© 2003 American Thoracic Society DOI: 10.1165/rcmb.2002-0220OC Evaluation of Inducible Costimulator/B7-Related Protein-1 as a Therapeutic Target in a Murine Model of Allergic Airway InflammationDivision of Respiratory Diseases and Allergy, Centre for Gene Therapeutics, and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and Department of Experimental Medicine, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts Address correspondence to: Dr. Manel Jordana, Department of Pathology and Molecular Medicine, Room 4H17, Health Sciences Centre, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5 Canada. E-mail: jordanam{at}mcmaster.ca 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.
Abbreviations: adenovirus, Ad • B7-related protein-1, B7RP-1 • bronchoalveolar lavage, BAL • enzyme-linked immunosorbent assay, ELISA • granulocyte-macrophage colony-stimulating factor, GM-CSF • Hanks' balanced salt solution, HBSS • inducible costimulator, ICOS • immunoglobulin E, IgE • interleukin, IL • monoclonal antibody, mAb • ovalbumin, OVA • phosphate-buffered saline, PBS This article has been cited by other articles:
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