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A Helminth Immunomodulator Reduces Allergic and Inflammatory Responses by Induction of IL-10-Producing Macrophages¹

Corinna Schnoeller^*, Sebastian Rausch^*, Smitha Pillai^*, Angela Avagyan, Bianca M. Wittig, Christoph Loddenkemper, Alf Hamann^¶, Eckard Hamelmann, Richard Lucius^* and Susanne Hartmann^2,*

^* Department of Molecular Parasitology, Humboldt University; and Pediatric Pneumology and Immunology, Gastroenterology/Infectiology/Rheumatology, Pathology/Research Center for ImmunoScience, and ^¶ Experimental Rheumatology, Charité, Berlin, Germany

The coincidence between infections with parasitic worms and the reduced prevalence of allergic disease in humans and in animal models has prompted the search for helminth molecules with antiallergic and antiinflammatory potential. We report herein that filarial cystatin, a secreted protease inhibitor of filarial nematodes, suppresses Th2-related inflammation and the ensuing asthmatic disease in a murine model of OVA-induced allergic airway responsiveness. Treatment with recombinant filarial cystatin inhibited eosinophil recruitment, reduced levels of OVA-specific and total IgE, down-regulated IL-4 production, and suppressed allergic airway hyperreactivity when applied during or after sensitization and before challenge with the allergen. Depletion of macrophages by clodronate-containing liposomes prevented the curative effects and restored the levels of infiltrating cells, IgE, and allergic airway reactivity. Blocking of IL-10 by application of anti-IL-10 receptor Abs restored the reduced number of infiltrating cells and the levels of OVA-specific IgE. In contrast, depletion of regulatory T cells by anti-CD25 Abs had only limited effects. Cystatin also modulated macrophage-mediated inflammation in a murine model of dextran sulfate sodium-induced colitis, leading to reduction of inflammatory infiltrations and epithelial damage. Our data demonstrate that treatment with a single helminth protein can exert the antiallergic effects of helminth infections.

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 research was supported by German Research Council Grants SFB 650 and SFB 618 (to S.H., A.H., and R.L.).

² Address correspondence and reprint requests to Dr. Susanne Hartmann, Department of Molecular Parasitology, Humboldt University, Philippstrasse 13, 10115 Berlin, Germany. E-mail address: susanne.hartmann{at}rz.hu-berlin.de

³ Abbreviations used in this paper: Treg, regulatory T cell; AHR, airway hyperreactivity; Av17, 17-kDa cystatin of Acanthocheilonema viteae; BALF, bronchoalveolar lavage fluid; DHFR, dihydrofolate reductase; DSS, dextran sodium sulfate; EU, endotoxin unit; MCh, methacholine; MLV, multilamellar vesicle; PBLNC, peribronchial lymph node cells.