Anti-Siglec-F antibody reduces allergen-induced eosinophilic inflammation and airway remodeling.
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-beta(+) cells, suggesting that reduced levels of eosinophil-derived TGF-beta 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.
Department of Medicine, University of California San Diego, San Diego, CA 92093, USA.
Dae Jin
DJ
Song
Jae Youn
JY
Cho
Sang Yeub
SY
Lee
Marina
M
Miller
Peter
P
Rosenthal
Pejman
P
Soroosh
Michael
M
Croft
Mai
M
Zhang
Ajit
A
Varki
David H
DH
Broide
D000485:Allergens / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D004802:Eosinophilia / Q000473:pathology / Q000628:therapy*; D004804:Eosinophils / Q000276:immunology; D005355:Fibrosis; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage; D007249:Inflammation / Q000473:pathology / Q000628:therapy*; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
D000485:Allergens; D000911:Antibodies, Monoclonal; D015214:Antigens, Differentiation, Myelomonocytic; D007140:Immunoglobulin Fab Fragments; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C443130:Siglecf protein, mouse; D016212:Transforming Growth Factor beta; D010047:Ovalbumin