EFFECT OF FK506 ON CYCLOPHOSPHAMIDE-INDUCED DIABETES IN NOD MICE

Despite the presence of insulitis, the non-obese diabetic mouse (NOD/UM) colony experience a low incidence of spontaneous diabetes. Hyperglycemia can, however, be precipitated by two injections of cyclophosphamide (CY) at 9 and 11 weeks of age. In this study, we investigated whether FK506, a new immunosuppressive agent, would influence CY-induced NOD diabetes. Five different groups of 4 week old female NOD mice were studied. Group 1: placebo s.c. injection every other day, group 2: placebo injection and CY (300 mg/kg i.p. at 9 and 11 weeks of age), group 3: FK506 at 0.2 mg/kg s.c. every other day and CY, group 4: FK506 at 1.0 mg/kg s.c. every other day and CY and group 5: FK506 at 2.0 mg/kg s.c. every other day and CY. The study was terminated at 15 weeks of age. Hematoxilin and eosin stained sections of pancreata from all animals were evaluated and insulitis lesions were graded from 0 to 4 (0=no insulitis, 1=peri-islet infiltration. 2=mild insulitis, < 50% of the islet was affected, and 3=severe insulitis, > 50% of the islet was affected and 4=obliteration of the entire islet). We concluded that FK506 prevents CY-induced insulitis and hyperglycemia in NOD mice in an apparent dose-dependent manner. The protection against diabetes in CY-induced and spontaneously occurring hyperglycemia in NOD's and BB/W rats provides further rationale for considering FK506 as an intervention agent in new onset human IDDM.