A metalloproteinase inhibitor prevents lethal acute graft-versus-host disease in mice.
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.
Hattori
K
K
Department of Internal Medicine, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
Hirano
T
T
Ushiyama
C
C
Miyajima
H
H
Yamakawa
N
N
Ebata
T
T
Wada
Y
Y
Ikeda
S
S
Yoshino
K
K
Tateno
M
M
Oshimi
K
K
Kayagaki
N
N
Yagita
H
H
Okumura
K
K
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
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