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Blood, 15 November 2003, Vol. 102, No. 10, pp. 3668-3674. Prepublished online as a Blood First Edition Paper on July 10, 2003; DOI 10.1182/blood-2003-05-1408. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-05-1408v1 102/10/3668    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kuppner, M. C. Articles by Issels, R. D. Search for Related Content PubMed PubMed Citation Articles by Kuppner, M. C. Articles by Issels, R. D. Related Collections Immunobiology Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Ifosfamide impairs the allostimulatory capacity of human dendritic cells by intracellular glutathione depletion Maria C. Kuppner, Anabel Scharner, Valeria Milani, Christoph von Hesler, Katharina E. Tschöp, Oksana Heinz, and Rolf D. Issels From the Klinikum Grosshadern, Medical Clinic III, Ludwig-Maximillians-University, Munich, Germany; GSF, National Research Center for Environment and Health, Institute of Molecular Immunology, Munich, Germany; and the Clinical Cooperation Group on Hyperthermia, Ludwig-Maximillians-University, Munich, Germany. Ifosfamide, a clinically potent chemotherapeutic agent, causes the depletion of intracellular glutathione (GSH) levels in various cell types. GSH is the major intracellular reductant against oxidative stress. 4-Hydroxyifosfamide (4-OH-IF), the activated form of ifosfamide, depletes GSH levels in T cells and natural killer (NK) cells; this is accompanied by a decrease in T-cell and NK-cell function. Here we demonstrate for the first time that human monocyte-derived dendritic cells (DCs) express higher constitutive levels of GSH and are less sensitive to 4-OH-IF-induced GSH depletion than T cells and NK cells. Treatment of DCs with 4-OH-IF significantly reduced their ability to stimulate allogeneic T-cell proliferation and interferon- (IFN-) production. Ifosfamide also decreased DC interleukin-12p70 (IL-12p70) production after stimulation with lipopolysaccharide (LPS) and IFN-. The decrease in allostimulatory capacity and in IFN- and IL-12 production correlated with a decrease in intracellular GSH in the DCs. The responses could be restored by reconstituting DC GSH levels with glutathione monoethyl ester (GSH-OEt). 4-OH-IF had no inhibitory effect on the ability of DCs to present exogenously added tyrosinase peptide to tyrosinase-specific cytotoxic T lymphocytes (CTLs). These studies suggest that in cancer patients treated with ifosfamide, protection strategies based on glutathione reconstitution may enhance DC function. (Blood. 2003;102: 3668-3674) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Agrawal, P. Kaushal, S. Agrawal, S. Gollapudi, and S. Gupta Thimerosal induces TH2 responses via influencing cytokine secretion by human dendritic cells J. Leukoc. Biol., February 1, 2007; 81(2): 474 - 482. [Abstract] [Full Text] [PDF] J. Zhang, M. A. Alston, H. Huang, and R. L. Rabin Human T cell cytokine responses are dependent on multidrug resistance protein-1 Int. Immunol., March 1, 2006; 18(3): 485 - 493. [Abstract] [Full Text] [PDF]

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