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

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.

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.

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.

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.