title: Evaluation of inducible costimulator/B7-related protein-1 as a therapeutic target in a murine model of allergic airway inflammation.
abstract: Given its primary role in the execution of T cell, and especially Th2, effector activity, the inducible costimulator (ICOS)/B7-related protein (RP)-1 costimulatory pathway is currently being heralded as a promising therapeutic target for immune-inflammatory disorders such as asthma. This study investigates the merits of ICOS blockade in a murine model of experimental asthma in which mice are sensitized to ovalbumin (OVA) through the respiratory mucosa. Intraperitoneal treatment of mice with anti-ICOS neutralizing antibody during sensitization resulted in a marked reduction in airway eosinophilia and IL-5 in bronchoalveolar lavage, but had no effect on interleukin (IL)-4, IL-13, and eotaxin content in bronchoalveolar lavage or the production of OVA-specific immunoglobulin E in serum. Cultured splenocytes from mice sensitized to OVA in the context of ICOS ablation produced enhanced levels of IL-4 and IL-5 upon stimulation with OVA, and this correlated with elevated inflammation and immunoglobulin E secretion upon long-term in vivo OVA recall; the deleterious effects ICOS blockade, however, were not associated with reduced IL-10 production by splenocytes. Peculiarly, anti-ICOS intervention during OVA rechallenge had no effect on airway inflammation or immunoglobulin production, despite high levels of ICOS expression on infiltrating CD4+ T cells. This study provides in vivo evidence of an exacerbated long-term immune-inflammatory response following acute ICOS blockade, and suggests that ICOS costimulation is functionally redundant in established allergic disease.
authors.affiliation: Division of Respiratory Diseases and Allergy, Centre for Gene Therapeutics, and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Wiley
authors.forename: Susanna
authors.initials: S
authors.lastname: Goncharova
authors.forename: Theresa
authors.initials: T
authors.lastname: Shea
authors.forename: Jill R
authors.initials: JR
authors.lastname: Johnson
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: Manel
authors.initials: M
authors.lastname: Jordana
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000187:drug effects* / Q000276:immunology; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D018122:B7-1 Antigen / Q000187:drug effects* / Q000378:metabolism; D018893:Bronchoalveolar Lavage; D002478:Cells, Cultured; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000378:metabolism; D003888:Desensitization, Immunologic; D004195:Disease Models, Animal; D005260:Female; D007073:Immunoglobulin E / Q000097:blood; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D016753:Interleukin-10 / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D000906:Antibodies; D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; C556694:Icos protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D018793:Interleukin-13; D015848:Interleukin-5; D016753:Interleukin-10; D015847:Interleukin-4; D007073:Immunoglobulin E; D010047:Ovalbumin