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 lim it the success of clinical islet transplantation for treatment of insulin-d ependent diabetes mellitus. In this study, we investigated whether drugs su ch 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 releas e 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 methylprednisolon e, pentoxifylline, cyclosporin A, and nicotinamide (concentrations for each substance as described above) inhibited TNFa generation by 74+/-6% (mean v al 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 inh ibit cytokine release but does not affect the generation of potentially isl et-toxic superoxide from mononuclear cells.