Ifosfamide impairs the allostimulatory capacity of human dendritic cells by intracellular glutathione depletion.

نویسندگان

  • Maria C Kuppner
  • Anabel Scharner
  • Valeria Milani
  • Christoph Von Hesler
  • Katharina E Tschop
  • Oksana Heinz
  • Rolf D Issels
چکیده

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-gamma (IFN-gamma) production. Ifosfamide also decreased DC interleukin-12p70 (IL-12p70) production after stimulation with lipopolysaccharide (LPS) and IFN-gamma. The decrease in allostimulatory capacity and in IFN-gamma 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.

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Ifosfamide impairs the allostimulatory capacity of human dendritic cells by intracellular glutathione depletion . Running title : Ifosfamide regulates DC glutathione levels and function

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عنوان ژورنال:
  • Blood

دوره 102 10  شماره 

صفحات  -

تاریخ انتشار 2003