Interleukin-12: role of interferon-gamma in IL-12 adverse effects

Interleukin 12 (IL-12) activates natural killer and T cells with the secondary synthesis and release of interferon-gamma (IFN-gamma) and therefore enhances a Th1- or cell-mediated immune response. The immunostimulatory property of IL-12 may be used clinically in cancer and viral diseases. Safety studies in rodents and primates demonstrated a rather small therapeutic window with hepato- and splenomegaly, myelodepression, and lung edema. Investigations in mutant mice deficient for the IFN-gamma receptor (IFN-gamma R-/-) revealed that both the biologic and toxic effects are indirect and largely due to IL-12-induced IFN-gamma. The significance of these findings for the safety in man needs to be explored.