A metalloproteinase inhibitor prevents acute graft-versus-host disease while preserving the graft-versus-leukaemia effect of allogeneic bone marrow transplantation.
Tumor necrosis factor (TNF) and Fas ligand (FasL) have been implicated in the pathogenesis of graft-versus-host disease (GVHD). Several recent studies have shown that some metalloproteinase mediates TNF-alpha and FasL processing. We examined the ameliorating effect of a hydroxamic acid-based metalloproteinase inhibitor (KB-R7785) that inhibits TNF-alpha and FasL release in a lethal acuteGVHD model in mice. The ameliorating effect of KB-R7785 was superior to that of anti-TNF-alpha antibody. We also examined the effect of KB-R7785, which we previously demonstrated a potent ameliorating effect on acute GVHD, on graft-versus-leukemia (GVL) effect of allogeneic bone marrow transplantation (BMT). Administration of KB-R7785 without bone marrow cells and spleen cells (BMS). significantly prolonged the survival of IgE-producing B53 hybridoma cell-inoculated (C57BL/6 x BALB/c) F1 (CBF1) mice by inhibiting the infiltration of B53 cells into the liver and spleen. Transplantation of B6 BMS without KB-R7785 resulted in the death of most recipients due to acute GVHD while efficiently eliminating B53 cells. Administration of KB-R7785 along with B6 BMS resulted in 50% survival of B53-inoculated CBF1 mice over 50 days without histological manifestations of acute GVHD or residual B53 cells. These results suggest that KB-R7785 could be a potent therapeutic agent for GVHD, and indicate the beneficial effects of KB-R7785 that inhibit tumor infiltration and prevent acute GVHD while preserving the GVL effect of allogeneic BMT.
Hattori
K
K
Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Hirano
T
T
Oshimi
K
K
Yagita
H
H
Okumura
K
K
D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D053222:Fas Ligand Protein; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect; D006825:Hybridomas / Q000473:pathology; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D008562:Membrane Glycoproteins; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051379:Mice; D011480:Protease Inhibitors / Q000008:administration & dosage*; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006877:Hydroxamic Acids; C107086:KB R7785; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; D008666:Metalloendopeptidases; D005998:Glycine