RAPID COMMUNICATION A Metalloproteinase Inhibitor Prevents Lethal Acute Graft-Versus-Host Disease in Mice

Tumor necrosis factor (TNF) and Fas ligand (FasL) have been reduced the mortality and weight loss in association with implicated in the pathogenesis of graft-versus-host disease minimal signs of GVHD pathology in the liver, intestine, and (GVHD), which is a major complication after allogeneic bone hematopoietic tissues. The ameliorating effect of KB-R7785 marrow transplantation. We examined here the ameliorat- was superior to that of anti–TNF-a antibody. Our results ing effect of a metalloproteinase inhibitor (KB-R7785) that suggest that KB-R7785 could be a potent therapeutic agent inhibits TNF-a and FasL release in a lethal acute GVHD for GVHD. model in mice. Administration of KB-R7785 into (BALB/c Ì q 1997 by The American Society of Hematology. C57BL/6) F1 that received C57BL/6 spleen cells markedly A have been obtained in the phase I-II clinical trials.8 Theseobservations substantiate that TNF-a is an important targetLLOGENEIC bone marrow transplantation (BMT) hasbeen a clinical treatment modality for hematopoietic disorders and hematologic malignancies.1 Graft-versus-host for the clinical treatment of GVHD. Recently, the ligand for Fas (FasL) has been also impli-disease (GVHD) remains a principal complication after allo-geneic BMT, occurring in up to 75 % of unmanipulated HLA- cated in the pathogenesis of GVHD. Fas (APO-1, CD95) is a member of the TNF receptor family and transmits an apo-matched marrow recipients.2 An acute lethal form of GVHD is caused by activation of the host-reactive donor T cells as ptotic cell death signal upon ligation by FasL.9 Fas is expressed in various tissues, including the skin,represented by a murine model that is caused by transfusio