(4-(n-hydroxyamino)-2r-isobutyl-3s-methylsuccinyl)-l-phenylglycine-n-methylamide and Graft-vs-Host-Disease

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.

Topics: Animals; B-Lymphocytes; Bone Marrow Transplantation; Fas Ligand Protein; Glycine; Graft vs Host Disease; Graft vs Leukemia Effect; Hybridomas; Hydroxamic Acids; Membrane Glycoproteins; Metalloendopeptidases; Mice; Protease Inhibitors; Transplantation, Homologous; Tumor Necrosis Factor-alpha

We examined the effect of a hydroxamic acid-based matrix metalloproteinase inhibitor (KB-R7785), which we previously demonstrated to have a potent ameliorating effect on acute graft-versus-host disease (GVHD), and on the graft-versus-leukaemia (GVL) effect of allogeneic bone marrow transplantation (BMT). KB-R7785 was administered to (C57BL/6 x BALB/c) F1 (CBF1) mice that had been inoculated with IgE-producing B53 hybridoma cells of BALB/c origin as a model tumour, 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 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 a 50% survival of B53-inoculated CBF1 mice over 50 d without histological manifestations of acute GVHD or residual B53 cells. These results indicate the beneficial effects of KB-R7785 that inhibit tumour infiltration and prevent acute GVHD while preserving the GVL effect of allogeneic BMT.

Topics: Animals; Bone Marrow Transplantation; Female; Flow Cytometry; Glycine; Graft vs Host Disease; Graft vs Tumor Effect; Humans; Hydroxamic Acids; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Protease Inhibitors; Transplantation, Homologous

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 have examined the ameliorating effect of a metalloproteinase inhibitor (KB-R7785) that inhibits TNF-alpha and FasL release in a murine acute GVHD model after bone marrow transplantation. Administration of KB-R7785 to irradiated (BALB/c x C57BL/6) F1 mice that received C57BL/6 bone marrow cells and spleen cells reduced the mortality and weight loss in association with minimal signs of GVHD pathology in the liver, intestine, and hematopoietic tissues. The KB-R7785 treatment did not affect hematopoietic reconstitution by donor cells. Therefore, KB-R7785 could be a potent therapeutic agent for GVHD after bone marrow transplantation.

Topics: Animals; Bone Marrow Transplantation; Cell Separation; Female; Flow Cytometry; Glycine; Graft vs Host Disease; Hematopoiesis; Hydroxamic Acids; Lymphocytes; Metalloendopeptidases; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Protease Inhibitors; Weight Loss

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

Topics: Animals; Crosses, Genetic; Fas Ligand Protein; Female; Glycine; Graft vs Host Disease; Humans; Hydroxamic Acids; Intestines; Lipopolysaccharides; Liver; Lymphocyte Transfusion; Membrane Glycoproteins; Metalloendopeptidases; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Protease Inhibitors; Recombinant Proteins; Shock, Septic; Spleen; Survival Rate; Transfection; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha