Low-Dose Interleukin-2 Combined With Rapamycin Led to an Expansion of CD4+CD25+FOXP3+Regulatory T Cells and Prolonged Human Islet Allograft Survival in Humanized Mice

Abstract

Islet transplantation is an emerging therapy for type 1 diabetes and hypoglycemic 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 humanized NOD-scidIL2R gamma(null)(NSG) mouse model of T-cell-mediated human islet allograft rejection and developed a therapeutic regimen of low-dose recombinant human interleukin-2 (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 x 10(7)of human spleen mononuclear cells 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 x 10(6)IU/m(2)or 1 x 10(6)IU/m(2)) or rapamycin alone (0.5-1 mg/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(+)regulatory T cells (Tregs) and enhanced transforming growth factor-beta production by CD4(+)T cells. CD8(+)T cells showed reduced interferon-gamma 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 suppressing effector cell function and could be the basis of effective tolerance-based regimens.