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A metalloproteinase inhibitor prevents acute graft-versus-host disease while preserving the graft-versus-leukaemia effect of allogeneic bone marrow transplantation.

Abstract
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.
AuthorsK Hattori, T Hirano, K Oshimi, H Yagita, K Okumura
JournalLeukemia & lymphoma (Leuk Lymphoma) Vol. 38 Issue 5-6 Pg. 553-61 (Aug 2000) ISSN: 1042-8194 [Print] United States
PMID10953977 (Publication Type: Journal Article)
Chemical References
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Hydroxamic Acids
  • KB R7785
  • Membrane Glycoproteins
  • Protease Inhibitors
  • Tumor Necrosis Factor-alpha
  • Metalloendopeptidases
  • Glycine
Topics
  • Animals
  • B-Lymphocytes (pathology)
  • Bone Marrow Transplantation (adverse effects)
  • Fas Ligand Protein
  • Glycine (administration & dosage, analogs & derivatives)
  • Graft vs Host Disease (etiology, prevention & control)
  • Graft vs Leukemia Effect
  • Hybridomas (pathology)
  • Hydroxamic Acids (administration & dosage)
  • Membrane Glycoproteins
  • Metalloendopeptidases (antagonists & inhibitors)
  • Mice
  • Protease Inhibitors (administration & dosage)
  • Transplantation, Homologous
  • Tumor Necrosis Factor-alpha

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