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.