Alternative Immunomodulatory Strategies for Xenotransplantation: CD40/154 Pathway‐Sparing Regimens Promote Xenograft Survival

Immunosuppressive therapies that block the CD40/CD154 costimulatory pathway have proven to be uniquely effective in preclinical xenotransplant models. Given the challenges facing clinical translation of CD40/CD154 pathway blockade, we examined the efficacy and tolerability of CD40/CD154 pathway‐sparing immunomodulatory strategies in a pig‐to‐nonhuman primate islet xenotransplant model. Rhesus macaques were rendered diabetic with streptozocin and given an intraportal infusion of ∼50 000 islet equivalents/kg wild‐type neonatal porcine islets. Base immunosuppression for all recipients included maintenance therapy with belatacept and mycophenolate mofetil plus induction with basiliximab and LFA‐1 blockade. Cohort 1 recipients (n = 3) were treated with the base regimen alone; cohort 2 recipients (n = 5) were additionally treated with tacrolimus induction and cohort 3 recipients (n = 5) were treated with alefacept in place of basiliximab, and more intense LFA‐1 blockade. Three of five recipients in both cohorts 2 and 3 achieved sustained insulin‐independent normoglycemia (median rejection‐free survivals 60 and 111 days, respectively), compared to zero of three recipients in cohort 1. These data show that CD40/CD154 pathway‐sparing regimens can promote xenoislet survival. Further optimization of these strategies is warranted to aid the clinical translation of islet xenotransplantation. Novel immunosuppressive regimens containing the LFA‐1‐specific monoclonal antibody TS‐1/22 in combination with LFA‐3Ig or tacrolimus protect porcine islets from rejection in a nonhuman primate model of xenotransplantation without requiring the use of CD154‐specific monoclonal antibodies.