Anti-CD40-based Costimulation Blockade Enhances Neonatal Porcine Islet Survival in Nonhuman Primates

摘要

The widespread clinical implementation of alloislet transplantation as therapy for type 1 diabetes has been hindered by the lack of suitable islet donors. Pig-to-human islet xenotransplantation is one strategy with potential to alleviate this shortage. Long-term survival of porcine islets has been achieved using antibodies targeting CD154; however, this approach lacks translational potential secondary to associated thromboembolic sequelae. As an alternative strategy targeting the CD40/CD154 T cell activation pathway, we evaluate the ability of a chimeric anti-CD40 monoclonal antibody (Chi220) to protect islet xenografts. Neonatal porcine islets (~50,000 IEQ/kg) were transplanted intraportally into surgically-induced diabetic macaques. Immunosuppression consisted of induction therapy with Chi220 and anti-IL-2 receptor (basiliximab), and maintenance therapy with sirolimus and belatacept (a high-affinity CTLA-4Ig variant). Chi220 effectively promoted xenoislet engraftment and survival; five of six treated recipients achieved insulin-independent normoglycemia (mean length of graft survival 90.8 days, maximum survival of 203 days). No thromboembolic phenomena were noted. CD40 represents a promising alternative to CD154 as a therapeutic target in xenoislet transplantation; other potentially translatable anti-CD40 antibodies warrant further investigation in non-human primate models.