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Title: The IL-17 family in paediatric severe therapy resistant asthma
Author: Adams, Alexandra
ISNI:       0000 0004 6496 6939
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Paediatric asthma has traditionally been considered a T Helper 2 (TH2) cell mediated disease with the TH2 cytokines interleukin (IL)-4, IL-5 and IL-13 promoting eosinophilic airway inflammation, hyper-responsiveness and remodelling. In the majority of patients airway inflammation can be well controlled with low dose inhaled corticosteroids. There is however a small group in whom control is not achieved despite high dose corticosteroids, these children have severe therapy resistant asthma (STRA). Previous work in paediatric STRA showed a relative absence of the TH2 cytokines in the airways, but preliminary data identified raised levels of IL-17. Elevated IL-17 has been associated with severe asthma in adults, but its role in children was unknown. The overarching hypothesis of this work is paediatric STRA is mediated by the IL-17 family of cytokines and this is the mechanism resulting in steroid resistant and persistent airway inflammation. Children undergoing clinically indicated bronchoscopy were recruited to the study. Broncho-alveolar lavage, endobronchial biopsies, bronchial epithelial brushings and peripheral blood were collected from STRA children and results were compared to a disease control group, undergoing bronchoscopy for recurrent respiratory infections, as a positive control group previously shown to have TH-17 activation. Flow cytometry protocols were developed to identify IL-17A producing cells (TH17, gamma delta T cells and innate lymphoid cells) in BAL. ELISA and bead based multiplex were used to measure cytokines in the BAL, endobronchial biopsies were stained for IL-17 and primary human bronchial epithelial cells were cultured and stimulated in the presence of budesonide to investigate the mechanisms of steroid resistance in vitro. As found in previous work, TH2 mediators (IL-4, IL-5 and IL-13) were not raised in STRA children. Contrary to one of the hypotheses of this thesis, neither IL-17 producing T cells nor IL-17A were elevated in the airways of STRA children. 16 HBE cells (human bronchial epithelial cell line) were cultured and stimulated with IL-17A and/or budesonide and secretion of IL-6 and IL-8 was measured to develop the steroid resistance protocol. Subsequently, primary bronchial epithelial cells from STRA children and controls were cultured and shown to demonstrate steroid resistant properties and behave significantly differently to 16HBE cells. I have confirmed that the TH2 related cytokines were not raised in children with STRA. Although IL-17A was associated with increased steroid resistance, levels were not increased in STRA compared to disease controls. These data suggest IL-17A is not responsible for the persistent airway inflammation in this group treated with high doses of corticosteroids. The role of IL-17A in mediating paediatric STRA is therefore less certain than in adult severe disease.
Supervisor: Lloyd, Clare ; Saglani, Sejal ; Bush, Andrew Sponsor: Asthma UK
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral