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Presenter: Peter, Cowan, Melbourne, Australia
Authors: Eddy Lee1,2, Lisa Murray-Segal1, Evelyn Salvaris1, Jean Christian Roussel3, Bruce Hall4, Suzanne Hodgkinson4, Anthony d'Apice1,2, Hilton Gock1,2, Peter Cowan1,2
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Protective effects of EPCR overexpression in mouse cardiac xenografts and islet isografts
Eddy Lee1,2, Lisa Murray-Segal1, Evelyn Salvaris1, Jean Christian Roussel3, Bruce Hall4, Suzanne Hodgkinson4, Anthony d’Apice1,2, Hilton Gock1,2, Peter Cowan1,2
1Immunology Research Centre, St. Vincent’s Hospital Melbourne, Melbourne, Australia; 2Department of Medicine, University of Melbourne, Melbourne, Australia; 3Department of Cardiothoracic Surgery, Nantes Hospital University, Nantes, France; 4Faculty of Medicine, University of New South Wales, Sydney, Australia
Background: Thrombosis is a major challenge for porcine solid organ and intraportal islet xenografts. Endothelial protein C receptor (EPCR) is a potent enhancer of protein C activation by the thrombin/thrombomodulin complex, and has independent anti-inflammatory and cytoprotective properties. We have previously generated transgenic mice that strongly express human (h)EPCR throughout the tissues, and shown that these mice are protected against renal ischemia-reperfusion injury. This study examined whether hEPCR-mediated protection extended to heart and islet grafts.
Aims: To determine whether hEPCR expression protects (1) cardiac xenografts in a mouse-to-rat model; (2) marginal mass intraportal islet isografts in a mouse model.
Methods: (1) Hearts from transgenic mice (hEPCR, n=9) and wild type littermates (WT, n=7) were transplanted heterotopically into C6-deficient PVG rats. Xenograft function was measured by daily palpation, and rejected hearts were assessed by histology. (2) Islets were examined for hEPCR and insulin expression by immunostaining. 250 hEPCR or WT islets (n=7/group) were transplanted intraportally into diabetic mice and non-fasting blood glucose levels were monitored daily until day 30, when livers were removed for analysis.
Results: (1) hEPCR cardiac xenografts had a small but significant survival advantage compared to WT xenografts (median survival 6 days versus 5 days, p<0.05), and exhibited less hemorrhage, oedema and cellular infiltration. (2) Transgenic islets strongly expressed hEPCR insitu and maintained expression after isolation and at 30 days post-transplantation. Recipients of hEPCR islets showed significantly improved blood glucose control compared to recipients of WT islets (Figure 1). hEPCR grafts showed preserved morphology and more intense insulin staining than WT grafts.
Conclusion: Overexpression of hEPCR provided modest protection in the stringent mouse-to-rat cardiac xenograft model, and more pronounced protection to marginal mass intraportal islet grafts. This may therefore be a useful genetic modification of the donor in pig-to-human xenotransplantation.
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