276 Long-term Survival Of Genetically Modified Porcine Neonatal Islet Xenografts In Baboons
Monday November 16, 2015 from 11:00 to 12:30
Room 109

Wayne J Hawthorne, Australia


National Pancreas and Islet Transplant Laboratories

Westmead Hospital


Long-term Survival Of Genetically Modified Porcine Neonatal Islet Xenografts In Baboons

Wayne Hawthorne1, Joanne Hawkes1, Evelyn Salvaris2, David Liuwantara1, Yi Vee Chew1, Sussan Davies1, Helen Barlow2, Jamie Brady3, Andrew Lew3, Simon Robson4, 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; 3Walter and Eliza Hall Institute, Melbourne, Australia; 4Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA, United States; 5Department of Obstetrics and Gynaecology, University of Adelaide, Adelaide, Australia

Aim: Transgenic expression of human complement regulatory proteins or deletion of aGal (GTKO) can protect porcine adult islet and neonatal islet cell cluster (NICC) xenografts, respectively, in monkeys. We investigated the combined effects of these modifications on the outcome of intraportal NICC transplantation in immunosuppressed baboons.
Method: 1-5 day old GTKO piglets transgenic for human CD55, CD59 and H-transferase were used as donors. Recipient baboons received GTKO/CD55-CD59-HT NICC under standard (ATG, tacrolimus, mycophenolate mofetil; n=5) or costimulation blockade-based immunosuppression (anti CD2, anti CD154, belatacept, tacrolimus; n=4).  Graft survival and function was followed by daily blood sugar levels, IVGTT, OGTT and graft immunohistochemical analysis for up to 12 months post-transplant.
Results: Regardless of immunosuppressive regimen no GTKO/CD55-CD59-HT xenograft exhibited any sign of early thrombosis or infiltrate, nor change to recipient platelet counts, fibrinogen and D-dimer levels from baseline. Analysis of liver biopsies from recipients under standard immunosuppression revealed loss of GTKO/CD55-CD59-HT NICC within one month, with heavy T and B cell infiltrates. However, the change to costimulation blockade-based immunosuppression reduced cellular infiltration, and cells staining positive for insulin, glucagon and somatostatin were present in all GTKO/CD55-CD59-HT xenografts at three months. On the extended protocol one animal has normal glucose handling out to one-year post transplant.
Conclusions: Deletion of aGal and expression of human CD55 and CD59 prevent early thrombotic destruction of porcine NICCs in the baboon model. Costimulation blockade-based immunosuppression appears to be more effective than standard immunosuppression in prolonging the survival of genetically modified porcine NICC xenografts.

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