Cytokine specific ELIspot assays were used to monitor the number of cells secreting IL-4 and IFN gamma in MRL-lpr/lpr mice of different ages. The cytokine repertoire expressed by MRL-lpr/lpr mice was skewed towards the over-production of IFN gamma (and away from IL-4) when compared to that of MRL-+/-/+/- and BALB/c mice. With increasing age and disease severity, the ratio of IFN gamma: IL-4 secreting cells rose in MRL-lpr/lpr mice but decreased in normal animals. This changing ratio of IFN gamma: IL-4 secreting cells correlated with changes in the ratio of IgG2a: IgG1 secreting cells in these mice. Our findings suggest that cytokine secreting CD4+ and CD8+ cells are hyperactivated in young MRL-lpr/lpr mice, and that disease progression is associated with a disruption in the normal ratio of Th1:Th2 production in vivo.