Km. Casteels et al., SEX DIFFERENCE IN RESISTANCE TO DEXAMETHASONE-INDUCED APOPTOSIS IN NOD MICE TREATMENT WITH 1,25(OH)(2)D-3 RESTORES DEFECT, Diabetes, 47(7), 1998, pp. 1033-1037
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.