title: A metalloproteinase inhibitor prevents lethal acute graft-versus-host disease in mice.
abstract: Tumor necrosis factor (TNF) and Fas ligand (FasL) have been implicated in the pathogenesis of graft-versus-host disease (GVHD), which is a major complication after allogeneic bone marrow transplantation. We examined here the ameliorating effect of a metalloproteinase inhibitor (KB-R7785) that inhibits TNF-alpha and FasL release in a lethal acute GVHD model in mice. Administration of KB-R7785 into (BALB/c x C57BL/6) F1 that received C57BL/6 spleen cells markedly reduced the mortality and weight loss in association with minimal signs of GVHD pathology in the liver, intestine, and hematopoietic tissues. The ameliorating effect of KB-R7785 was superior to that of anti-TNF-alpha antibody. Our results suggest that KB-R7785 could be a potent therapeutic agent for GVHD.
authors.affiliation: Department of Internal Medicine, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hattori
authors.forename: T
authors.initials: T
authors.lastname: Hirano
authors.forename: C
authors.initials: C
authors.lastname: Ushiyama
authors.forename: H
authors.initials: H
authors.lastname: Miyajima
authors.forename: N
authors.initials: N
authors.lastname: Yamakawa
authors.forename: T
authors.initials: T
authors.lastname: Ebata
authors.forename: Y
authors.initials: Y
authors.lastname: Wada
authors.forename: S
authors.initials: S
authors.lastname: Ikeda
authors.forename: K
authors.initials: K
authors.lastname: Yoshino
authors.forename: M
authors.initials: M
authors.lastname: Tateno
authors.forename: K
authors.initials: K
authors.lastname: Oshimi
authors.forename: N
authors.initials: N
authors.lastname: Kayagaki
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: K
authors.initials: K
authors.lastname: Okumura
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D053222:Fas Ligand Protein; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006086:Graft vs Host Disease / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007422:Intestines / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000473:pathology; D017710:Lymphocyte Transfusion; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011480:Protease Inhibitors / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D012772:Shock, Septic / Q000473:pathology / Q000503:physiopathology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D015996:Survival Rate; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006877:Hydroxamic Acids; C107086:KB R7785; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D008666:Metalloendopeptidases; D005998:Glycine