A novel engineered cytokine immunotherapy reduces clinical features of disease in a mouse model of steroid-resistant asthma 2253062

Abstract

Abstract Introduction Asthma is a disease of chronic airway inflammation associated with heterogenous immune phenotypes. While current immunotherapies have shown efficacy in treating allergic asthma, steroid resistant asthma critically lacks a druggable target, making it a major contributor of asthma morbidity and mortality. Here, we developed a cytokine immunotherapy to ameliorate clinical and pathological features of asthma in the steroid-resistant A/J mouse strain. Methods A/J mice subjected to house dust mite extract-induced allergy to induce asthma pathology. Mice were then subjected to methacholine induced airway hyperresponsiveness challenges to evaluate asthma physiology. The immunological makeup of the lungs and bronchoalveolar space were also evaluated with flow cytometry. Results Mice treated with the engineered cytokine exhibited reduced airway hyperresponsiveness to methacholine challenges, in contrast to those treated with dexamethasone. Notably, dexamethasone-treated mice presented with worse airway hyperresponsiveness than untreated controls. Histology demonstrated a reduction of airway inflammation and pathologic markers of disease whereas cytometry analysis revealed suppressed airway eosinophilia and neutrophilia. Cytokine immunotherapy reduced features associated with CD4+ T cell activation while increasing molecular markers of regulatory T cell activity. Conclusion Taken together, this cytokine immunotherapy has demonstrated promising results at ameliorating disease features in a pre-clinical model of steroid-resistant asthma which could lead towards a scalable and translatable treatment for patients with asthma. Funding Source NIH T32 (Medical Scientist Training Program), AHA Predoctoral Fellowship Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)