Antagonism of cytokine-induced eosinophil accumulation in asthma

Asthma is a chronic inflammatory condition of the airways characterized by reversible airway obstruction, airway hyperresponsiveness (AHR) to normally harmless stimuli and airway inflammation. Eosinophilic asthma is a phenotype of the condition characterized by increased blood or sputum eosinophils whose numbers correlate with disease severity. Release of their potent pro-inflammatory arsenal by infiltrating tissue eosinophils, including granule-derived basic proteins, mediators, cytokines and chemokines, contributes to airway inflammation, and lung tissue remodeling that includes airway thickening and fibrosis. More recent evidence suggests that in addition to their role as degranulating effector cells, eosinophils have the capacity to act as antigen presenting cells resulting in T cell proliferation and activation (Blanchard and Rothenberg, 2009). Eosinophil extravasation from the post-capillary venules, migration within the interstitium, cellular activation and tissue retention are controlled by cell adhesion molecules, i.e., selections, integrins and members of the immunoglobulin superfamily (Barthel et al., 2008; Barnes, 2011). The expression and function of these adhesion molecules and the subsequent chemotactic attraction and activation of infiltrating pro-inflammatory cells are controlled by a myriad of cytokines, chemokines and mediators with the Th2 cytokines IL-4, IL-5, and IL-13 representing essential and central coordinators of asthmatic inflammation (Barrett and Austen, 2009; Walsh, 2010). Thus, modulating the cytokine network in asthma with biological therapy targeted to patients with particular eosinophilic phenotypes represents a plausible paradigm for treatment of this important condition (Petsky et al., 2007; Barnes, 2008; Desai and Brightling, 2009; Walsh, 2011).