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

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We here examined the effect. of a hydroxamic acid-based matrix metalloproteinase inhibitor (KB-R7785), which we previously demonstrated a potent ameliorating effect on acute graft-versus-host disease (GVHD), on graft-versus-leukemia (GVL) effect of allogeneic bone marrow transplantation (BMT), KB-R7785 was administrated into (C57BL/6 x BALB/c) Fl (CBF1) mice, that had been inoculated with IgE-producing B53 hybridoma cells of BALB/c origin as a model tumor, along with or without transplantation of C57BL/6 (B6) bone marrow cells and spleen cells (BMS). Administration of KB-R7785 without BMS significantly prolonged the survival of B53-inoculated CBF1 mice by inhibiting the infiltration of B53 cells into the liver and spleen. Transplantation o fB6 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 indicate beneficial effects of KB-R7785 that inhibit tumor infiltration and prevent acute GVHD while preserving the GVL effect of allogeneic BMT.