Low Dose IL-2 Combined with Rapamycin Led to an Expansion of CD4+CD25+FOXP3+ Tregs and Prolonged Human Islet-allograft Survival in Humanized Mice

<a>Islet transplantation is an emerging therapy for type 1 diabetes (T1D) and hypoglycaemic unawareness. However, a key challenge for islet transplantation is cellular rejection and the requirement for long-term immunosuppression. In this study we established a diabetic-humanizedNOD-scidIL2Rnull(NSG) mouse model of T cell mediated human islet-allograft rejection and developed a therapeutic regimen of low-dose recombinant human interleukin2(IL-2) combined with low-dose rapamycin to prolong graft survival. NSG-mice that had received renal-subcapsular human islet-allografts and were transfused with 1×107 of human-spleen-mononuclear-cells (hSPMCs), reconstituted human CD45+ cells that were predominantly CD3+ T cells and rejected their grafts with a median survival time of 27 days. IL-2 alone (0.3×106 IU/m2 or 1×106 IU/m2), or rapamycin alone (0.5-1mg/kg) for 3 weeks did not prolong survival. However, the combination of rapamycin with IL-2 for 3 weeks significantly prolonged human islet-allograft survival. Graft survival was associated with expansion of CD4+CD25+FOXP3+ Tregs and enhanced TGF-β production by CD4+ T cells. CD8+ T cells showed reduced IFN-γ production and reduced expression of perforin-1. The combination of IL-2 and rapamycin has the potential to inhibit human islet-allograft rejection by expanding CD4+FOXP3+ Tregs in vivo and supressing effector cell function, and could be the basis of effective tolerance-based regimens.</a>