Oxygen Free-Radical Scavengers and Immune Destruction of Murine Islets in Allograft Rejection and Multiple Low-Dose Streptozocin-Induced Insulitis

Abstract

We examined the effects of desferrioxamine (DFX), a potent inhibitor of the formation of oxygen-derived hydroxyl radicals, and nicotinamide (NIC), a poly(ADP-ribose) synthetase inhibitor and a weak free-radical scavenger, on two models of immune destruction of murine islets [i.e., allograft rejection and multiple low-dose streptozocin (STZ)-induced insulitis]. Freshly isolated or low-temperature-cultured BALB/cJ islets were transplanted beneath the kidney capsules of C57BL/6J recipients. The recipients were treated with NIC alone (500 mg.kg-1.day-1), DFX alone (4.2 mg/day x 14 days), or NIC + DFX. Only recipients treated with NIC + DFX, receiving cultured islets, showed a mean graft survival time significantly longer than control mice receiving freshly isolated or cultured islets. Control CD-1 mice treated with multiple low doses of STZ developed insulitis and diabetes. Treatment with NIC alone, DFX alone, or NIC + DFX decreased the severity of hyperglycemia relative to the controls. Treatment with DFX alone was more effective than NIC alone or NIC + DFX. Only the group treated with DFX alone had a lower incidence of diabetes (mean plasma glucose level greater than 200 mg/dl) than the controls after 4 wk. Histologically, islets from control mice showed severe insulitis, islet destruction, and absence of stainable insulin, whereas islets from DFX-treated mice showed only mild peri-insulitis and a relative preservation of beta-cell granulation. Our study showed that NIC and DFX partially protect islets from immune destruction in allograft rejection and in low-dose STZ-induced insulitis. Apparently, hydroxyl radicals play important roles in both of these models.