Specific tolerance induction of allo-K(b)-skin grafts by FK506 in the CD8-depleted H-2(k) recipients required low amounts of K(b)-antigen

Abstract

MHC class I allo-grafts can be directly rejected by recipient CD8 T cells and be indirectly rejected by recipient CD4 T cells. Although the experimental results using the bm mutant and C57BL/6 mice indicated that CD4-mediated rejection of class I-disparate grafts is a relatively weak process and is expected to be more sensitive to additional exogenous immunosuppression, it is unclear that whether this mechanism can be used for inducing a specific tolerance of class I disparate grafts. In this study, we hypothesize that a short course of FK506 may induce a specific tolerance of class I-disparate skin grafts in the CD8-depleted recipients. K(b)-transgenic C3H mice, Tg.H-2 K(b)-1 and Tg.H-2 K(b)-2 mice that express high copies and low copies of K(b)-antigen respectively were used as donors. Wild type C3H mice (H-2(k)) in which either CD4 or CD8 T cells were depleted by administration of anti-CD4 or CD8 monoclonal antibody (mAb) were used as recipients. Results showed that FK506 promoted longer survival of allo-K(b) skin grafts in CD8-depleted C3H mice than in CD4-depleted C3H mice. Graft survival from Tg.H-2 K(b)-2 mice was significantly longer than Tg.H-2 K(b)-1 mice. A short course of FK506 induced long-term survival of skin grafts from Tg.H-2K(b)-2 mice, but not from Tg.H-2K(b)-1 mice in CD8-depleted C3H recipients, even after FK506 was stopped. These mice also accepted grafts of Tg.H-2K(b)-1 mice when challenged with skin grafts from Tg.H-2K(b)-1 mice, but promptly rejected third party skin grafts from BALB/c (H-2(d)) mice. T cells from K(b)-tolerant C3H mice did not respond to allo-K(b)-antigen in in vitro assays of mixed lymphocyte culture and cell-mediated cytotoxicity. In conclusion we found that a short course of FK506 treatment and low amounts of K(b)-antigen induced a K(b)-specific tolerance in the CD8-depleted recipients, and this tolerance maintained even after withdrawing the anti-CD8 mAb treatment.