Effects of Long-Term Administration of Recombinant Human Protein C in Xenografted Primates

Simioni, Paolo; Boldrin, M; Gavasso, Sabrina; Seveso, M; Radu, Claudia; Bulato, Cristiana; Calabrese, Fiorella; Cavicchioli, Laura; Bertini, D; Benedictis, Giulia Maria De; Besenzon, F; Baldan, N; Spiezia, Luca; Plebani, Mario; Ancona, Ermanno

doi:10.1097/tp.0b013e318200ba0e

Cited by 14 publications

(13 citation statements)

References 29 publications

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“…Some groups routinely administer continuous heparin to baboon recipients of pig renal (42) and cardiac (140, 141) xenografts, although it is difficult to assess the efficacy of this treatment. Administration of recombinant human antithrombin was clearly protective in the first week after pig-to-baboon renal xenotransplantation (98), but had no apparent long-term benefit in the pig-to-macaque renal model (142), even when combined with human activated protein C (143). Other reagents have also produced mixed results, and it would be reasonable to conclude that both genetic modification and pharmacotherapy will be necessary to fully control inflammation and coagulation in renal xenotransplantation (144).…”

Section: Preventing Kidney Xenograft Rejectionmentioning

confidence: 99%

Kidney xenotransplantation

Cowan

Cooper

d’Apice

2014

Kidney International

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Xenotransplantation using pigs as donors offers the possibility of eliminating the chronic shortage of donor kidneys, but there are several obstacles to be overcome before this goal can be achieved. Preclinical studies have shown that while porcine renal xenografts are broadly compatible physiologically, they provoke a complex rejection process involving preformed and elicited antibodies, heightened innate immune cell reactivity, dysregulated coagulation, and a strong T cell-mediated adaptive response. Furthermore, the susceptibility of the xenograft to pro-inflammatory and pro-coagulant stimuli is probably increased by cross-species molecular defects in regulatory pathways. To balance these disadvantages, xenotransplantation has at its disposal a unique tool to address particular rejection mechanisms and incompatibilities: genetic modification of the donor. This review focuses on the pathophysiology of porcine renal xenograft rejection, and on the significant genetic, pharmacological and technical progress that has been made to prolong xenograft survival.

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Section: Preventing Kidney Xenograft Rejectionmentioning

confidence: 99%

Kidney xenotransplantation

Cowan

Cooper

d’Apice

2014

Kidney International

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“…These disparities may also contribute to systemic derangement of coagulation parameters sometimes reported after xenotransplantation (63). Systemic therapies using clinical antiplatelet and antithrombotic drugs or using activated protein C fail to prevent MT, fibrin deposition, or prolong xenograft survival (64–68). This result may be due to the level of redundancy in haemostatic regulation, the intensity of non-Gal antibody-mediated rejection, or a failure to durably control haemostasis at the surface of the vascular EC.…”

Section: Coagulation and Xenograft Rejectionmentioning

confidence: 99%

Cardiac xenotransplantation

Byrne¹,

McGregor²

2012

Current Opinion in Organ Transplantation

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Purpose of Review Cardiac xenotransplantation (CXTx) remains a promising approach to alleviate the chronic shortage of donor hearts. This review summarizes recent results of heterotopic and orthotopic CXTx, highlights the role of non-Gal antibody in xenograft rejection, and discusses challenges to clinical orthotopic CXTx. Recent Findings Pigs mutated in the α 1,3 galactosyltransferase gene (GTKO pigs) are devoid of the galactose α 1,3 galactose (αGal) carbohydrate antigen. This effectively eliminated any role for anti-Gal antibody in GTKO cardiac xenograft rejection. Survival of heterotopic GTKO cardiac xenografts in nonhuman primates continues to increase. GTKO graft rejection commonly involves vascular antibody deposition and variable complement deposition. Non-Gal antibody responses to porcine antigens associated with inflammation, complement, and hemostatic regulation and to new carbohydrate antigens have been identified. Their contribution to rejection remains under investigation. Orthotopic CXTx is limited by early perioperative cardiac xenograft dysfunction (PCXD). However, hearts affected by PCXD recover full cardiac function and orthotopic survival up to 2 months without rejection has been reported. Summary CXTx remains a promising technology for treating end-stage cardiac failure. Genetic modification of the donor and refinement of immunosuppressive regimens have extended heterotopic cardiac xenograft survival from minutes to in excess of 8 months.

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“…However, all xenografts were eventually lost to humoral rejection at 5 weeks and exhibited significant fibrin staining at explant. This lack of effect on the long-term outcome may have been because of failure to achieve a sufficient local concentration of rhAPC to counter developing rejection (37).…”

Section: Discussionmentioning

confidence: 99%

“…Recombinant human APC (rhAPC) is used clinically for the treatment of severe sepsis, although its use is associated with a modestly increased risk of spontaneous hemorrhage (36). Simioni et al reported that continuous infusion of rhAPC prevented fibrin deposition in pig-to-monkey renal xenografts in the first 2 weeks after transplantation, without causing serious bleeding problems (37). However, all xenografts were eventually lost to humoral rejection at 5 weeks and exhibited significant fibrin staining at explant.…”

Section: Discussionmentioning

confidence: 99%

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

Lee

Lü

Roussel

et al. 2012

American Journal of Transplantation

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†Equal senior authors.Thrombosis and inflammation are major obstacles to successful pig-to-human solid organ xenotransplantation. A potential solution is genetic modification of the donor pig to overexpress molecules such as the endothelial protein C receptor (EPCR), which has anticoagulant, anti-inflammatory and cytoprotective signaling properties. Transgenic mice expressing human EPCR (hEPCR) were generated and characterized to test this approach. hEPCR was expressed widely and its compatibility with the mouse protein C pathway was evident from the anticoagulant phenotype of the transgenic mice, which exhibited a prolonged tail bleeding time and resistance to collagen-induced thrombosis. hEPCR mice were protected in a model of warm renal ischemia reperfusion injury compared to wild type (WT) littermates (mean serum creatinine 39.0 ± 2.3 lmol/L vs. 78.5 ± 10.0 lmol/L, p < 0.05; mean injury score 31 ± 7% vs. 56 ± 5%, p < 0.05). Heterotopic cardiac xenografts from hEPCR mice showed a small but significant prolongation of survival in C6-deficient PVG rat recipients compared to WT grafts (median graft survival 6 vs. 5 days, p < 0.05), with less hemorrhage and edema in rejected transgenic grafts. These data indicate that it is possible to overexpress EPCR at a sufficient level to provide protection against transplantrelated thrombotic and inflammatory injury, without detrimental effects in the donor animal.

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Effects of Long-Term Administration of Recombinant Human Protein C in Xenografted Primates

Abstract: In this pig to primate model, rhaPC confers a short advantage in the prevention of early perioperative xenograft damage but does not represent an effective strategy for preventing AHXR.

Cited by 14 publications

References 29 publications

Kidney xenotransplantation

Kidney xenotransplantation

Cardiac xenotransplantation

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

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