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

2002; Oxford University Press; Volume: 129; Issue: 1 Linguagem: Inglês

10.1046/j.1365-2249.2002.01857.x

1365-2249

Junko Ohata, Jinkyo Sakurai, Kiyoshi Saito, Kenzaburo Tani, S Asano, Miyuki Azuma,

Immunotherapy and Immune Responses

SUMMARY 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.