Date: Monday, June 3, 2019
Session Name: Concurrent Session: Islet and Cell Transplantation
Session Time: 4:30pm-6:00pm
Presentation Time: 4:42pm-4:54pm
Location: Room 309
*Purpose: Porcine islet xenotransplantation has progressed significantly in non-human primate (NHP) studies. However, all successful NHP studies have relied upon immunosuppressive regimens that utilize drugs that are clinically unavailable. Here, we have tested two costimulation blockade-based regimens in an NHP islet xenotransplantation model using only clinically available agents.
*Methods: Rhesus macaques (3.2-6.8kg) were used as xenograft recipients. Diabetes was induced with Streptozotocin (STZ, 1250 mg/m2, IV). Neonatal porcine islets (NPI) were isolated from GKO or GKO/hCD46 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, 1, 2, 3, 4 (n=6). All recipients were maintained on CTLA4Ig (20mg/kg, on days -2, 0, 4, 7, 14, 21 and biweekly afterwards), tacrolimus (0.1mg/kg/d) from days -2 to 21, sirolimus (0.05mg/kg/d) from day 22 onwards, and mycophenolate mofetil daily (25mg/kg/d). All recipients received daily CMV prophylaxis with ganciclovir followed by valganciclovir. Following transplantation, graft function was monitored with daily morning fasting glucose, biweekly intravenous glucose tolerance testing (IVGTT), and biweekly serum porcine c-peptide level.
*Results: Twelve rhesus macaques successfully underwent NPI xenotransplantation. Of the six receiving basiliximab induction, engraftment was achieved in 4 and the median graft survival, as defined by the last day of detectable porcine c-peptide in plasma, was 14 days. Of the six receiving rhATG induction, all achieved sustained lymphocyte depletion following induction. All engrafted and the median graft survival was 40.5 days, significantly longer compared with the basiliximab group (p=0.0337). Graft rejection was confirmed by immunohistochemistry, demonstrating islets with a dense lymphocytic infiltrate.
*Conclusions: In summary, we demonstrated partial islet engraftment using two clinically available immunosuppression regimens. Depletional induction followed by costimulation blockade appears to significantly prolong graft survival.
To cite this abstract in AMA style:Fitch ZW, Gao Q, Davis RP, Mulvihill MS, Song M, Leopardi F, Ribeiro M, How T, Reimann K, Devi GR, Collins BH, Kirk AD. Islet Xenotransplantation: A Quest for Clinically Available Immunosuppression Regimens [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/islet-xenotransplantation-a-quest-for-clinically-available-immunosuppression-regimens-2/. Accessed September 22, 2019.
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