N-acetyl-L-cysteine increases acute graft-versus-host disease and promotes T-cell-mediated immunity in vitro

N-acetyl-L-cysteine (NAC) is a thiol antioxidant that stimulates glutathione synthesis in cells. Several studies indicate that NAC possesses immunomodulatory properties in vitro, but both inhibitory and activating effects on immunity have been reported. We observed that allogeneic stem cell transplantation (ASCT) patients who were randomized to receive NAC 100 mg/kg/day (n=73) had an increased prevalence of grade II-V acute graft-versus-host disease (GvHD) compared to patients who did not receive NAC (n=87), indicating that NAC has an immunostimulatory effect in vivo. When studying the effect of NAC on T-cell-mediated immunity in vitro, we found that moderate levels of NAC (0.4-3.2mM) increased alloantigen-induced proliferation, expression of activation markers CD25 and CD71 on T cells, and production of IFN-gamma and IL-10. In contrast, high concentrations of NAC (12.5-50mM) were suppressive, which may explain previously conflicting data. NAC did not cause an increase in expression of CD86, CD80, and CD83 on mature DCs at any concentration, whereas high concentrations suppressed DC maturation. Furthermore, T cells exposed to suppressive concentrations of NAC in a primary stimulation were highly responsive when re-stimulated in the absence of NAC. To conclude, NAC appears to increase acute GvHD and has an immunostimulatory effect on alloantigen-specific T cells.