THE MOLECULAR BIOLOGY OF CCR-4 MEDIATED ALLERGIC REACTION IN NASAL MUCOSA AND ITS REGULATION

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Eotaxin (CCL11) is a potent eosinophil chemoattractant belonging to the C-C chemokine. To evaluate the role of eotaxin in eosinophilic inflammation in nasal mucosa, we investigated the levels of eosinophil chemoattractants in nasal lavage fluids obtained after antigen challenge, and compared with eosinophil counts and eosinophil protein X (EPX) levels. In subjects with allergic rhinitis, allergen challenge led to parallel increases in eosinophil counts, levels of EPX and eotaxin concentrations in nasal lavage fluid. The levels of eotaxin in lavage samples showed strong correlation with lavage levels of eosinophil counts and EPX. Normal subjects had few, if any, eosinophils and EPX as well as the measured parameters in their nasal lavage fluids before and after antigen challenge. In our experiments of eosinophil endothelial transmigration (TEM) assay using the nasal microvascular endothelial cells, eotaxin showed most potent effect among various eosinophil chemoattractants. In addition, … More treatment of eosinophils with anti CCR3 mAb significantly blocked eosinophil TEM induced by homogenate of nasal mucosa. These results indicate that eotaxin has an important role in eosinophil-dependent inflammation in nasal mucosa and suggest that blocking eotaxin or CCR-3 might be useful for new therapeutic tools of allergic rhinitis.It has been shown that interactions between CCR4 and MDC/CCL22 and TARC/CCL17, as well as between CCR8 and I-309/CCL1, are critical for the recruitment of Th2 cells in the airway mucosa of allergic diseases in response to allergen stimulation. To gain a better understanding of the role of TARC in the pathogenesis of allergic rhinitis, we have investigated the cellular sources of this chemokine in nasal mucosa. In addition, the effect of cytokines on the TARC production has been investigated. Epithelial cells in nasal mucosa in subjects with allergic rhinitis expressed higher signal level than those in non-allergy patients. The combined stimulation with IL-4 and TNF-α, as well as IL-13 and TNF-α, synergistically induced TARC expression in epithelial cells. Furthermore, the amount of TARC induced by these cytokines was higher in epithelial cells obtained from nasal allergy patients than in those from non-allergy patients. These results demonstrate a crucial role of nasal epithelial cells in the expression of TARC, and that Th2 cytokine IL-4 and IL-13 may promote Th2 responses by inducing TARC production from epithelial cells.Next we examined the difference of CCR4 expression on peripheral blood T cell among healthy subjects and allergic rhinitis subjects. The percent expression of CCR4 on peripheral blood CD4+CD45RO+ T cells in healthy subjects and allergic rhinitis subjects. There is no significant difference between the mild and moderate groups and healthy subjects. However, the CCR4 expression in the severe group was significantly higher than that seen in the healthy subjects. Treatment of mononuclear cells with anti CCR-4 monoclonal antibody and soating using flowcytometer divided them to CCR-4 positive and negative cells. CCR4+ T cells predominantly produce IL-4 but not IFN-γ when they were stimulated with PMA and IOM, whereas CCR4-T cells preferentially produce IFN-γ but not IL-4. These results suggest that CCR4 was expressed preferentially on Th2 cells and that cytokine profile is markedly inclined to Th2 predominance, in severe allergic rhinitis. Less