Tateo Masamoto

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.

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.

Interleukin-6 and Tumour Necrosis Factor Alpha Synthesized by Cholesteatoma Cells Affect Mucociliary Function in the Eustachian Tube

The aims of this study were to investigate the possible synthesis of IL-6 and TNF-alpha by cholesteatoma cells in culture and the effect of IL-6 and TNF-alpha produced by cultured cholesteatoma cells on the function of the mucociliary system in the tubotympanum. Cholesteatoma cells were collected from 10 patients, and the medium supernatants in which cholesteatoma cells or normal human epidermoid cells had been cultured for 48 h were collected. The concentrations of IL-6 and TNF-alpha in the supernatants were measured by enzyme-linked immunosorbent assays. The effect of the culture supernatants on ciliary activity was examined using an in vitro experimental system. The supernatants were injected into the tympanic cavities of guinea pigs, and mucociliary clearance time of the Eustachian tube was determined according to our dye transport technique 24 h after the intratympanic injection. Human cholesteatoma cells produced larger amounts of IL-6 and TNF-alpha than normal human epidermoid cells. The supernatants of cholesteatoma cells compromised ciliary activity and mucociliary clearance of the Eustachian tube in the guinea pigs. The effects of the supernatants of cholesteatoma cells on the ciliary activity and mucociliary clearance were correlated with the concentration of IL-6 and TNF-alpha in the supernatants. In conclusion, cholesteatoma cells can produce IL-6 and TNF-alpha, which are able to compromise the mucociliary function in the tubotympanum. IL-6 and TNF-alpha produced in middle ear cholesteatoma might aggravate the disease by the wide range of their biological activities on the mucociliary system, the proliferation of cholesteatoma cells and the bone metabolism.

Soluble Intercellular Adhesion Molecule‐1 Level in Sera Is Elevated in Perennial Allergic Rhinitis

Soluble intercellular adhesion molecule‐1 (sICAM‐1) in sera was measured in some allergic disorders, but serum sICAM‐1 levels in perennial allergic rhinitis remain to be determined. Our study was aimed at elucidating whether the serum sICAM‐1 levels in patients with perennial allergic rhinitis are different from those in nonatopic healthy volunteers and whether immunotherapy can modulate sICAM‐1 levels. Serum sICAM‐1 was determined in 20 nonallergic volunteers and 137 patients with perennial allergic rhinitis by a sandwich enzyme‐linked immunosorbent assay. Our study demonstrated that the level of sICAM‐1 in untreated patients is significantly elevated, as compared with nonatopic subjects. Immunotherapy could decrease sICAM‐1 in perennial allergic rhinitis, but this suppressive effect became apparent only after many years of immunotherapy. In patients on immunotherapy, a close correlation was observed between sICAM‐1 and nasal symptom scores. To take these lines of evidence together, a decrease in sICAM‐1 might be related to the working mechanism of immunotherapy, and serum sICAM‐1 could be used to monitor the effect of immunotherapy.

Effect of Immunotherapy on seasonal changes in serum-specific IgE and IgG4 in patients with pollen allergic rhinitis

Serum specific IgE and IgG4 in 70 patients with seasonal rhinitis caused by Japanese cedar pollens were determined before and during the pollen season. Seasonal increase rate in specific IgE was significantly smaller in the immunotherapy patients than the pharmacotherapy patients, and seasonal increase in specific IgG4 was significant in the immunotherapy patients only. Seasonal increase rate in specific IgE was not significantly different between the patients who responded markedly to short‐term immunotherapy and those who did not. On the other hand, seasonal increase rate in specific IgG4 was significantly different between them. In contrast, seasonal increase rate in specific IgE was significantly smaller in the patients who showed marked response to the long‐term immunotherapy than those who did not show marked response to the long‐term immunotherapy, but seasonal increase rate in specific IgG4 was not significantly different between them. In conclusion, our results suggest that modulation of specific IgG4 response and specific IgE response might be involved in the early and late symptom relief during immunotherapy, respectively. However, further studies might be necessary to definitively establish the clinical roles of specific IgE and specific IgG4 in immunotherapy.

Soluble Vascular Cell Adhesion Molecule-1 in Perennial Allergic Rhinitis

Since the expression of vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells plays a central part in the selective recruitment of eosinophils into allergic inflammatory lesions, VCAM-1 may be a key molecule in allergic inflammatory diseases. Soluble forms of VCAM-1 (sVCAM-1) have recently been identified in the circulation, but there is limited published information on levels of sVCAM-1 in the circulation. If the levels of sVCAM-1 vary between patients with allergic diseases and normal controls, this variance would be very useful to investigate the state of the allergic disease and underlying inflammation. This study investigated the serum sVCAM-1 level in patients with perennial allergic rhinitis (rhinitis group) in comparison with non-atopic healthy volunteers (control group). No significant difference in the serum sVCAM-1 level was seen between the two groups (p = 0.4342). However, the serum sVCAM-1 levels in the severe rhinitis group were significantly higher than those in both the control group (p = 0.0067) and the mild rhinitis group (p = 0.0015), whereas no significant difference was observed between the mild rhinitis group and the control group (p = 0.1113). In addition, the serum levels of sVCAM-1 were significantly correlated with the nasal symptoms in the rhinitis group (rs = 0.486, p < 0.0001). In conclusion, serum concentrations of sVCAM-1 are increased in patients with severe perennial allergic rhinitis, and measurement of sVCAM-1 concentrations in sera is likely to be a useful tool for investigation of the severity of allergic rhinitis and underlying inflammatory reactions.

Platelet activating factor compromises airway epithelial defense functions

BACKGROUND The mechanism of disruption of the epithelial defense function observed in asthmatic airways is considered to be largely the result of mediators involved in allergic responses. Platelet activating factor (PAF) might be a key mediator involved in this mechanism. OBJECTIVE This study was designed to determine whether PAF is capable of compromising the epithelial defense functions, such as tight junctional barriers and the mucociliary system. METHODS A total of 120 healthy rabbits were used. Twenty of them were used as normal controls. Eighty rabbits were treated with inhalation of 10 ml of PAF (200 microg/ml), and 20 animals were used for the examination of epithelial defense functions of the trachea at 1, 10, 20, and 30 days after inhalation of PAF. Epithelial defense functions of the trachea were evaluated by ciliary activity, mucociliary transport velocity, epithelial permeability to fluorescein isothiocyanate dextrans (70,000 d), and electron microscopy of the epithelial structure. RESULTS PAF inhalation induced a significant decrease in ciliary activity and mucociliary transport velocity, which persisted for up to 20 days. PAF inhalation also caused a significant 7.4-fold increase in epithelial permeability to fluorescein isothiocyanate dextrans at I and 10 days. This increased epithelial permeability returned to the normal level 20 days after PAF inhalation. However, electron microscopy demonstrated no apparent evidence of epithelial shedding. CONCLUSIONS PAF-induced prolonged dysfunction of both the epithelial junctional barrier and the mucociliary system may allow enhanced entry of allergen molecules, as well as bronchoactive agonists to the airway parenchyma and may also significantly contribute to an increased airway responsiveness.

Specific immunoglobulin e, interleukin-4, and soluble vascular cell adhesion molecule-1 in sera in patients with seasonal allergic rhinitis

This study included 23 nonatopic volunteers and 84 patients with seasonal allergic rhinitis due to Japanese cedar pollen. Serum interleukin-4 (IL-4) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in the patients were significantly higher than those in the nonatopic individuals, even outside of the pollen season. Both the good responders and the poor responders to antihistamine tablets showed significant increases in IL-4 and specific IgE during the pollen season, whereas such seasonal increases were not observed in the good responders to immunotherapy. Seasonal increases in IL-4 were significantly correlated with those of specific IgE. However, seasonal increases in sVCAM-1 were not significant. Seasonal increases in sVCAM-1 were not significantly different between the good responders and the poor responders to pharmacotherapy or immunotherapy. In conclusion, serum IL-4 and sVCAM-1 are increased in patients with seasonal allergic rhinitis, even outside of the pollen season; this finding might suggest underlying preponderant in vivo activation of T helper cell-2-like cells and inflammatory events in seasonal allergic rhinitis. A seasonal increase in IL-4 in sera might be at least partly involved in the seasonal increase in specific IgE in sera. Immunotherapys inhibitory effect on IL-4 production and specific IgE response might be one of its working mechanisms.