Oxygen radical production in human mononuclear blood cells is not suppressed by drugs used in clinical islet transplantation

Inflammatory islet damage mediated by cytokines and oxygen radicals may limit the success of clinical islet transplantation for treatment of insulin-dependent diabetes mellitus. In this study, we investigated whether drugs such as currently used in islet-transplanted patients inhibit the release of IL-1 beta, TNF alpha, and superoxide from mononuclear blood cells in vitro. Methylprednisolone (10 mu g/ml) inhibited the release of IL-1 beta and TNF alpha, but had no effect on superoxide generation. Both pentoxifylline (66 mu g/ml) and cyclosporin A (300 ng/ml) slightly inhibited TNF alpha release without affecting IL-1 beta or superoxide generation. Nicotinamide (0.25 mM) did not interfere with the generation TNF alpha or superoxide and only slightly inhibited IL-1 beta production. A combination of methylprednisolone, pentoxifylline, cyclosporin A, and nicotinamide (concentrations for each substance as described above) inhibited TNFa generation by 74+/-6% (mean val ue+/-SEM, mononuclear blood cells from seven diabetic patients) without affecting IL-1 beta or superoxide generation. These data show that standard immunosuppressive therapy in islet transplanted patients may partially inhibit cytokine release but does not affect the generation of potentially islet-toxic superoxide from mononuclear cells.