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IL-23 Is Required for the Development of Severe Egg-Induced Immunopathology in Schistosomiasis and for Lesional Expression of IL-17¹

Laura I. Rutitzky^*, Lindsey Bazzone^*, Mara G. Shainheit^*, Barbara Joyce-Shaikh, Daniel J. Cua and Miguel J. Stadecker^2,*

^* Department of Pathology, School of Medicine, Tufts University, Boston, MA 02111; and Discovery Research, Schering Plough Biopharma, Palo Alto, CA 94304

In infection with the trematode helminth Schistosoma mansoni, the severity of CD4 T cell-mediated hepatic granulomatous and fibrosing inflammation against parasite eggs varies considerably in humans and among mouse strains. In mice, either the natural high pathology, or high pathology induced by concomitant immunization with schistosome egg Ags (SEA) in CFA (SEA/CFA), results from a failure to contain a net proinflammatory cytokine environment. We previously demonstrated that the induction of severe immunopathology was dependent on the IL-12/IL-23 common p40 subunit, and correlated with an increase in IL-17, thus implying IL-23 in the pathogenesis. We now show that mice lacking the IL-23-specific subunit p19 are impaired in developing severe immunopathology following immunization with SEA/CFA, which is associated with a marked drop of IL-17 in the granulomas, but not in the draining mesenteric lymph nodes, and with a markedly suppressed SEA-specific IFN- response regulated by a striking increase in IL-10. The granulomas are characterized by a significant reduction in Gr-1⁺ cell recruitment and by alternative macrophage activation. Taken together, these results demonstrate that IL-23 per se is not necessary for the generation of IL-17-producing T cells, but is essential for the development of severe schistosome egg-induced immunopathology, and its absence cannot be overcome with other possible compensatory mechanisms.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Public Health Service Grant RO1-18919.

² Address correspondence and reprint requests to Dr. Miguel J. Stadecker, Department of Pathology, School of Medicine, Tufts University, 150 Harrison Avenue, Boston, MA 02111. E-mail address: miguel.stadecker{at}tufts.edu

³ Abbreviations used in this paper: SEA, schistosome egg Ag; MLN, mesenteric lymph node; Ct, cycle threshold; GC, granuloma cell; MLNC, MLN cell; INOS, inducible NO synthase.

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