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Title: The role of Tumor Necrosis Factor alpha (TNF-α) in asthma
Author: Babu, Kesavan Suresh
ISNI:       0000 0001 3434 7692
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2006
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Asthma is an airway inflammatory disorder characterised by variable airflow obstruction and airway hyperresponsiveness on a background of diffuse airway inflammation. The pathophysiological features are complex involving various inflammatory cells and cytokines orchestrating the inflammatory process. TNF -a is a pro-inflammatory cytokine implicated in the modulation of inflammation in various diseases including asthma. While TNF-a blocking strategies have been an effective therapeutic modality in diseases like rheumatoid arthritis its role in asthma and the effects of its blockade in asthma is poorly understood. This thesis looks at the role of TNF-a in asthma and the effects of blocking TNF-a as a possible therapeutic option in patients with severe corticosteroid dependent asthma. Allergen challenge induces the pro inflammatory cytokines and has been used to study the pathogenic mechanisms in asthma. The study presented in Chapter 3 used a repeated low dose allergen challenge model which is more likely to simulate natural allergen exposure to investigate the effects of allergen on bronchial biopsies from mild allergic asthmatics. Low dose allergen exposure results in up regulation of TNFa in the bronchial biopsies. This increase was associated with a parallel increase in mast cell numbers suggesting the possible source of TNF -a as the mast cells. This was associated with an associated increase in adhesion molecules ICAM-l and VCAM-l. In the ex vivo study on bronchial biopsies of moderately severe asthmatics the results were similar to the low dose allergen exposure where TNF -a levels were increased following exposure to Der p and this was suppressed in the presence of CDP 870- a TNF-a blocking monoclonal antibody. CDP 870 was also able to suppress the levels of IL-8 and adhesion molecules. Having seen a positive response with CDP 870 we had the opportunity of observing the effects of blocking TNF-a with a soluble fusion protein-p75 receptor (etanercept) on patients with chronic severe corticosteroid refractory asthma. Administration of 25 mg of etanercept twice a week for 12 weeks produced improvements in lung function seen as improvements in FEVl , FVC and both morning and evening PEF. There was a marked improvement in asthma control and a 2.5 fold doubling dose increase in methacholine airway hyperresponsiveness. Treatment with etanercept markedly reduced the need for rescue medications as all the subjects completely withdrew from their nebulised salbutamol by the end of the study. The medication was well tolerated with minimal side effects. This thesis provided evidence for an important role for TNF -a in asthma pathophysiology especially those with severe disease and a possible therapeutic option in such patients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available