IN-VIVO IL-12 ADMINISTRATION INDUCES PROFOUND BUT TRANSIENT COMMITMENT TO T-HELPER CELL-TYPE 1-ASSOCIATED PATTERNS OF CYTOKINE AND ANTIBODY-PRODUCTION

There is much interest in the utility of exogenous IL-12 as a biologic adjuvant in immediate hypersensitivity and infectious or parasitic di seases where the induction of Th1 responses is strongly associated wit h protective immunity, Using an immediate hypersensitivity model in wh ich C57Bl/6 mice immunized with OVA (alum) normally generate Th2-domin ated responses, we examined the ability of rIL-12 to direct and mainta in OVA-specific cytokine and Ab responses in a Th1 direction. Exogenou s IL-12 administered coincident with OVA immunization stimulated eleva ted serum IFN-gamma levels, enhanced IFN-gamma synthesis, and inhibite d IL-4 synthesis in bulk culture; 80 to 99% inhibited primary Ag-speci fic serum IgE and IgG1 responses; and 15- to 20-fold enhanced IgG2a sy nthesis. However, each of these effects was highly transient, as exoge nous IL-12, given at levels up to those associated with serious toxici ty, failed to have a lasting impact on the OVA-specific T or B cell re sponse. This transience was evident in primary bulk culture cytokine s ynthesis; in limiting dilution analysis of the frequency of OVA-specif ic IFN-gamma-, IL-4-, or IL-10-producing CD4 T cells; and, most import antly, in vivo effector responses such as IgE production to secondary and tertiary OVA immunization. The finding that the intense. Th1-like phenomena seen following in vivo administration of rIL-12 with this ex agenous Ag are highly transient and are neat associated with alteratio ns ire the allergen-specific CD4 T cell repertoire to Th1-like pattern s suggests a need for caution in the enthusiasm for the use of this cy tokine as a biologic adjuvant.