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

  1. Paul E Lacy
  1. Department of Pathology, Washington University School of Medicine St. Louis, Missouri Department of Endocrinology, Clinical Hospital of Barcelona Barcelona, Spain Department of Pathology, Izaak Walton Killan Hospital for Children, Dalhousie University Faculty of Medicine Halifax, Nova Scotia, Canada
  1. Address correspondence and reprint requests to Paul E. Lacy, MD, PhD, Department of Pathology, Box 8118, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110.

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 × 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 >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 β-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.

  • Received July 11, 1988.
  • Revision received September 20, 1988.
  • Accepted September 20, 1988.
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