Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma

Background: IL-25 (IL-17E), a member of the IL-17 family of immunoregulatory cytokines, has been implicated in the regulation of type 2 immunity. Its roles in antigen-driven airway inflammation and airway hyperresponsiveness (AHR) remain to be fully established. Objective: We sought to determine whether a neutralizing antibody against IL-25 represents a novel therapeutic for airway inflammation and hyperresponsiveness. Methods: We generated a neutralizing mAb against IL-25 and used this to inhibit IL-25 in a mouse model of allergic airway disease. Results: Blocking IL-25 in an experimental model of allergic asthma prevented AHR, a critical feature of clinical asthma. Administration of anti-IL-25 mAb during the sensitization phase resulted in significantly reduced levels of IL-5 and IL-13 production, eosinophil infiltration, goblet cell hyperplasia, and serum IgE secretion, and prevented AHR. Even more striking was the ability of anti-IL-25 mAb, administered only during the challenge phase of the response, specifically to prevent A even during an ongoing type 2 inflammatory response in the lungs. Conclusion: IL-25 is critical for development of AHR. Clinical implications: We define a novel pathway for the induction of AHR and suggest that IL-25 represents an important therapeutic target for the treatment of asthma. Significantly, our antibody also blocks the binding of human IL-25 to its receptor.