FK506 INHIBITS TOLERANCE INDUCTION IN MICE LIVER TRANSPLANTATION

Abstract

P1209 Aims: In the orthotopic mice liver transplantation model, hepatic allografts are inevitably accepted without immunosuppression and donor specific tolerance is gradually induced across the MHC barriers until complete tolerance after 40days. This model is very unique for the natural tolerance induction. Some specific mechanisms of tolerance induction are sopposed to be involved. On the other hands, although FK506 is a well-known immunosuppressive agent, the influence on tolerance induction is little known. The aim of this study is to elucidate the mechanism of tolerance induction by investigating the influence of FK506 on mice liver transplantation model. Methods: Orthotopic liver transplantation was performed using the cuff technique from a B10.BR/SgSn (Kk, I-Ak, I-Ek, Dk) donor to a B10.D2/SgSn (Kd, I-Ad, I-Ed, Dd) recipient. In the experimental group (n=5), FK506 (1mg/kg/day) was given subcutaneously to the recipients from Day0 to Day21, whereas in the control group (n=5), placebo (1mg/kg/day) was given in the same manner. On Day40, donor skin grafts were transplanted to the recipient of the both groups. The survival time of recipients and skin grafts were examined. On Day14, donor-type cells in the recipient were examined by RT-PCR using the specific donor-type MHC class I and class II primers in the blood, slpeen, kidney, thymus, and lymphnodes. Results: In the both groups, all recipients survived for more than 100days. Mean survival time of skin graft of the experimental grouop was significantly reduced compared to that of the control group (19.2days vs. 212.8days; p< 0.012). On Day14, either the donor-type MHC class I or class II-positive cell was detected in the control group, whereas the donor-derived MHC class II–positive cell disappeared in the experimental group. Conclusions: FK506 in the early phase of mice liver transplantation inhibits tolerance induction. Some donor-derived MHC class II- positive regulatory cells play an important role in tolerance induction.