title: Differential graft-versus-leukaemia effect by CD28 and CD40 co-stimulatory blockade after graft-versus-host disease prophylaxis.
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 IFNgamma 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.
authors.affiliation: Department of Immunology, National Children's Medical Research Center, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Ohata
authors.forename: J
authors.initials: J
authors.lastname: Sakurai
authors.forename: K
authors.initials: K
authors.lastname: Saito
authors.forename: K
authors.initials: K
authors.lastname: Tani
authors.forename: S
authors.initials: S
authors.lastname: Asano
authors.forename: M
authors.initials: M
authors.lastname: Azuma
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen; D016026:Bone Marrow Transplantation / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006086:Graft vs Host Disease / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect / Q000187:drug effects / Q000276:immunology*; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D007942:Leukemia, Experimental / Q000276:immunology* / Q000628:therapy; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D012333:RNA, Messenger / Q000096:biosynthesis; D011828:Radiation Chimera; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma