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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Crosses, Genetic
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Fas Ligand Protein
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Female
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Glycine / analogs & derivatives*
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Glycine / pharmacology
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Graft vs Host Disease / pathology
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Graft vs Host Disease / prevention & control*
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Humans
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Hydroxamic Acids / pharmacology*
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Intestines / pathology
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Lipopolysaccharides / toxicity
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Liver / pathology
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Lymphocyte Transfusion*
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Membrane Glycoproteins / biosynthesis*
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Metalloendopeptidases / antagonists & inhibitors*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Protease Inhibitors / pharmacology*
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Recombinant Proteins / biosynthesis
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Shock, Septic / pathology
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Shock, Septic / physiopathology
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Spleen / immunology
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Spleen / pathology
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Survival Rate
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Transfection
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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FASLG protein, human
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Fas Ligand Protein
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Fasl protein, mouse
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Hydroxamic Acids
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KB R7785
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Lipopolysaccharides
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Membrane Glycoproteins
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Protease Inhibitors
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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Metalloendopeptidases
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Glycine