Novel immunosuppressive effect of FK506 by augmentation of T cell apoptosis

We have recently reported the accumulation of oligoclonal activated T cells in the spontaneously developed autoimmune pancreatitis in aly/aly mouse. I n this study, we examined the effects of FK506 in this mouse model in preve nting autoimmune pancreatitis and investigated its action on calcium signal ling apoptosis of alymphoplasia (aly) lymphocytes in vitro. Mice were treat ed with FK506 from 8 to 25 weeks of age. At the age of 15 weeks, minimal mo nonuclear cell infiltration was observed in the pancreas in both the FK506 treated group and the control group. Furthermore, a marked cell infiltratio n associated with destruction of acini and partial fatty changes were obser ved in 25-week-old control mice. In contrast, FK506 treated mice showed alm ost no tissue destruction or mononuclear cell infiltration at the age of 25 weeks. Furthermore, at 15 weeks of age, most mononuclear cells in FK506-tr eated mice were TUNEL positive, whereas only a few were positive in control mice. This augmentation of T cell apoptosis by FK506 was confirmed using n aive splenocytes activated by PMA and ionomycin in vitro. Finally, a suppre ssive effect of FK506 on Bcl-2 production but not on Bax production was con firmed by Western blotting. This unique effect of FK506 on the augmentation of T cell apoptosis is probably one of the mechanisms explaining its benef icial effect on aly autoimmune pancreatitis.