IL-10 and the dangers of immune polarization: Excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis

To dissect the controversial roles of type 1 and type 2 cytokines to the pa thogenesis of schistosomiasis, we generated IL-10m-4 and IL-10/IL-12-defici ent mice that develop highly polarized type 1 and type 2 cytokine responses , respectively. Interestingly, the Th1-polarized IL-10/IL-4-deficient mice rapidly lost weight at the onset of egg-laying and displayed 100% mortality by wk 9 postinfection. This acute mortality was linked to overexpression o f the proinflammatory mediators IFN-gamma, TNF-alpha, and inducible NO and the formation of nonfibrotic granulomas. Elevated serum aspartate transamin ase levels confirmed that mortality was in part attributable to acute hepat otoxicity, In contrast, the Th2-polarized IL-10/IL-12-deficient mice develo ped a progressive wasting disease that correlated with increased hepatic fi brosis, formation of large eosinophil-rich granulomas, a l0-fold increase i n IL-4 and IL-13, and significant mortality during the chronic stages of in fection. Surprisingly, IL-10-deficient mice displayed pathological Features that were characteristic of both extremes, while wild-type mice developed relatively successful long term chronic infections. These data demonstrate that IL-10 significantly suppresses type 1 and type 2 cytokine development in IL-4- and IL-12-deficient mice, respectively, thereby impeding the devel opment of severe egg-induced pathology in the single cytokine-deficient ani mals. Together, these findings reveal the central regulatory role of IL-10 in the pathogenesis of schistosomiasis and illustrate that excessive type 1 and type 2 cytokine responses trigger distinct, but equally detrimental, f orms of pathology following infection.