Graft-versus-leukemia effect and graft-versus-host disease can be differentiated by cytotoxic mechanisms in a murine model of allogeneic bone marrow transplantation.
Allogeneic bone marrow transplantation (allo-BMT) is associated with both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect. In the present study, we examined the contribution of cytotoxic effector mechanisms, which are mediated by tumor necrosis factor-alpha (TNF-alpha), Fas ligand (FasL), or perforin, to GVHD and GVL effect in a murine BMT model. Bone marrow cells plus spleen cells (BMS) from wild-type, FasL-defective, or perforin-deficient donors were transferred into lethally irradiated recipients in the parent (C57BL/6) to F1 (C57BL/6 x DBA/2) BMT model with or without prior inoculation of DBA/2 leukemia L1210 or P815 mast cytoma cells. The effect of anti-TNF-alpha antibody administration was also examined. Whereas the defect or blockade of each cytotoxic pathway could ameliorate lethal acute GVHD, the GVL effect was differentially affected. The wild-type BMS recipients died of acute GVHD within 50 days without residual leukemia cells. The FasL-defective BMS recipients showed 60%< survival over 80 days without acute GVHD or residual leukemia cells. Administration of anti-TNF-alpha antibody resulted in early leukemia relapse and the recipients died within 25 days with massive leukemia infiltration in the liver. The perforin-deficient BMS recipients died within 60 days with residual leukemia cells. These results suggest that blockade of the Fas/FasL pathway could be used for ameliorating GVHD without impairing GVL effect in allo-BMT.
Tsukada
N
N
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Kobata
T
T
Aizawa
Y
Y
Yagita
H
H
Okumura
K
K
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D003433:Crosses, Genetic; D003937:Diagnosis, Differential; D005260:Female; D006086:Graft vs Host Disease / Q000175:diagnosis / Q000276:immunology*; D020350:Graft vs Tumor Effect / Q000276:immunology*; D007939:Leukemia L1210 / Q000276:immunology* / Q000473:pathology; D007941:Leukemia P388 / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000502:physiology
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D054353:Perforin