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

Tumor necrosis factor (TNF) and Fas ligand (FasL) have been implicated in t he pathogenesis of graft-versus-host disease (GVHD). Several recent studies have shown that some metalloproteinase mediates TNF-alpha and Fast process ing. We examined the ameliorating effect of a hydroxamic acid-based metallo proteinase inhibitor (KB-R7785) that inhibits TNF-alpha and Fast 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 marro w transplantation (BMT), Administration of KB-R7785 without bone marrow cel ls and spleen cells (BMS). significantly prolonged the survival of IgE-prod ucing B53 hybridoma cell-inoculated (C57BL/6 x BALB/c) F1 (CBF1) mice by in hibiting the infiltration of B53 cells into the liver and spleen. Transplan tation of B6 BMS without KB-R7785 resulted in the death of most recipients due to acute GVHD while efficiently eliminating B53 cells. Administration o f KB-R7785 along with B6 EMS resulted ill 50% survival of B53-inoculated CB F1 mice over 50 days without histological manifestations of acute GVHD or r esidual B53 cells. These results: suggest that KB-R7785 could be a potent t herapeutic 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.