Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis

in several allergic, autoimmune, and infectious diseases, fibrosis is a maj or cause of morbidity and mortality. Here, using a model of infection-induc ed liver fibrosis, we show that interleukin (IL)-13 is required at all stag es of Schistosomiasis mansoni infection to induce fibrosis. IL-4 production was preserved in IL-13-deficient mice, yet failed to significantly contrib ute to the fibrotic response in either acute or chronic infection. Signific ant fibrosis develops in all infected mice, although the magnitude of the r esponse varies widely in inbred mice. C3H/HeN, BALB/c, and C57BL/6 mice dev elop high, intermediate, and low levels of fibrosis, respectively. Despite these differences, IL-13 antagonism resulted in a marked amelioration of fi brosis in all strains. The fibrotic mechanism in the high- and low-responde r strains was unrelated to their tissue eosinophil or mast cell responses, but did correlate with their patterns of IL-13, IL-10, and interferon gamma (IFN-gamma) mRNA expression. Indeed, severe fibrosis correlated with a hig h IL-13 and low IFN-gamma /IL-10 mRNA response. Because fibrotic diseases a re typically progressive disorders, an important issue was to determine whe ther IL-13 inactivation might be used to treat an established and ongoing f ibrotic disease. Here, IL-13 antagonism was highly efficacious, even after fibrosis and the Th2 cytokine response were firmly established. These studi es demonstrate the central role played by IL-13 in fibrogenesis and suggest that therapeutic approaches aimed at disrupting the IL-13 pathway will be highly effective at preventing fibrotic disease caused by chronic Th2-media ted inflammatory reactions.