An experimental model for steroid-refractory immune response in severe asthma (P6216)

Abstract

Abstract Asthma is a disease of the airways caused by a dysregulated immune response. Although for the most part, asthma can be controlled by inhaled corticosteroids (CS), severe asthma (SA) is difficult to control by either inhaled or systemic CS. It is becoming increasingly apparent that the most severe and poorly controlled form of SA displays mixed neutrophilic/eosinophilic airway inflammation, often displaying neutrophil dominance. The lack of animal models for SA has limited our understanding of mechanisms governing steroid refractoriness in SA as well as the development of alternatives to CS therapy. Our analysis of human asthma samples has shown that unlike patients with milder disease, SA patients consistently have a mixed Th1/Th17 immune profile in their airways with residual Th2 responses despite high dose CS therapy. With the association of viral and bacterial infections with asthma exacerbations, we hypothesized that the combination of an allergen with agents that mimic infection would induce a SA phenotype in mice. We would present a murine model of SA in which the induced immune response resembles that in severe asthmatics. As in humans, this immune response elicits mixed granulocytic airway inflammation and airway hyperresponsiveness that is poorly responsive to CS. This model would allow us to understand interactions between innate and adaptive immune responses that induce the SA phenotype. Additionally, the model would be amenable to testing novel therapies for SA.