Differential graft-versus-leukaemia effect by CD28 and CD40 co-stimulatory blockade after graft-versus-host disease prophylaxis

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Abstract
Co‐stimulatory blockade may be a promising strategy for tolerance induction in transplantation. In allogeneic bone marrow transplantation (BMT) for leukaemia treatment, however, preservation of the graft‐versus‐leukaemia (GVL) effect is another critical requirement for clinical application. In this study, we have compared the effect on GVL of using CD28 and CD40 co‐stimulatory blockades as graft‐versus‐host disease (GVHD) prophylaxis in a murine allogeneic BMT model with simultaneous transfer of BCL1 leukaemia. Despite the relative improvement of GVHD as assessed by survival and body weight in both treatment regimes, treatment with anti‐CD154 moAb clearly diminished the GVL effect, whereas treatment with anti‐CD80 and CD86 MoAbs maintained this effect. Although T cell‐mediated effector function at 14 days post‐BMT assessed by IFNγ expression and cytotoxicity against host alloantigen was comparable between both co‐stimulatory blockades, IL‐12 mRNA expression was preferentially reduced by CD40 blockade. Our results suggest the differential involvement of the CD28 and CD40 co‐stimulatory pathways in the development of GVHD and GVL effects. CD28 blockade may be a favourable strategy for tolerance induction in leukaemia patients undergoing BMT.

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