B. Decallonne et al., Streptococcal wall component OK432 restores sensitivity of non-obese diabetic (NOD) thymocytes to apoptotic signals, DIABETOLOG, 43(10), 2000, pp. 1302-1308
Aims/hypothesis. The streptococcal wall component, OK432, prevents diabetes
in NOD mice and BE rats by elimination of effector cells. Based on the kno
wledge of a link between autoimmunity and resistance of immune cells to eli
mination by apoptosis, we investigated whether OK432 treatment restored the
sensitivity of NOD lymphocytes to apoptotic signals centrally (thymus) or
peripherally (spleen) or both and we examined the pathways for the enhanced
apoptosis rate.
Methods. We treated NOD mice with OK432 (0.1 mg/kg i.p. weekly from 21 to 7
0 days). Apoptosis was measured by TUNEL 16 h after cyclophosphamide (70 mg
/kg) and 24 h after dexamethasone (0.2 mg/mouse). Real time quantitative RT
-PCR was used to investigate changes in gene expression.
Results. Thymocyte apoptosis levels after cyclophosphamide were restored by
OK432 treatment to levels observed in C57BL/6 mice: in NOD males apoptosis
increased from 8 +/- 1% to 18 +/- 5 % (p < 0.05) compared with 20 +/- 4% i
n C57BL/6 males, and in NOD females from 6 +/- 2% to 11+/-2% (p < 0.05) com
pared with 12 +/- 2% in C57BL/6 females. The dexamethasone-induced thymocyt
e apoptosis rate was equally restored by OK432 treatment (58 +/- 4% vs 41 /- 3 % in control males (p < 0.0005) and 39 +/- 5% vs 26 +/- 3% in control
females (p < 0.05)]. No change in apoptosis levels was on the contrary obse
rved in splenocytes after OK432 treatment. By RT-PCR analysis of a panel of
apoptosis-related genes in thymocytes we showed a down-regulation of anti-
apoptotic Bcl-xL and c-myc by OK432 treatment.
Conclusions/interpretation. Our data suggest that OK432 prevents diabetes i
n NOD mice by better elimination of effector cells through increased sensit
ivity to apoptotic signals centrally in the thymus.