ADMINISTRATION OF IL-12 DURING ONGOING IMMUNE-RESPONSES FAILS TO PERMANENTLY SUPPRESS AND CAN EVEN ENHANCE THE SYNTHESIS OF ANTIGEN-SPECIFIC IGE

The synthesis of antibodies of the IgE isotype in mice largely depends on IL-4, a cytokine that is released by T lymphocytes of the T(h)2 su btype. IL-12 is a cytokine considered to direct Th cell development in to a T(h)1 direction and to suppress T(h)2 responses including the syn thesis of IgE. Here we report about the influence of IL-12 on the IgE response of mice immunized with protein antigens adsorbed to aluminum hydroxide. To avoid problems with the detection of IgE caused by an ex cess of competitive IgG antibodies produced in IL-12-treated mice, ser um IgE was first extracted from the serum by plate-bound anti-IgE mAb and then determined either as total IgE or as antigen-specific IgE by using biotinylated anti-IgE or biotinylated antigen. Depending on the strain of mice and the dose of IL-12 injected together with the antige n, IL-12 can either temporarily suppress or augment the synthesis of ( antigen-specific) IgE antibodies. This applies for CBA/J mice immunize d six times in biweekly intervals with minute (0.1 mu g/injection) or three-times with large (5 mu g/injection) amounts of the bee venom all ergen phospholipase A(2) (PLA(2)). Under both conditions the antibody response is characterized by the production of predominantly IgG1 as w ell as IgE but very little IgG2a, IgG2b and IgG3 antibodies. Simultane ous application of low doses of IL-12 (1 or 10 ng/day) led to a 2- to 4-fold enhancement of IgE production (PLA(2)-specific IgE or total IgE ). Only a high dose of 1 mu g IL-12/day resulted in a 3- to 10-fold re duction of the IgE response. This suppression was not stable, however, because the synthesis of IgE antibodies was stimulated to a high leve l when these mice subsequently received a second course of immunizatio ns in the absence of IL-12. Likewise, the synthesis of IgE was only te mporarily suppressed by IL-12 treatment in CBA/J mice immunized with k eyhole limpet hemocyanin (KLH) as antigen. However, application of low (10 ng/day) or high (1 mu g/day) doses of IL-12 during the primary co urse of immunizations of CBA/J mice with KLH suppressed the IgE respon se slightly or strongly respectively, in striking contrast, the KLH-sp ecific IgE response of BALB/c mice was upregulated even when high dose s of IL-12 (1 mu g/day) were injected simultaneously with the immuniza tions. Thus, these results demonstrate a great variability regarding t he influence of IL-12 treatment on ongoing IgE responses in vivo.