A metalloproteinase inhibitor prevents acute graft-versus-host disease while preserving the graft-versus-leukaemia effect of allogeneic bone marrow transplantation Journal Article
| Authors: | Hattori, K.; Hirano, T.; Oshimi, K.; Yagita, H.; Okumura, K. |
| Article Title: | A metalloproteinase inhibitor prevents acute graft-versus-host disease while preserving the graft-versus-leukaemia effect of allogeneic bone marrow transplantation |
| Abstract: | 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-α and FasL processing. We examined the ameliorating effect of a hydroxamic acid-based metalloproteinase inhibitor (KB-R7785) that inhibits TNF-α and FasL release in a lethal acuteGVHD model in mice. The ameliorating effect of KB-R7785 was superior to that of anti-TNF-α 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. |
| Keywords: | controlled study; transplantation, homologous; unclassified drug; pathogenesis; nonhuman; animals; mice; animal tissue; cell survival; protease inhibitors; cell infiltration; fas ligand; animal experiment; animal model; allogenic bone marrow transplantation; histology; b-lymphocytes; death; tumor necrosis factor-alpha; membrane glycoproteins; graft versus host reaction; hydroxamic acids; fas ligand protein; bone marrow cell; hybridoma; tumor growth; bone marrow transplantation; graft vs host disease; graft versus leukemia effect; glycine; tumor necrosis factor; spleen cell; immunoglobulin e; allogeneic transplantation; hydroxamic acid derivative; graft vs leukemia effect; bmt; metalloproteinase inhibitor; hybridomas; acute gvhd; metalloendopeptidases; priority journal; article; preservation of gvl; prevention of gvhd; 4 (n hydroxyamino) 2 isobutyl 3 methylsuccinyl phenylglycine n methylamide; [4 (n hydroxyamino) 2 isobutyl 3 methylsuccinyl]phenylglycine n methylamide |
| Journal Title: | Leukemia and Lymphoma |
| Volume: | 38 |
| Issue: | 5-6 |
| ISSN: | 1042-8194 |
| Publisher: | Taylor & Francis Group |
| Date Published: | 2000-01-01 |
| Start Page: | 553 |
| End Page: | 561 |
| Language: | English |
| PUBMED: | 10953977 |
| PROVIDER: | scopus |
| DOI: | 10.3109/10428190009059275 |
| DOI/URL: | |
| Notes: | Export Date: 18 November 2015 -- Source: Scopus |
