The role of CD40 costimulation in murine cardiac allograft rejection

The costimulatory activity of CD40:CD154 interaction plays an important role for full T-cell activation. We investigated whether disruption of this pathway induces a specific state of tolerance beneficial for cardiac allograft survival. In a fully histoincompatible murine model, infusion of allogeneic CD40-deficient B cells from B6 mice (H-2b) caused donor-specific T-cell hyporesponsiveness in Balb/c mice (H-2d), as shown in a mixed lymphocyte reaction. Concomitant administration of cyclosporin A inhibited this effect, suggesting that induction of T-cell tolerance is an active, calcineurin-sensitive process. Balb/c hosts preimmunized with naive CD40-/- B cells were transplanted with hearts from wild-type B6 mice. The median survival time (MST) of heart grafts was 9.3 d whereas MST of grafts in CD40+/+ immunized mice was significantly lower (4.0 d). Moreover, acceptance of CD40-deficient hearts in CD40-/- preimmunized mice was further enhanced, with a MST of 13.7 d. In the absence of immunization, survival of wild-type hearts was 5.6 d and was not different from survival of CD40-deficient grafts. T-cell function in CD40-/- immunized mice corre-lated with the rejection kinetics, as evidenced by diminished in vitro donor- specific proliferation and cytokine secretion in the early post-transplantation period. In conclusion, our study defines the importance of CD40 engagement for T-cell activation during initial direct allorecognition, and may provide an approach to induce prolonged survival of cardiac allografts.