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Title: Long-term exposure to interleukin-8, lung remodelling and altered T cell immunity in the context of chronic infection with Pseudomonas aeruginosa in chronic lung disease
Author: Quigley, Kathryn
ISNI:       0000 0004 7656 7409
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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In the lung, the fine balance between an appropriate immune response that defends against incoming pathogens while avoiding excessive inflammation leading to collateral tissue damage is dependent on appropriate and effective immune regulation. Lung disease can result in situations where the balance is tipped and excessive or inappropriate inflammation results in acute or chronic lung damage and impaired lung function. This is the case in non-CF bronchiectasis where enhanced inflammation and chronic lung infection are associated with irreversible tissue damage. Bronchiectasis is a pathological endpoint with several causes. It is often associated with chronic Pseudomonas aeruginosa infection and elevated levels of interleukin (IL)-8, a neutrophil chemoattractant, in bronchoalveolar lavage (BAL) and sputum. This thesis investigates the following hypotheses: 1) long-term exposure to high levels of IL-8 causes lung-remodeling and alters susceptibility to Pseudomonas aeruginosa infection; 2) individuals with bronchiectasis that are chronically infected with Pseudomonas aeruginosa have altered T cell immunity to the pathogen. To investigate the impact of long-term exposure to IL-8 on lung-remodelling and susceptibility to Pseudomonas, a transgenic model made by the Boyton lab was used. IL-8 transgenic mice show enhanced mucus secretion, lung fibrosis and remodelling with leaky tight junctions, but effectively clear Pseudomonas aeruginosa compared to controls. Differences in T cell immunity were tested in a cohort of patients with non-CF bronchiectasis, with or without Pseudomonas aeruginosa, to the outer membrane porin F (OprF) protein. A narrowed repertoire of T cell epitopes and different adaptive immune responses were observed in patients chronically infected with Pseudomonas aeruginosa. HLA-restricted OprF T cell epitopes were identified in HLA class II transgenics. The Boyton lab has previously identified a genetic susceptibility to idiopathic bronchiectasis associated with the presence of the HLA-Cw*03. In this thesis, the association between HLA-Cw*03 and functional immunity was investigated.
Supervisor: Boyton, Rosemary Sponsor: Medical Research Council ; Asthma UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral