation of thrombus. In addition, adjunctive pharmacologic anti-platelet therapy may be required. The genetic manipulations that are currently being tested are reviewed, as are the potential pharmacologic agents that may prove beneficial.

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“…This entails a reduction of platelet activation and a decrease in thrombotic microangiopathy (Cerchiara et al 2007 ). Lee et al ( 2012 ) obtained transgenic mice expressing human EPCR (hEPCR), which were protected against warm renal ischemia reperfusion injury. Hearts from these transgenic mice demonstrated a significant prolongation of survival after heterotropic transplantation in rat recipients and showed less edema and hemorrhage.…”

Section: Coagulation Barriermentioning

confidence: 99%

Immune Modulation in Xenotransplantation

Boksa

Zeyland

Słomski

et al. 2014

Arch. Immunol. Ther. Exp.

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The use of animals as donors of tissues and organs for xenotransplantations may help in meeting the increasing demand for organs for human transplantations. Clinical studies indicate that the domestic pig best satisfies the criteria of organ suitability for xenotransplantation. However, the considerable phylogenetic distance between humans and the pig causes tremendous immunological problems after transplantation, thus genetic modifications need to be introduced to the porcine genome, with the aim of reducing xenotransplant immunogenicity. Advances in genetic engineering have facilitated the incorporation of human genes regulating the complement into the porcine genome, knockout of the gene encoding the formation of the Gal antigen (α1,3-galactosyltransferase) or modification of surface proteins in donor cells. The next step is two-fold. Firstly, to inhibit processes of cell-mediated xenograft rejection, involving natural killer cells and macrophages. Secondly, to inhibit rejection caused by the incompatibility of proteins participating in the regulation of the coagulation system, which leads to a disruption of the equilibrium in pro- and anti-coagulant activity. Only a simultaneous incorporation of several gene constructs will make it possible to produce multitransgenic animals whose organs, when transplanted to human recipients, would be resistant to hyperacute and delayed xenograft rejection.

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Protective Effects of Transgenic Human Endothelial Protein C Receptor Expression in Murine Models of Transplantation

Cited by 15 publications

References 48 publications

The current state of xenotransplantation

The current state of xenotransplantation

The role of platelets in coagulation dysfunction in xenotransplantation, and therapeutic options

Immune Modulation in Xenotransplantation

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