TGF-beta 1 and donor dendritic cells are common key components in donor-specific blood transfusion and anti-class II heart graft enhancement, whereastolerance induction also required inflammatory cytokines down-regulation

Heart allograft tolerance in adult recipients can be induced in the LEW.1W to LEW.1A congeneic strain combination by pre-graft donor-specific blood tr ansfusion (DST). Long-term survivors accept LEW.1W graft but reject third p arty skin grafts. As tolerant recipients of heart allografts showed an incr ease in anti-donor class II antibodies, we hypothesize that these antibodie s could be instrumental in tolerance induction. However, anti-donor MHC cla ss II alone prolonged graft survival but did not induce heart allograft tol erance in this combination. We analyzed the immune response patterns in hea rt allograft recipients following the injection of anti-donor class II anti bodies (prolongation) or DST priming (tolerance). As suggested by the diffe rent phenomena, several immunological patterns were strikingly different be tween the two models. In strong contrast to DST-tolerant recipients, at 5 d ays after transplantation, neither Th1/Th2 nor inflammatory cytokines were inhibited in recipients treated with anti-donor class II antibodies, in whi ch only prolongation of graft survival was induced. Nevertheless, in both m odels, depletion of resident dendritic cells (DC) from donor hearts inhibit ed tolerance induction (DST) or shortened allograft survival (anti-donor cl ass II antibodies). Moreover, TGF-beta1 was not down-regulated and administ ration of neutralizing anti-TGF-beta1 antibody, which inhibited tolerance i nduction (DST), also shortened allograft survival (anti-donor class II anti bodies). These results suggest that, in these two MHC class II-restricted m odels, both TGF-beta1 and donor DC have a pivotal role in prolonging graft survival. However, in the days following transplantation, further inhibitio n of inflammatory cytokine production, particularly Th1 and macrophage-deri ved cytokines is required for tolerance induction.