This study was designed to determine seasonal changes in cytokines, soluble CD23 and specific IgE in the serum of patients with seasonal allergic rhinitis, and the effect of immunotherapy on these seasonal changes. Fifty-four patients with seasonal allergic rhinitis caused by Japanese cedar pollens were divided into a medication group and an immunotherapy group. The patients of the medication group were treated with nonsedating antihistamines alone during the pollen season. The patients of the immunotherapy group had been treated for variable periods (mean, 5.0 Ϯ 3.2 years) with immunotherapy using Japanese cedar pollen antigens. Serum samples were collected before and during the pollen season from each patient, to determine specific IgE, interleukin-4 (IL-4), interferon-g (IFN-g) and soluble CD23 levels in serum. A significant increase in specific IgE and IL-4 and a significant decrease in IFN-g were observed during the pollen season in the medication group. In contrast, in the immunotherapy group, none of specific IgE, IL-4 and IFN-g was significantly changed following natural exposure to pollens. However, these effects were not significant in patients undergoing immunotherapy for 3 or fewer years. Seasonal rates of increase in specific IgE and IL-4 differed significantly between good responders and poor responders to immunotherapy, but seasonal rates of decrease in IFN-g did not. A seasonal rate of increase in soluble CD23 was significantly correlated with a seasonal rate of increase in specific IgE, in both the medication and the immunotherapy groups. The seasonal rate of increase in soluble CD23 was significantly smaller in the good responders than in the poor responders to immunotherapy. In conclusion, pollen immunotherapy reduces the seasonal increase in specific IgE, IL-4 and soluble CD23 in serum, and in addition switches the seasonal preferential activation of Th-2 cells to reciprocal activation of Th-1 cells with treatment over several years. It is likely that the mechanisms responsible for the clinically beneficial effects of immunotherapy principally involve the modulation of Th-2 rather than Th-1 cytokines.

Interleukin-4 (IL-4) may play a central role in the IgE synthesis system, the development of Th-2-like cells, and co-ordination as well as the persistence of airway inflammatory process in allergic disorders. Therefore, IL-4 plays a key role in airway allergic disorders. This study aimed at investigating the serum concentrations of IL-4 in patients with perennial allergic rhinitis, with special reference to the possible changes and the clinical relevance following long-term immunotherapy. The study has demonstrated that the serum level of IL-4 in allergic rhinitis patients before immunotherapy is significantly higher than that in non-atopic individuals. However, the serum IL-4 level in allergic rhinitis patients did not decrease following anti-allergic medications but significantly decreased following immunotherapy. The percentage decrease in IL-4 was correlated significantly with the percentage decrease in specific IgE antibodies following long-term immunotherapy. Immunotherapy also significantly decreased specific IgE anti-bodies, but this reduction in specific IgE antibodies was not significantly correlated with the clinical improvement. In contrast, the percentage decrease in serum IL-4 was significantly correlated with the percentage decrease in symptomatic scores. The authors interpret these data to mean that immunotherapy alters T-cell cytokine profiles in the long-term, and a decline of IL-4 following immunotherapy could modulate not only production of specific IgE antibodies but also inflammatory cellular events, leading to symptomatic relief in allergic rhinitis.

Some individuals with detectable levels of Japanese cedar (Criptomeria japonica) pollen-specific immunoglobulin (Ig)E in serum have no apparent nasal symptoms during the pollen season. The response of CD4+ T-helper (Th) cells to the pollen allergen might differ fundamentally between asymptomatic and symptomatic individuals who are already sensitized to the pollen. The aim of this study was to discern the possible differences in responses of peripheral blood mononuclear cells (PBMCs) to the pollen allergen between asymptomatic and symptomatic subjects who have been sensitized to the pollen. This study included 20 non-atopic healthy volunteers (non-atopic group) and 48 patients who had detectable levels of the pollen-specific IgE before the pollen season in 1997. In the review of nasal symptoms during the pollen season 1997, 24 patients had typical symptoms of seasonal allergic rhinitis (symptomatic group), and the remainder had no seasonal aggravation of nasal symptoms (asymptomatic group). Peripheral blood mononuclear cells (1.0 x 10(7) cells/well) were obtained from each individual during the pollen season and cultured in the absence or presence of 12.5 microg of Cry j 1 for 4 days. The concentrations of IgE, interleukin-5 (IL-5), and interferon-gamma (IFN-gamma) in the culture supernatants were measured. The levels of IgE produced by Cry j 1-stimulated PBMCs of the asymptomatic and symptomatic groups were significantly higher than those of the non-atopic group, but did not differ between the asymptomatic and symptomatic groups. The levels of IL-5 produced by Cry j 1-stimulated PBMCs did not differ significantly between the non-atopic group and the asymptomatic group, but the levels of IL-5 were significantly higher in the symptomatic group than in the asymptomatic group as well as the non-atopic group. The levels of IFN-gamma produced by Cry j 1-stimulated PBMCs did not differ significantly among the three groups. In conclusion, our study has suggested that Japanese cedar pollen-induced synthesis of IL-5, but not of IgE or IFN-gamma, is likely to be a key mechanism linked to the symptomatic episode of seasonal allergic rhinitis in individuals sensitized to the pollen.

Increased attention has recently been directed at the possibility that the clinical efficacy of immunotherapy might be elaborated by alteration of T-cell reactivity. However, there is no general agreement among different investigators regarding the effect of immunotherapy on Th-cell reactivity. Peripheral blood mononuclear cells (PBMCs) from 15 nonatopic subjects and 76 patients with perennial allergic rhinitis (18 untreated patients and 58 patients on immunotherapy) were cultured in the absence and in the presence of a major Dermatophagoides farinae allergen, Der f 1, and the levels of IgE, interleukin-5 (IL-5), interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the culture supernatants were determined. The difference between the absence and presence of Der f 1 was calculated to consider the Der f 1-dependent synthesis of IgE, IL-5, IFN-gamma and TNF-alpha. The levels of Der f 1-dependent synthesis of IgE, IL-5 and TNF-alpha were significantly higher in the untreated group than in the nonatopic group, whereas Der f 1-dependent synthesis of IFN-gamma was significantly lower in the untreated group than in the nonatopic group. Immunotherapy decreased the enhanced Der f 1-dependent synthesis of IgE, IL-5 and TNF-alpha, and further decreased the suppressed Der f 1-dependent synthesis of IFN-gamma as the therapy proceeded. The levels of Der f 1-dependent synthesis of IgE and IL-5 did not differ between nonatopic individuals and patients whose duration of immunotherapy was 10 or more years. The levels of Der f 1-dependent synthesis of IgE and IL-5, but not of IFN-gamma and TNF-alpha, were correlated significantly with the levels of symptom scores. In addition, the levels of Der f 1-dependent synthesis of IgE and IL-5, but not of IFN-gamma and TNF-alpha, differed significantly between good and poor responders. In conclusion, immunotherapy for perennial allergic rhinitis may possibly work via induction of tolerance or anergy of both Th1- and Th2 cells. However, our study is likely to support a view that the mechanisms responsible for the clinically beneficial effects of immunotherapy principally involve the tolerance of Th2- rather than Th1 cells. In addition, suppression of IgE synthesis is also likely to be linked to the clinical efficacy of immunotherapy for perennial allergic rhinitis.

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