Abortive alloantigen presentation by donor dendritic cells leads to donor-specific tolerance: a study with a preoperative CTLA4Ig inoculation

Donor dendritic cells (DCs) within allografts initiate the induction of an allospecific T cell response, while an abortive alloantigen presentation by DCs may induce allospecific unresponsiveness. We thus investigated the tol erogenic effect of donor DCs that were made incompetent in alloantigen pres entation by treatment of CTLA4Ig. When we treated rats with donor DCs (2 x 10(6)/rat i.v.) on the preoperative day, nine rejected allografts in an acc elerated manner (5.0 +/- 2.2 vs. 8.2 +/- 1.6 days in the control group). Pr eoperative inoculation of DCs pulsed with CTLA4Ig, a procedure which suppre sses an allogeneic mixed lymphocyte reaction (MLR), also provoked an accele rated rejection (5.6 +/- 1.7 days). When DCs and CTLA4Ig (500 mu g/rat i.p. on days -9, -7 and -5) were concomitantly inoculated, allograft survival w as significantly prolonged (>38.7 +/- 40.0 days); a preoperative CTLA4Ig in oculation alone failed to do so (7.5 +/- 1.2 days). Long-term graft survivo rs tolerated skin grafts from the donor but not from those from a third par ty. These results indicate that abortive alloantigen presentation by donor DCs, upon which an accessory signal pathway is suppressed by CTLA4Ig, leads to prolonged graft survival and donor-specific tolerance.