A heritable defect in IL-12 signaling in B10.Q/J mice. II. Effect on acuteresistance to Toxoplasma gondii and rescue by IL-18 treatment

This study documents a defect in IL-12-dependent IFN-gamma responses in a s ubstrain (BlO.Q-H2-q/Sgj) of B10.Q mice that manifests as an acute suscepti bility to infection by the intracellular protozoan pathogen, Toxoplasma gon dii. Despite robust systemic production of IL-12, infected B10.Q/j animals fail to mount an early IFN-gamma response after parasite inoculation. Genet ic experiments revealed that the host resistance and IFN-gamma production d efects are determined by a single autosomal recessive locus distinct from t he Stat4 gene. Nonetheless, a delayed IL-12-mediated IFN-gamma response eme rges in later stages of acute infection but is unable to prevent host morta lity. IL-18 administration restores, in an IL-12-dependent manner, the earl y IFN-gamma response and host resistance of B10.Q/j animals. These in vivo studies indicate that the partially impaired IL-12 responsiveness in B10.Q/ j mice can result in defective host resistance and demonstrate a therapeuti c function for IL-18 in reversing a genetically based immunodeficiency in I L-12-dependent IFN-gamma production.