Abstract
The occurrence of acute graft-versus-host disease (aGVHD) and tumor relapse represent the two major obstacles impeding the efficacy of allogeneic bone marrow transplantation (BMT) in cancer. We have previously shown that the synthetic triterpenoid 2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid (CDDO) can inhibit murine early aGVHD, but antitumor effects were not assessed. In the current study, we found that a new derivative of CDDO, CDDO-Me, had an increased ability to inhibit allogeneic T cell responses and induce cell death of alloreactive T cells in vitro. Administration of CDDO-Me to mice following allogeneic BMT resulted in significant and increased protection from lethal aGVHD compared to CDDO. This correlated with reduced TNF-alpha production, reduced donor T cell proliferation, and decreased adhesion molecule (alpha(4)beta(7) integrin) expression on the donor T cells. CDDO-Me was also superior to CDDO in inhibiting leukemia growth in vitro. When CDDO-Me was administered following an allogeneic BMT to leukemia-bearing mice, significant increases in survival were observed. These findings suggest that CDDO-Me is superior to CDDO in delaying aGVHD, while preserving or possibly even augmenting GVT effects.
Copyright 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / immunology
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Bone Marrow Transplantation / methods*
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Colon / pathology
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Female
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Graft vs Host Disease / blood
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Graft vs Host Disease / pathology
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Graft vs Host Disease / prevention & control*
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Graft vs Tumor Effect / drug effects
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Graft vs Tumor Effect / immunology*
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Immunosuppressive Agents / administration & dosage
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Immunosuppressive Agents / pharmacology
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Immunosuppressive Agents / therapeutic use
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Integrins / metabolism
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Leukemia, Myeloid, Acute / drug therapy
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Leukemia, Myeloid, Acute / therapy
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Liver / pathology
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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Lymphocyte Culture Test, Mixed
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Oleanolic Acid / administration & dosage
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Oleanolic Acid / analogs & derivatives*
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Oleanolic Acid / pharmacology
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Oleanolic Acid / therapeutic use
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Spleen / cytology
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Spleen / immunology
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Survival Analysis
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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T-Lymphocytes / transplantation
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Transplantation, Homologous
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Tumor Necrosis Factor-alpha / blood
Substances
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Immunosuppressive Agents
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Integrins
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Tumor Necrosis Factor-alpha
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integrin alpha4beta7
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Oleanolic Acid
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bardoxolone methyl