Approaches To Immunological Intervention In Schistosomiasis

National Institute Of Allergy And Infectious Diseases

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Abstract

1) Because IL-10 and IL-13Rα2 are both capable of modulating IL-13 effector functions, we examined whether the regulatory activities of IL-10 were associated with changes in IL-13Rα2 production and/or function in schistosomiasis. We found that IL-10 inhibits granulomatous inflammation, with IL-10-/- mice developing much larger granulomas in the gut and liver, but, paradoxically, displaying reduced liver fibrosis following acute Schistosoma mansoni infection. Interestingly, the reduced pathological responses in IL-10-/- mice were associated with increased IL-13Rα2 production in the serum and liver. Therefore, to determine whether the observed changes in IL-13Rα2 expression were responsible for the modified pathological responses in IL-10-/- mice, we generated IL-10-/-IL-13Rα2-/- double-KO (dKO) mice. We found that dKO mice developed significantly more fibrosis compared with either single-KO mouse, demonstrating that IL-13Rα2 cooperates with IL-10 to control Th2-driven fibrosis. To determine whether local changes in Th2 effector function were responsible for the exacerbated fibrotic responses in the dKO mice, three distinct subsets of genes were analyzed, including markers of alternative macrophage activation (Ym1 and FIZZ1), MMPs (MMP-9 and MMP-12), and interstitial collagens (COL III and COL VI), all linked with Th2 effector responses. Interestingly, deletion of IL-10 alone had little effect. However, deleting IL-13Rα2 alone or in combination with IL-10 led to significantly increased Ym-1, FIZZ-1, MMP-9, MMP-12, pro-Col III, and pro-Col VI mRNA expression when compared with WT mice. These data suggest that IL-13Rα2 is the dominant regulator of IL-13 effector responses in the tissues. In fact, the only consistent difference between IL-13Rα2-/- and dKO mice was a slight increase in Ym-1 and MMP-9 and a small but significant increase in MMP-12 and IL-5 in the dKO mice. Thus, although -10 and IL-13Rα2 both regulate Th2-driven disease, they target distinct pathological features, with IL-10 inhibiting inflammation and IL-13Rα2 suppressing IL-13dependent effector responses (i.e. fibrosis).[unreadable] [unreadable] 2) Because the IL-4Rα chain functions as the primary signaling receptor for IL-4 and IL-13, it has been the most widely studied of the four receptor subunits that engage these cytokines. However, while it is now clear that the IL-4Rα chain plays a central role in the pathogenesis of a wide variety of Th2-associated diseases including schistosomiasis, thus far it has been impossible to assign the various functions of the IL-4Rα to either the Type-I or Type-II IL-4R signaling pathways, because both receptor signaling pathways are deleted in IL-4Ra-deficient animals. Therefore, to elucidate the contributions of the Type-II receptor, we generated mice with a targeted deletion of the IL13Ra1 gene and examined the effects on Th2 response development and fibrosis in schistosomiasis. Survival studies were performed with S. mansoni and as expected, by wk 10 of infection, greater than 75% of IL-4/IL-13 dKO (Type-I and Type-II receptor signaling blocked) had succumbed to the infection. In contrast, only 50% mortality was observed in the WT group by wk 18. Strikingly however, more than 80% of the IL-13Rα1-/- mice survived through week 22, demonstrating that type-II IL-4R was highly pathogenic during S. mansoni infection, while the Type-I receptor played a protective function. The enhanced survival of the chronically infected IL-13Rα1-/- mice was also associated with a marked reduction in fibrosis, determined by both hydroxyproline assay and by picrosirius red staining of tissue sections. In addition, markers of hepatocellular damage and biliary obstruction (alanine aminotransferase ALT, aspartate aminotransferase AST, and alkaline phosphatase AP) were also significantly decreased in the sera of chronically infected IL-13Rα1-/- mice. [unreadable] Functional studies suggested that the type-II IL-4R was involved in the activation of important mesenchymal cells, like fibroblasts and epithelial cells, which contribute to the development of fibrosis and mortality in schistosomiasis. As such, these findings suggest that for some chronic fibrotic diseases, it may be advantageous to inhibit the pathogenic type-II IL-4R while leaving the protective type-I IL-4R pathway intact