A Report of Four Depletional Induction Strategies in Non-Human Primate Islet Xenotransplantation.

BACKGROUND: Porcine islet xenotransplantation is limited by the availability of clinically applicable immunosuppressive regimens. We tested four depletional induction strategies and maintenance regimens in a non-human primate (NHP) islet xenotransplant model. METHODS: Genetically modified or wild-type neonatal porcine islets were transplanted via portal vein infusion in diabetic NHPs. Induction consisted of rhesus anti-thymocyte globulin (rhATG) (Group 1, n = 4), anti-CD4 monoclonal antibody (mAb, Group 2, n = 3), or human anti-thymocyte globulin (huATG) tocilizumab (Groups 3 and 4; n = 3 and n = 4, respectively). Maintenance consisted of B7 (Groups 1-3) or anti-CD154 (Group 4) costimulation blockade, tacrolimus transitioned to sirolimus (sirolimus only in Group 4), and mycophenolate mofetil. Xenografts were monitored for blood glucose and porcine c-peptide. RESULTS: Median graft survivals were <14 days (Group 1), <14 days (Group 2), 99 days (Group 3), and 119 days (Group 4). Insulin independence was achieved in one animal in Group 4. Graft survival significantly correlated with islet dose >40,000 IEQ/kg. Rejection was predominately CD3+ T-cell mediated. Selective depletion of CD4+ T cells led to increased proliferation of CD8+ T cells and CD8+ infiltrates. CONCLUSIONS: Induction with huATG/tocilizumab and maintenance with 5c8 led to the best functional outcomes. CD4 T-cell depletion with anti-CD4 mAb induced compensatory CD8 T-cell proliferation and graft infiltration.

Duke Scholars

Author Joseph Ladowski  

Author Xunrong Luo Medicine, Nephrology

Author Allan Douglas Kirk Surgery, Abdominal Transplant Surgery

Author He Xu Surgery, Surgical Sciences

Author Imran Anwar  

Author Shu Li Surgery, Abdominal Transplant Surgery