Two cytokines, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), which play critical roles in the regulation of serum IgE level by directing the interplay of T helper (Th)1 and Th2 cells, were chosen as targets for gene therapy. Anti-allergic activity was evaluated by determining the serum IgE level, and the functional status of each helper T cell was monitored by the serum concentrations of IgG1 and IgG2a. Experimental animals (BALB/c mice) were divided into four groups: the control group; the ovalbumin (OVA) group; the IFN-gamma group; and the IL-4 group. The control group was injected with saline and the OVA group with OVA-alum. The IFN-gamma and IL-4 groups were treated with OVA-alum plus the cDNAs of mouse IFN-gamma and IL-4 in an expression vector. These treatments were applied intramuscularly on a monthly basis for 4 months. OVA-alum treatment significantly increased the serum IgE and IgG1 concentrations, but did not affect IgG2a. Concomitant treatments with the cDNA of IFN-gamma or IL-4 returned the serum IgE almost to the control level and significantly suppressed the OVA-induced increase of IgG1. IFN-gamma cDNA increased the serum IgG2a but IL-4 cDNA had no affect. These results suggest that IFN-gamma inhibited the OVA-induced IgE production by suppressing the Th2 pathway and by enhancing the Th1 pathway. Administration of IL-4 cDNA suppressed the OVA-induced enhancement of IgE production by inhibiting the Th2 pathway rather than by potentiating it.