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Reversal of Thymic Stromal Lymphopoietin-Induced Airway Inflammation through Inhibition of Th2 Responses¹

Baohua Zhou^2,3,*, Mark B. Headley^*,, Theingi Aye^*, Joel Tocker, Michael R. Comeau and Steven F. Ziegler^3,*,

^* Immunology Program, Benaroya Research Institute, Seattle, WA 98101; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98196; and Department of Inflammation, Amgen, Seattle, WA 98119

Lung-specific thymic stromal lymphopoietin (TSLP) expression is sufficient for the development of an asthma-like chronic airway inflammatory disease. However, the nature of the downstream pathways that regulate disease development are not known. In this study, we used IL-4- and Stat6-deficient mice to establish the role of Th2-type responses downstream of TSLP. IL-4 deficiency greatly reduced, but did not eliminate, TSLP-induced airway hyperresponsiveness, airway inflammation, eosinophilia, and goblet cell metaplasia, while Stat6 deficiency eliminated these asthma-like symptoms. We further demonstrate, using the chronic model of TSLP-mediated airway inflammation, that blockade of both IL-4 and IL-13 responses, through administration of an anti-IL-4R mAb, reversed asthma-like symptoms, when given to mice with established disease. Collectively these data provide insight into the pathways engaged in TSLP-driven airway inflammation and demonstrate that simultaneous blockade of IL-4 and IL-13 can reverse established airway disease, suggesting that this may be an effective approach for the therapy of Th2-mediated inflammatory respiratory disease.

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 National Institutes of Health Grants AI44259, AI68731, and AI71130, Department of Defense Grant USAMRAA W81XWH-07-0246 (to S.F.Z.), a grant from the American Lung Association (to B.Z.), and National Cancer Institute training Grant Basic Immunology T32, CA009537 (to M.B.H.).

² Current address: Department of Pediatrics, H. B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202.

³ Address correspondence and reprint requests to Dr. Baohua Zhou, Department of Pediatrics, H. B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, or Dr. Steven F. Ziegler, Benaroya Research Institute, 1201 9th Avenue, Seattle, WA 98101. E-mail addresses: zhoub{at}iupui.edu or sziegler{at}benaroyaresearch.org

⁴ Abbreviations used in this paper: AHR, airway hyperreactivity; DC, dendritic cell; TSLP, thymic stromal lymphopoietin; BAL, bronchoalveolar lavage; PAS, periodic acid Schiff; MAP, MultiAnalyte profiling; P_enh, enhanced pause; RIgG, rat IgG.

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