813 Enhanced Survival of GalT KO/hCD55-hCD59 Pig Renal Xenografts in Baboons
Wednesday November 18, 2015 from 15:30 to 17:00
Room 109

Wayne J Hawthorne, Australia


National Pancreas and Islet Transplant Laboratories

Westmead Hospital


Enhanced Survival of GalT KO/hCD55-hCD59 Pig Renal Xenografts in Baboons

Wayne Hawthorne1, Evelyn Salvaris2, Joanne Hawkes1, Yi Vee Chew1, Sussan Davies1, Helen Barlow2, David Liuwantara1, Simon Robson3, Andrew Lew4, Mark Nottle5, Philip O'Connell1, Peter Cowan2.

1The Centre for Transplant & Renal Research, Westmead Millennium Institute, Westmead, Australia; 2Immunology Research Centre, St Vincents Hospital, Melbourne, Australia; 3Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA, United States; 4Walter and Eliza Hall Institute, Melbourne, Australia; 5Department of Obstetrics and Gynaecology, University of Adelaide, Adelaide, Australia

Acute humoral rejection remains one of the major barriers to successful xenotransplantation in preclinical pig-to-primate models. It primarily results in microvascular thrombosis of the transplanted graft, which we have previously reported in renal xenografts from hCD55-hCD59-HTF transgenic or GalT KO pigs that were rejected in untreated baboons within 4 days. Those recipients underwent a consumptive coagulopathy (CC) characterised by thrombocytopenia, prolonged clotting times and rising D-dimer levels. In this study, we examined the combined effects of enhanced complement regulation and the absence of Gal on renal xenograft survival and the development of CC in recipients when given immunosuppression.
Aim: To determine whether the combination of deletion of GalT and transgenic expression of hCD55-hCD59 under cover of immunosuppression enhances survival and function in a pig-to-baboon renal xenograft model.
Materials and Methods: Kidneys from GalT KO/hCD55-hCD59-HTF pigs were transplanted into four baboons. They also received immunosuppression commencing day-3 consisting of Thymoglobulin 5mg/kg, MMF 500mg bolus, Tacrolimus 2mg/kg and Anti CD154 20mg/kg. Regular blood samples were taken from an indwelling central venous cannula to assess renal function, coagulation parameters, antibody levels and complement factors. The transplanted donor pig kidneys were biopsied at days 3, 7 and at rejection for histological examination.
Results: All grafts demonstrated excellent reperfusion and immediate urine production and showed no signs of rejection. Grafts functioned normally for 4, 5, 9 & 10 days before the recipients developed significant decreases in platelet, Red blood cell and Haemoglobin levels as well as significant changes in coagulation parameters.
Analysis of the grafts at day 3 revealed normal renal architecture with no cellular infiltrate or haemorrhagic change consistent with normal renal function. However, as platelet counts decreased micro thrombi were seen in glomeruli and smaller vessels. There were also patchy haemorrhagic changes that were consistent with triggering of a consumptive coagulopathy.
Conclusion: These results suggest that the combination of hCD55-hCD59 expression with GalT KO improves renal xenograft survival and delays the development of CC. However, further genetic modifications to inhibit thrombosis and the humoral and cellular immune responses are warranted in order to further extend survival.

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