Treatment of allergic airway inflammation and airway hyperresponsiveness using RORγt specific RNAi

Introduction: Recent studies suggest T helper 17 (TH17) cells as important players in the progression of asthma towards a severe phenotype. Characterized by the production of pro-inflammatory cytokines like TNF-α, IL-1ß, IL-22 and IL-17A, TH17 cells appear to act as general promoters of chronic inflammatory responses. These effector functions are initiated by the transcription factor Retinoic acid-related Orphan Receptor gamma (RORγ) t, which is exclusively expressed in TH17 cells and essential for their differentiation. Objective: To evaluate whether targeting the TH17-specific transcription factor RORγt is a suitable approach towards neutralizing TH17 cells in bronchial allergic asthma. Methods: At first, we generated OVA-specific TH17 cells in-vitro which were transfected with siRNA candidates targeting RORγt. Then, the most active siRNA was selected for testing the effects of RORγt downregulation in a mouse model of neutrophilic asthma. For this purpose, female C57BL/6 mice were sensitized to ovalbumin (OVA) by intra-tracheal instillation of OVA together with LPS and subsequently challenged with OVA aerosol. Mice received RORγt-specific siRNA intratracheally 24 hours prior OVA-challenge. Results: Intratracheal application of the RORγt-specific siRNA, which was most active in the in vitro setting, inhibited the development of airway hyperresponsiveness (AHR) to methacholine and prevented airway inflammation characterized by a significantly reduced number of neutrophils and also of lymphocytes. Conclusion: These results indicate that targeting RORγt could be a new approach for the treatment of neutrophilic asthma.