Introduction

The field of porcine islet xenotransplantation has made significant progress in non-human primate studies in recent years. However, one major barrier preventing clinical translation of islet xenotransplantation is the lack of a clinically available immunosuppressive regimen. Here, we tested two costimulation blockade-based regimens in a non-human primate islet xenotransplantation model.

Methods

Rhesus macaques (3–7 kg) were used as xenograft recipients. Diabetes was induced with Streptozotocin. Neonatal porcine islets were isolated from GKO or hCD46/GKO transgenic piglets (Revivicor, Inc.) by a modified Korbutt technique. All recipients underwent laparotomy and islet cell suspensions (50,000 IEQ/kg) were subsequently infused into the portal vein. Recipients were induced with either basiliximab at 0.3 mg/kg on days 0, 2 (n=6) or rhesus anti-thymocyte globulin (rhATG, NHP Reagent Resource) at 4mg/kg/day on days 0-4 (n=3). All recipients were maintained on belatacept (20mg/kg, on days -2, 0, 3, 7, 14, 21 and biweekly afterwards), tacrolimus (0.1mg/kg/d) from days -2 to 22, sirolimus (0.05mg/kg/d) from day 21 onwards, and mycophenolate mofetil daily (25mg/kg/d). All recipients receive daily CMV prophylaxis with ganciclovir. Following transplantation, graft function was monitored with daily morning fasting glucose and biweekly intravenous glucose tolerance testing.

Results

Nine rhesus macaques successfully underwent NPI xenotransplantation. Out of the six receiving basiliximab induction, none achieved insulin independence following transplant. The median graft survival, as defined by the last day of detectable porcine c-peptide in serum, was 14 days, and 2 recipients did not have detectable porcine c-peptide at day 14, when c-peptide was first measured post-transplant. Out of the three receiving rhATG induction, all achieved sustained lymphocyte depletion following induction. Although none reached insulin independence, graft survival was 14, 44 and 83 days respectively (median survival=44 days). A Graft rejection was confirmed by immunohistochemistry, demonstrating islets with a dense lymphocytic infiltrate and no insulin positivity.

Conclusions

In summary, we demonstrated partial islet engraftment using two clinically available immunosuppression regimens. In addition, depletional induction followed by costimulation blockade may potentially prolong graft survival.

CITATION INFORMATION: Gao Q., Davis R., Mulvihill M., Song M., Leopardi F., Ribeiro M., How T., Devi G., Collins B., Kirk A. Islet Xenotransplantation: A Quest for Clinically Available Immunosuppression Regimens Am J Transplant. 2017;17 (suppl 3).

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