Yushi Washio

Serum Level of Interleukin-4 in Patients with Perennial Allergic Rhinitis During Allergen-Specific Immunotherapy

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 antibodies, 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.

Immunotherapy Affects the Seasonal Increase in Specific IgE and Interleukin‐4 in Serum of Patients with Seasonal Allergic Rhinitis

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 non‐sedating antihistamines alone during the pollen season. The patients of the immunotherapy group had been treated for variable periods (mean, 5.0 ± 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‐γ (IFN‐γ) and soluble CD23 levels in serum. A significant increase in specific IgE and IL‐4 and a significant decrease in IFN‐γ were observed during the pollen season in the medication group. In contrast, in the immunotherapy group, none of specific IgE, IL‐4 and IFN‐γ 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‐γ 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.

Allergen-Induced Synthesis of Interleukin-5, but not of IgE, is a Key Mechanism Linked to Symptomatic Episodes of Seasonal Allergic Rhinitis in Sensitized Individuals

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 × 107 cells/well) were obtained from each individual during the pollen season and cultured in the absence or presence of 12.5 μg of Cry j 1 for 4 days. The concentrations of IgE, interleukin‐5 (IL‐5), and interferon‐gamma (IFN‐γ) 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‐γ 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‐γ, is likely to be a key mechanism linked to the symptomatic episode of seasonal allergic rhinitis in individuals sensitized to the pollen.

Nitrogen dioxide compromises defence functions of the airway epithelium

The effect of nitrogen dioxide (NO2) exposure on airway epithelial defence functions, such as ciliary activity, mucociliary transport velocity and junctional barrier function, remains to be elucidated. Our study investigates the effect of 24-h exposure to 3.0 ppm of NO2 on the airway epithelial defence functions in the healthy rabbit. Fifty-two healthy rabbits were exposed to 3.0 ppm of NO2 (NO2 group) or pure air (control group) for 24 successive hours in exposure chambers. After completion of the exposure sequence, the ciliary activity in the trachea was examined by a photoelectric method, the mucociliary transport velocity in the trachea by an endoscopic method and epithelial permeability of the trachea to fluorescein isothiocyanate-dextrans (FD-70s; molecular weight: 70,000 daltons) by an in vitro tracheal sac method. In the NO2 group, all epithelial defence functions, including ciliary activity, mucociliary transport velocity and epithelial permeability were significantly inferior to those in the control group. Although there was considerable overlap in the parameters examined between the two groups, approximately two-thirds of the animals were susceptible to 24-h exposure to 3 ppm of NO2. Dysfunction of both the junctional barrier and the mucociliary system could allow easier entry of allergen molecules to the airway parenchyma, where immunocomponent cells exist. NO2 might be involved to some extent in the clinical manifestation of airway allergic disorders through epithelial dysfunction.

Suplatast Tosilate affects the Initial Increase in Specific IgE and Interleukin-4 during Immunotherapy for Perennial Allergic Rhinitis

Suplatast tosilate can inhibit IL-4 production and suppress IgE synthesis in vitro. However, the theory that the agent causes changes in production of IL-4 and IgE in vivo has little experimental support. Immunotherapy could decrease the specific IgE response, but such a favourable effect is only possible with prolonged therapy after an initial increase in specific IgE. The use of suplatast tosilate together with immunotherapy may blunt the initial rise in specific IgE and decrease serum levels of specific IgE more quickly. Eighty-three adult patients with perennial allergic rhinitis due to Dermatophagoides farinae (D. farinae) were treated for 6 months with one of 3 treatments. Seventeen patients were treated with oral administration of 300 mg/day suplatast tosilate alone. Forty-six patients were treated with immunotherapy using standardized D. farinae alone. Twenty patients were treated with immunotherapy together with concurrent oral administration of 300 mg/day suplatast tosilate. Serum samples were collected 3 times from each patient, at enrollment, at 3 months and at 6 months after enrollment. Oral administration of suplatast tosilate for 3 and 6 months significantly decreased serum levels of IL-4 and specific IgE, and the rate of decrease in specific IgE correlated significantly with the rate of decrease in IL-4. The rates of decrease in IL-4 and specific IgE at 3 and 6 months were significantly greater in the patients treated with suplatast tosilate and immunotherapy than in those treated with immunotherapy alone. In conclusion, suplatast tosilate is able significantly to decrease serum levels of IL-4 and specific IgE, and the use of the drug together with immunotherapy can blunt the initial increase in specific IgE during the first 6 months of immunotherapy.

The Herbal Medicine Shoseiryu-to inhibits Allergen-induced Synthesis of Tumour Necrosis Factor Alpha by Peripheral Blood Mononuclear Cells in Patients with Perennial Allergic Rhinitis

The herbal medicine shoseiryu-to is an effective agent in the treatment of allergic rhinitis. However, the mechanism by which it exerts its action in improving patient symptoms remains unclear. It might affect the allergen-induced TH1 and/or TH2 responses. This study investigated whether the herbal medicine could affect cytokine synthesis by peripheral blood mononuclear cells (PBMCs) in response to the major Dermatophagoides farinae (D. farinae) allergen, Der f 1. PBMCs were obtained from 15 patients with perennial allergic rhinitis due to D. farinae, and were stimulated for 96 h with 10 micrograms/ml Der f 1 in the presence or absence of 45 mg/ml shoseiryu-to. The culture supernatants were harvested to determine the synthesis of IgE, interleukin 5 (IL-5), IL-6, IL-10, interferon-gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha). The agent did not affect the allergen-induced synthesis of IL-5, IL-6 and IFN-gamma, but somewhat decreased the synthesis of IgE and IL-10. This study highlighted an interesting pharmacological action of shoseiryu-to to substantially inhibit the allergen-induced synthesis of TNF-alpha. Our study suggests that the shoseiryu-to may alleviate nasal symptoms in allergic rhinitis through control of the allergen-induced inflammatory process.

Serum Levels of Specific IgE, Soluble Interleukin-2 Receptor, and Soluble Intercellular Adhesion Molecule-1 in Seasonal Allergic Rhinitis

BACKGROUND There is increasing evidence that soluble interleukin-2 receptor (sIL-2R) might reflect T cell activation in vivo and soluble intercellular adhesion molecule-1 (sICAM-1) might reflect the ongoing inflammatory response in the inflamed site. OBJECTIVE The aim of this study was to determine the effect of antihistamine tablets and allergen-specific immunotherapy on the seasonal changes in specific IgE, sIL-2R, and sICAM-1 in the serum of patients with seasonal allergic rhinitis. METHODS This prospective study included 99 patients with seasonal allergic rhinitis due to Japanese cedar pollens and 27 nonatopic healthy volunteers. The patients were divided into an antihistamine-treated group and an immunotherapy group. Serum samples were collected before and during the pollen season from each patient to determine specific IgE, sIL-2R, and sICAM-1. RESULTS Levels of sIL-2R before the pollen season did not differ significantly among the nonatopic group, the antihistamine-treated group, and the immunotherapy group. The levels of sICAM-1 before the pollen season were significantly higher in the antihistamine-treated group and in the immunotherapy group than in the nonatopic group. Seasonal increase in specific IgE was significant in the antihistamine-treated group regardless of their clinical outcomes. In contrast, significant increase in specific IgE was observed during the pollen season in poor responders but not in good responders to immunotherapy. Serum levels of sIL-2R and sICAM-1 were significantly increased during the pollen season in poor responders of the antihistamine-treated group and the immunotherapy group. On the other hand, neither seasonal increase in sIL-2R nor sICAM-1 was significant in good responders of the antihistamine-treated group and the immunotherapy group. CONCLUSIONS Serum levels of sICAM-1 are higher in patients with seasonal allergic rhinitis, even outside of the pollen season when the allergen does not naturally exist. Seasonal changes in serum sICAM-1 as well as sIL-2R and specific IgE are probably objective markers to indicate the clinical efficacy of antihistamines and immunotherapy on seasonal allergic rhinitis.

Seasonal rise in interleukin-4 during pollen season is related to seasonal rise in specific IgE for pollens but not for mites

Since IL-4 plays a key role in inducing and increasing the generation of not only primary polyclonal but also secondary specific IgE responses by B lymphocytes, a seasonal increase in IL-4 is likely to be involved in such seasonal rises in specific IgE in seasonal allergic rhinitis. The first aim of this study was to investigate the possible seasonal increase in serum IL-4 in patients with seasonal allergic rhinitis due to Japanese cedar pollens. If serum IL-4 increases in response to seasonal pollen exposure and is responsible for the seasonal increase in pollen-specific IgE in sera, this increase in IL-4 might theoretically affect specific IgE synthesis for other allergens. The second aim was to investigate the effect of natural pollen exposure on serum concentrations of house dust mite-specific IgE in patients who have seasonal allergic rhinitis and concurrent perennial allergic rhinitis due to house dust mites. This study included 55 adult patients with seasonal and perennial allergic rhinitis due to Japanese cedar pollens and Dermatophagoides farinae (D. farinae). Venous blood was collected twice from each patient, before and during the cedar pollen season 1996, to determine IL-4, cedar pollen-specific IgE and D. farinae-specific IgE in sera. Both IL-4 and pollen-specific IgE in sera were significantly increased during the pollen season, and the seasonal increase rate in pollen-specific IgE was significantly correlated with the seasonal increase rate in IL-4. By contrast, D. farinae-specific IgE was not changed during the pollen season in these patients. In conclusion, an elevation of IL-4 in sera during the pollen season may play an important part in the seasonal rise in pollen-specific IgE, and enhancement of specific IgE synthesis is likely to need not only an increase in IL-4 but also an increase in the number and/or capacity of specific IgE-secreting B cells.

Risk Factors for Adverse Systemic Reactions Occurring during Immunotherapy with Standardized Dermatophagoides farinae Extracts

The most serious problem in practical immunotherapy is the risk of occasional, potentially life-threatening adverse systemic reactions. Elucidation of the incidence of, and possible risk factors for, systemic reactions would have a profound effect on the decision about how to manage allergic rhinitis. The aim of this retrospective study was to document the incidence and risk factors of adverse systemic reactions during immunotherapy using standardized Dermatophagoides farinae (D. farinae) extracts for perennial allergic rhinitis. This study included 386 patients (22,722 injections) with perennial allergic rhinitis who had received immunotherapy with standardized D. farinae extracts in our clinics for the past 5 years. The incidence of systemic reactions was 6.22% per patient and 0.12% per injection. The time of onset of systemic reactions ranged from 3 to 30 min (mean 11.3 min) after injections. Our study has demonstrated that asthma, atopic dermatitis and a high level of IgE in serum, but not a high level of specific IgE in serum, are important high risk factors that may induce severe adverse systemic reactions in patients who receive immunotherapy for perennial allergic rhinitis. The incidence of systemic reactions in those who had a high level of IgE (higher than 1000 U/ml) and asthma and/or atopic dermatitis was 66.67% (12/18) per patient. Conversely, the incidence of systemic reactions in those who had none of the risk factors was 1.64% per patient. Thus, the rate of systemic reactions is thought to be reduced by 75% if patients with high risk factors are strictly excluded from immunotherapy for allergic rhinitis.

Allergen-specific Immunotherapy for Allergic Rhinitis: A New Insight into its Clinical Efficacy and Mechanism

Immunotherapy has been used widely for allergic diseases for more than 90 years but, in the opinion of many physicians, it is still a controversial form of treatment. The exact mechanism of action of immunotherapy remains to be determined. In the present study, we review the clinical efficacy and mechanism of action of immunotherapy for allergic rhinitis. Recent double-blind placebo-controlled studies have demonstrated the clinical efficacy of immunotherapy for allergic rhinitis. This therapeutic method has several advantages over conventional pharmacological treatment. Immunotherapy is inferior to pharmacological treatment in the short term, but in the long term it is substantially superior with respect to clinical efficacy. Immunotherapy has the potential permanently to alleviate the abnormal immunological responses of allergic rhinitis and to cure the nasal symptoms in the long term, even after discontinuation of injections. In addition, immunotherapy can prevent the onset of new sensitizations in allergic patients and may prevent the progression of rhinitis to asthma. It may therefore be possible for immunotherapy to alter the natural history of allergic sensitization and its clinical manifestation. These lines of clinical evidence could affect strategies of long-term therapy for allergic rhinitis. Modern molecular biological techniques have suggested that immunotherapy may affect allergen-induced TH responses or cytokine profiles, but there is no general agreement among investigators. However, IL-5 is likely to be the most important cytokine involved in the clinical efficacy of immunotherapy, and the suppression of allergen-induced IL-5 synthesis is most likely to be involved in the mechanism of immunotherapy. Our recent investigations, focusing on specific IgE and IgG4 responses, suggest that immunotherapy-induced changes in these specific antibodies play a clinical role and are involved in the mechanism of action of immunotherapy. It is probable that immunotherapy modulates and affects many different immunological and non-immunological phenomena to produce clinical efficacy and that clinical improvement is a consequence of different mechanisms over time.