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Anti-Siglec-F Antibody Reduces Allergen-Induced Eosinophilic Inflammation and Airway Remodeling¹

Dae Jin Song,^* Jae Youn Cho,^* Sang Yeub Lee,^* Marina Miller,^* Peter Rosenthal,^* Pejman Soroosh, Michael Croft, Mai Zhang,^* Ajit Varki,^* and David H. Broide^2*

^*Department of Medicine, University of California San Diego, San Diego, CA 92093; Department of Pediatrics and Department of Medicine, College of Medicine, Korea University, Seoul, Korea; and Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92093

Siglec-F is a sialic acid-binding Ig superfamily receptor that is highly expressed on eosinophils. We have investigated whether administration of an anti-Siglec-F Ab to OVA-challenged wild-type mice would reduce levels of eosinophilic inflammation and levels of airway remodeling. Mice sensitized to OVA and challenged repetitively with OVA for 1 mo who were administered an anti-Siglec-F Ab had significantly reduced levels of peribronchial eosinophilic inflammation and significantly reduced levels of subepithelial fibrosis as assessed by either trichrome staining or lung collagen levels. The anti-Siglec-F Ab reduced the number of bone marrow, blood, and tissue eosinophils, suggesting that the anti-Siglec-F Ab was reducing the production of eosinophils. Administration of a F(ab')₂ fragment of an anti-Siglec-F Ab also significantly reduced levels of eosinophilic inflammation in the lung and blood. FACS analysis demonstrated increased numbers of apoptotic cells (annexin V⁺/CCR3⁺ bronchoalveolar lavage and bone marrow cells) in anti-Siglec-F Ab-treated mice challenged with OVA. The anti-Siglec-F Ab significantly reduced the number of peribronchial major basic protein⁺/TGF-β⁺ cells, suggesting that reduced levels of eosinophil-derived TGF-β in anti-Siglec-F Ab-treated mice contributed to reduced levels of peribronchial fibrosis. Administration of the anti-Siglec-F Ab modestly reduced levels of periodic acid-Schiff-positive mucus cells and the thickness of the smooth muscle layer. Overall, these studies suggest that administration of an anti-Siglec-F Ab can significantly reduce levels of allergen-induced eosinophilic airway inflammation and features of airway remodeling, in particular subepithelial fibrosis, by reducing the production of eosinophils and increasing the number of apoptotic eosinophils in lung and bone marrow.

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 study was supported by National Institutes of Health Grants AI038425 (to D.H.B.), AI072115 (to D.H.B. and A.V.), AI070535 (to D.H.B. and M.C.), and P01-HL057345 (A.V.).

² Address correspondence and reprint requests to Dr. David Broide, University of California San Diego, Biomedical Sciences Building, Room 5090, 9500 Gilman Drive, La Jolla, CA 92093. E-mail address: dbroide{at}ucsd.edu

³ Abbreviations used in this paper: MBP, major basic protein; BAL, bronchoalveolar lavage; IEX, ion exchange chromatography; PAS, periodic acid-Schiff.