IFN-GAMMA, IL-12, AND TNF-ALPHA ARE REQUIRED TO MAINTAIN REDUCED LIVER PATHOLOGY IN MICE VACCINATED WITH SCHISTOSOMA-MANSONI EGGS AND IL-12

The development of hepatic fibrosis and portal hypertension is the pri ncipal cause of morbidity and mortality in schistosomiasis mansoni, Ne vertheless, relatively little is known about the mechanisms that lead to excessive collagen deposition during infection with Schistosoma man soni. In the murine model, infection leads to significant egg-induced granuloma formation, tissue eosinophilia, and hepatic fibrosis, The pa thology has been linked to dominant type 2 cytokine expression, and ou r recent studies showed that sensitizing animals to egg Ags in combina tion with IL-12, before infection, led to a highly significant reducti on in egg-induced immunopathology, In this study, we demonstrate that in contrast with egg/IL-12-sensitized animals that showed marked decre ases in pathology, mice similarly sensitized but depleted of IFN-gamma , IL-12, or TNF-alpha at the time of egg laying developed granulomas t hat were similar to the non-IL-12-treated control group. Although all three anticytokine-treated groups exhibited a dominant type 1 response in lymph node cells restimulated ex vivo, the expression of type 2 cy tokine mRNA was markedly restored at the site of granuloma formation, which suggests that all three cytokines are required to maintain the s uppressed type 2 pattern. Moreover, egg/IL-12-sensitized mice depleted of IFN-gamma or IL-12 displayed a partial reduction in IFN-gamma prod uction, suggesting that multiple type 1 cytokines were required to mai ntain polarized type 1 responses to chronic type 2-inducing stimuli. T ogether, these data reveal key roles for IFN-gamma, IL-12, and TNF-alp ha in the protective effects mediated by this IL-12-based vaccine to p revent pathology.