The role of CCR4 and CRTH2 in asthma

Abstract

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+/CD4+ 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 IL-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 IL-5 measured in stimulated explants from healthy controls (p=<0.001). Allergen stimulation of explants from asthmatics but not control subjects also resulted in increased IL-4 release (p=0.015). Comparison of challenged explants from asthmatics and healthy control subjects also showed an increase in IL-13 production in asthmatic patients (p=0.014). CCL17 production increased significantly in the asthmatic explants only with significant differences between healthy subjects and asthmatics for both unchallenged and challenged samples (p=0.008 and 0.001 respectively). Further significant differences (i.e. increased production in asthmatic explants were seen for CCL22 (p=0.004), CCL2 (p=0.013), CCL19 (p=0.04), CCL20 (p=0.013) and CCL11 (p=0.002). Stimulation of PBMC from asthmatic donors with allergen resulted in increased IL-5 which was significantly reduced by selective depletion of CCR4+ cells (p=0.021), strongly suggesting that CCR4+ cells were the source of Th2 cytokines. In a final series of experiments where explant supernatants were used as the chemotactic stimulus, chemotactic activity that was dependent on CCR4 was not shown. The supernatants from healthy and asthmatic subjects failed to induce chemotactic activity of either the CCRF-CEM cells line with constitutive CCR4 expression or Th2 T cells polarised ex vivo.

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