SEX DIFFERENCE IN RESISTANCE TO DEXAMETHASONE-INDUCED APOPTOSIS IN NOD MICE TREATMENT WITH 1,25(OH)(2)D-3 RESTORES DEFECT

The NOD mouse, a model for type 1 diabetes, is characterized by resist ance to apoptosis in immunocytes. The aim of this study was to investi gate a link between apoptosis in NOD thymocytes and autoimmunity. Firs t, we demonstrated that the sexual dimorphism in diabetes incidence in NOD mice (females are more diabetes-prone than males) is reflected by differences in apoptosis. Apoptosis in NOD thymocytes, 24 h after dex amethasone, was decreased in both sexes compared with C57Bl/6, but it was lower in female mice (26 +/- 2%) than in male mice (50 +/- 3%, P < 0.001). Further, we demonstrated that sex hormones themselves play a central role in this difference, since castration of NOD male mice, wh ich increases diabetes incidence, decreased apoptosis levels (32 +/- 2 %), while treatment of NOD female mice with dihydrotestosterone, which protects against diabetes, restored apoptosis to male levels (42 +/- 1.5%). Finally, we demonstrated that 1,25-dihydroxyvitamin D-3, a ster oid hormone that prevents diabetes in NOD mice, restored apoptosis lev els to C57Bl/6 reference levels. This improved apoptosis was seen in m ale (68 +/- 1 vs. 50 +/- 3% in untreated NOD mice, P < 0.001) but espe cially in female NOD mice (51 +/- 5 vs. 26 +/- 2% in untreated NOD mic e, P < 0.001). Fluorescence-activated cell sorter analysis of thymocyt e subsets revealed marked differences, especially in CD4(+)CD8(+) and CD4(+) cells. We conclude that the sexual dimorphism in diabetes incid ence in NOD mice is paralleled by a dimorphism in resistance to apopto tic signals in NOD thymocytes. This resistance to apoptosis is driven by sex hormones and is corrected by 1,25-dihydroxyvitamin D-3.