The role of dermatophagoides pteronissinus allergen and TH2 cytokines in the airway inflammation of allergic asthma

Abstract

The study presented in chapter 3 has applied an integrated bronchial explant tissue culture system to investigate the hypothesis that CD-28 mediated T cell costimulation is required for cytokine production in moderately severe asthma. Allergen stimulation of bronchial explant cultures from mild asthmatics induces the production of IL-5 and IL-13 that is reduced by the fusion protein. CTLA-41g, which inhibits CD28-mediated costimulation. In chapter 3, I have shown that Dermatophagoides pteronissinus (Der p) allergen stimulates the production of IL-5, but not IL-13 by bronchial explants of moderately severe asthmatics. However, in contrast to similar explant studies in mild asthma, allergen-induced IL-5 production was not inhibited by CTLA-4Ig. Allergen stimulation of peripheral blood mononuclear cell cultures from these subjects resulted in increased production of IL-5 and IL-13, which was inhibited by CTLA-4Ig. This suggests that IL-5 production in the airways of moderately severe asthmatics is less dependent on CD-28 mediated co-stimulation. The difference in requirements of CD28-mediated costimulation in PBMC cultures compared to explant cultures suggests that the tissue micro-environment influences the pulmonary inflammatory response in severe asthma.

The study presented in chapter 6 has shown that exposure of bronchial epithelial cell cultures from normal subjects or allergic asthmatics to IL-4 or IL-13 for 24 hours leads to increased production of GM-CSF, IL-8 and RANTES, which can be reduced but not completely suppressed by the corticosteroid dexamethasone. A co-operative effect was noted for combined stimulation with IL-4 or IL-13 and Der p allergen for the production of GM-CSF, IL-8 and RANTES. IL-4 and IL-13 also stimulated the release of transforming growth factor-β, which promotes fibroblast proliferation and collagen deposition. Exposure of bronchial epithelial cells to either Der p allergen, IL-4, IL-13 or TNF-α led to increased release of the structurally unrelated transforming growth factor-α, which is a potent ligand for the epidermal growth factor receptor, and has been linked with goblet cell metaplasia and airway remodelling. Although there was no significant difference in the basal or stimulated production of GM-CSF and IL-8 by bronchial epithelial cells of normal or asthmatic subjects, the increased production of RANTES, TGF-β, and TGF-α was confined to bronchial epithelial cells of asthmatic subjects. The ability of Der p allergen and Th2 cytokines to remote the release of cytokines, chemokines and growth factors by bronchial epithelial cells of asthmatic subjects provides a link between environmental allergen, Th2 mediated inflammation, and airway remodelling in asthma.

The development of a reliable method for the culture of primary bronchial epithelial cells of atopic asthmatics paves the way for dissecting the involvement of the bronchial epithelium in airway inflammation, remodelling and mucus production atopic asthma.

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