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

Ifosfamide a clinically potent chemotherapeutic agent causes depletion of intracellular glutathione (GSH) levels in different 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 NK cells which is accompanied by a decrease in T cell and NK function. Here we demonstrate for the first time that human monocyte derived dendritic cells (DC) express higher constitutive levels of GSH and are less sensitive to 4-OH-IF induced GSH depletion in comparison to T cells and NK cells. Treatment of DC with 4-OH-IF significantly reduced their ability to stimulate allogeneic T cell proliferation and IFNγ production. Ifosfamide also decreased DC IL-12p70 production after stimulation with LPS and IFNγ. The decrease in allostimulatory capacity and in IFNγ and IL-12 production correlated with a decrease in intracellular GSH in the DC . 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 DC to present exogenously added tyrosinase peptide to tyrosinase specific CTL. These studies suggest that in cancer patients treated with ifosfamide protection strategies based on glutathione reconstitution may enhance DC function . E mail address. [email protected] For personal use only. on October 31, 2017. by guest www.bloodjournal.org From