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Title: The role of CCR4 and CRTI-I2 in asthma
Author: Durkin, Kesta
ISNI:       0000 0001 3436 1590
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2007
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Chemokine receptors CCR4 and CRTH2, both expressed preferentially on Th2 cells, have been proposed to play an important role in the recruitment of T cells in asthma. The aim of this thesis was to see if fu.rther evidence of the role of CCR4 and its ligands CCLl7 and CCL22 in allergic asthma could be obtained in a combination of descriptive and functional studies. Differences in the expression ofCCR4 and CRTH2 on peripheral blood T cells from healthy non-atopic subjects and mild atopic asthmatic patients were looked for. Also the expression of a selection of activation/memory markers on CD4+ T cells were studied to determine whether there are any differences in the co-expression ofthese markers on CCR4+ T cells between the two subject groups. In order to try and confirm or deny findings in peripheral blood, immunohistochemistry was used to look for any differences in the expression of CCR4 in bronchial biopsy tissue sections of healthy control and asthmatic subjects. A bronchial explant model was used to look for differences in the production of a selection of. cytokines and chemokines (the main focus being on CCLl7 and CCL22) between healthy and house dust mite allergic asthmatics. Bronchial biopsies from healthy and asthmatic subjects were cultured for 24 hr with/without allergen and supernatants were assessed for cytokines and chemokines. The chemotactic responses of a CCR4+ T cell line and peripheral blood T cells, polarised in vitro torwards a Th2 phenotype were assessed; to recombinant chemokines and bronchial biopsy supernatants from asthmatic and healthy subjects stimulated ex vivo with allergen. A final aim, using peripheral blood mononuclear cells from allergic asthmatics was to elucidate whether CCR4+ cells contain allergen specific T cells by assessing lL-5 production following stimulation with allergen of whole PBMC and PBMC depleted of CCR4+ cells. There were no significant differences between healthy subjects and asthmatic patients in levels of expression of CCR4 and CRTH2 on CD4+ T cells and expression of . activation/memory markers on either CD4+ or CCR4+ICD4+ T cells. Sections of bronchial biopsies from healthy or asthmatic subjects were found not to contain any CCR4 positive cells. Analysis of bronchial explant supernatants showed significantly decreased lL-2 production in allergen-challenged when compared to unchallenged explants in healthy controls. Allergen induced a significant increase in IL-5 (p=<0.001) in asthmatic explants; this was significantly higher when compared to lL-5 measured in stimulated explants from healthy controls (p=
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available