Cytokines and their soluble receptors in nasal fluids from school children with allergic rhinitis

Abstract: Allergic inflammation is associated with a shift in the balance between cytokines produced by two T helper subsets (Th1 and Th2) towards a preponderance of Th2 cells. Interleukin (IL)-4 is produced by Th2 cells and interferon-g (IFN-g) by Th1 cells. The ratio IL-4/IFN-g is often used as a marker of the balance between the cytokines. The effects of cytokines are modulated by soluble cytokine receptors (SCR). Aims: The general aim of the study was to find how Th1 and Th2 cytokines and their SCR regulate inflammatory cells and their products. For this nasal lavage fluid from school children with allergic rhinitis was examined as a local and in vivo model of allergic inflammation. A specific aim was to study the effects of topical treatment with glucocorticoids (GC) on Th1/Th2 cytokines, inflammatory cells and their products.Methods: Nasal fluids were obtained and handled in standardized ways: differential counts of inflammatory cells were measured by light microscopy, cytokine concentrations were assayed by ELISA; and eosinophil cationic protein (ECP) and IgE were determined by radioimmunoassay. Air pollen counts were determined daily by the Department of Botany in Göteborg.Material: Nasal lavage fluids from school children with allergic rhinitis and healthy controls were obtained before and during the pollen season, and from the allergic patients after treatment with a topical glucocorticoid. The study was performed during two consecutive pollen seasons, 1996 and 1997.Results: The nasal fluids were examined in a step-wise fashion, starting with Th1/Th2 cytokines. In the first study IL-4/IFN-g ratios were higher, and IFN-g levels lower in allergic patients during the pollen season compared to patients before season and compared to healthy controls. In the patients both IL-4/IFN-g ratios and IL-4 increased during the pollen season. In the second, larger, study these findings were repeated and in addition the Th2 cytokines IL-4, IL-5, and IL-10 - but not the Th1 cytokine IFN-g - were found to be higher in patients during than before the pollen season. Eosinophil counts and the levels of IgE and ECP in nasal fluid increased concurrently with development of clinical symptoms of rhinitis.In both studies IL-4 and IL-5 correlated with eosinophils, but not neutrophils, in the untreated patients with allergic rhinitis. Conversely, the neutrophil-associated chemokine IL-8 correlated with neutrophils, but not with eosinophils. In the second study the correlations between Th2 cytokines and IgE and ECP were analysed; IL-4, IL-5, IL-6 as well as IL-10 correlated with IgE and ECP.The soluble IL-4 receptor (IL-4sR), but neither IL-6sR, IL-1sR2, TNFsR1 nor TNFsR2 were found to increase in the patients during the pollen season. IL-4sR correlated with IgE and eosinophils. By contrast, none of the other soluble cytokine receptors correlated with IgE. Treatment with a topical glucocorticoid decreased the levels of IgE, ECP, and the Th2 cytokines IL-4, IL-5, IL-6, IL-10, but not IFN-g, nor the neutrophil associated cytokines IL-1b and TNF-a. In the treated patients IL-1b and TNF-a correlated with neutrophils and ECP, and IL-1b with eosinophils. Treated patients with high neutrophil counts had higher eosinophils and ECP, but not IgE, than patients with low counts.Conclusions: The results are compatible with the hypothesis that allergic rhinitis is causally related to a shift in the balance between Th1 and Th2 cytokines towards a Th2 predominance, possibly because of deficient IFN-g production. Correlation studies suggested that increase of the Th2 cytokines results in increased ECP, IgE and eosinophil counts. Theoretically the effects of the cytokines may be either inhibited or enhanced by SCR. Our findings of positive correlations between various SCR and either eosinophils, neutrophils, ECP or IgE might be explained by the existence of enhancing effects. Treatment with a topical steroid resulted in decrease of symptoms, eosinophils, ECP and IgE, but not of neutrophils. The treatment appeared to have a differential effect on cytokines, suppressing Th2 cytokines without any significant effect on the Th1 cytokine IFN-g. These effects of steroid treatment should be expected to be highly beneficial in view of the presumed, great importance of the Th1 and Th2 cytokine balance in the pathogenesis of allergic reactions.