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-α and FasL release in a lethal acute GVHD model in mice. Administration of KB-R7785 into (BALB/c × 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-α antibody. Our results suggest that KB-R7785 could be a potent therapeutic agent for GVHD.