Background.The recurrent autoimmune response to syngeneic pancreatic islet grafts transplanted into nonobese diabetic (NOD) mice is cell-mediated and relatively resistant to cyclosporine (CsA) therapy. Therefore, we asked whether interleukin (IL)-4 and IL-10, cytokines that inhibit cell-mediated immunity, might improve the therapeutic effect of CsA.Methods.We compared the survival of syngeneic islet grafts transplanted into diabetic NOD mice treated with IL-4, IL-10, and CsA, administered as single agents and in combinations. Additionally, we measured mRNA levels of type 1 cytokines (interferon-γ [IFN-γ], IL-2, and IL-12), type 2 cytokines (IL-4 and IL-10), and transforming growth factor-β (TGF-β) to determine whether graft rejection or survival might correlate with expression of these cytokines in the grafts.Results.CsA (20 mg/kg/day) significantly prolonged islet graft survival(median: 20 days vs. 10 days for vehicle-treated mice). Neither IL-4 (2.5μg, twice daily), nor IL-10 (10 μg, twice daily) significantly prolonged islet graft survival. By contrast, combination therapy with CsA and IL-10 significantly prolonged islet graft survival (median: 34 days) compared with vehicle-treated mice (median: 10 days), and combination therapy with CsA and IL-4 significantly prolonged islet graft survival (median: 59 days) compared with both vehicle-treated mice (median: 10 days) and mice treated with CsA alone (median: 20 days). Islet grafts from normoglycemic mice treated with CsA plus IL-10, and with CsA plus IL-4, were surrounded but not infiltrated by mononuclear leukocytes and β cells were intact, whereas islet grafts from mice treated with vehicle, IL-4, IL-10, and CsA (as single agents) were infiltrated by mononuclear leukocytes and fewer β cells were detected. Polymerase chain reaction analysis of cytokine mRNA expression in islet grafts at 8-12 days after transplantation revealed that CsA decreased mRNA levels of type 1 cytokines (IFN-γ and IL-12p40), whereas CsA plus IL-10 did not, and CsA plus IL-4 increased mRNA levels of IFN-γ, IL-12p40, and TGF-β.Conclusions.These results demonstrate that IL-4, and to a lesser extent IL-10, improves the ability of CsA to prevent autoimmune destruction of β cells in syngeneic islets transplanted into diabetic NOD mice; however, there is no simple correlation between the protective effects of the different treatment regimens (CsA, CsA plus IL-4, and CsA plus IL-10) and mRNA levels of type 1 cytokines (IFN-γ, IL-2, and IL-12), type 2 cytokines (IL-4 and IL-10), or TGF-β in the islet grafts.