IL-12 regulation of parasite antigen-driven IgE production in human helminth infections

Recombinant IL-12 inhibits IgE synthesis by IL-4-stimulated lymphocytes from healthy persons and influences the development of Th subset selection involved in Ig isotype selection. Whether endogenous IL-12 production modulates IgE synthesis in patients with elevated serum IgE is unknown. To examine this question we studied the effects of neutralizing anti-IL-12 or recombinant IL-12 on parasite Ag-driven polyclonal IgE production and corresponding IFN-gamma and IL-4 synthesis by PBMC from helminth-infected individuals. The addition of neutralizing anti-IL-12 Ab significantly inhibited parasite Ag-driven IgE production in 11 of 12 individuals (p < 0.001). Recombinant IL-12 (1-10 U/ml) suppressed Ag-driven IgE production in a dose-dependent fashion up to 94% relative to untreated cultures. The effect of endogenous IL-12 on IgE production occurred, in part, by suppressing Ag-induced IL-4 and augmenting IFN-gamma production. IL-12 did not suppress IgE synthesis by purified B cells. An IFN-gamma-independent effect of IL-12 on Ag-driven IgE production was suggested by the ability of human rIL-12 to suppress IgE synthesis in the presence of neutralizing anti-IFN-gamma. This study demonstrates that IL-12 modulates helminth Ag-driven IgE production, in part, by regulating the relative quantities of IFN-gamma and IL-4 generated by Ag-specific lymphocytes.