Motoyo Hayashi

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.

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 Soluble Interleukin-2 Receptor in Patients with Perennial Allergic Rhinitis Before and After Immunotherapy

BACKGROUND Interleukin-2 receptor (IL-2R) exists in soluble form in sera, and the rate of release of the soluble form of IL-2R (soluble IL-2R) reflects T cell activation in vivo. Since T lymphocytes play a central role in respiratory allergic disorders, the measurement of serum levels of soluble IL-2R may be useful in analyzing the disease state of allergic disorders. OBJECTIVE To investigate the serum concentrations of soluble IL-2R in 48 patients with perennial allergic rhinitis and 14 nonatopic healthy controls, with special reference to the possible changes following long-term immunotherapy. METHODS This retrospective study included 48 patients who had had variable periods of long-term immunotherapy with Dermatophagoides farinae extracts. The duration of immunotherapy ranged from 5 to 15 years. Serum samples were collected twice from each patient, before the initiation of immunotherapy and at the time of clinical assessment of immunotherapy. All the serum samples were simultaneously used for determination of soluble IL-2R concentrations, by the use of an enzyme-linked immunosorbent assay. To serve as controls, 14 nonallergic subjects of the same age range and sex were chosen. RESULTS Patients with allergic rhinitis before immunotherapy had significantly higher serum levels of soluble IL-2R than nonatopic subjects. Elevated serum levels of soluble IL-2R decreased significantly following immunotherapy and the serum levels of soluble IL-2R in patients with allergic rhinitis after immunotherapy were not statistically different from those of nonatopic subjects. In addition, the percent decrease in serum soluble IL-2R correlated significantly with the duration of immunotherapy. CONCLUSIONS Hyperactivity of helper T cells of atopic patients is altered after long-term immunotherapy, and such immunoregulatory changes could be theoretically involved in the mechanisms of immunotherapy.

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.

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.

Nitrogen Dioxide-induced Eosinophilia and Mucosal Injury in the Nose of the Guinea Pig

Nitrogen dioxide exposure-induced mucosal pathology of the guinea pig nose was studied. Guinea pigs were exposed to 3 ppm or 9 ppm of nitrogen dioxide for 6 h a day, 6 times weekly for 2 weeks, and sacrificed 24 h after the final exposure. Exposure to 3 ppm of nitrogen dioxide resulted in decreased ciliary activity and slight eosinophil accumulation on the epithelium and submucosal layer. More serious pathologies were observed in the nose of guinea pigs exposed to 9 ppm of nitrogen dioxide, including a more prominent eosinophil influx to the epithelium and epithelial injury due to activation of eosinophils. Epithelial damage induced by nitrogen dioxide could lead to hyperresponsiveness and may result in a prolonged allergic inflammation. Our study suggests that environmental nitrogen dioxide may contribute to hyperresponsiveness and thus be involved in the increased morbidity of allergic rhinitis.

A comparative study of the clinical efficacy of immunotherapy and conventional pharmacological treatment for patients with perennial allergic rhinitis.

This study was designed to compare the clinical outcome of prolonged immunotherapy for perennial allergic rhinitis with that of pharmacological treatment. Patients with perennial allergic rhinitis due to Dermatophagoides farinae (D. farinae) were divided into two groups; a pharmacotherapy group and an immunotherapy group. The pharmacotherapy group was treated with conventional pharmacological treatment using antihistamine tablets and topical steroid sprays and the immunotherapy group was treated with D. farinae extracts for 5 successive years. None of symptom scores at enrollment differed significantly between the groups. At 6 months and 1 year after the start of treatment the rate of decrease in each score was significantly greater in the pharmacotherapy group than in the immunotherapy group. The rate of decrease in sneezing scores, but not in the other scores, at 2 years after the start of treatment was also greater in the pharmacotherapy group than in the immunotherapy group. However, at 3 years the rate of decrease in any of the scores did not differ significantly between groups. The differences between the groups became clear-cut again after 5 years of treatment, when the rate of decrease in all of the scores was significantly greater in the immunotherapy group than in the pharmacotherapy group. Therefore, short-term treatment with pharmacological agents is probably superior to immunotherapy but, in the long-term, immunotherapy is apparently superior to pharmacological treatment with respect to clinical efficacy. In addition, prolonged immunotherapy provided long-term clinical efficacy and might provide a long-standing cure even after discontinuation of the therapy. In a questionnaire interview, approximately half of patients were very satisfied with prolonged immunotherapy and three-quarters were fairly satisfied or more. Additionally, the magnitude of improvement in nasal stuffiness contributed significantly and exclusively to the patient evaluation of immunotherapy. We propose that prolonged immunotherapy is never inferior to anti-allergenic pharmacological treatment and that it is possible to achieve long-term clinical efficacy or long-standing cure even after the discontinuation of immunotherapy, and that patients with perennial allergic rhinitis will be very satisfied with this prolonged therapeutic technique if nasal stuffiness is considerably alleviated.

Natural Course of Serum‐Specific Immunoglobulin E and Immunoglobulin G4 for a Span of Eight Years in Untreated Patients With Perennial Allergic Rhinitis

During the past two decades, considerable attention has been devoted to the clinical role of serum‐specific IgE and IgG4 following immunotherapy. To definitely discuss the clinical role of serum‐specific IgG4, we should know the natural course of serum‐specific IgG4 in the untreated patient with allergic rhinitis. To our knowledge, however, no such kind of study can be found in the literature. Our present study focused on the long‐term follow‐up of serum‐specific IgE and IgG4 in patients who were not treated with immunotherapy for perennial allergic rhinitis. They were scheduled to take no medication for their perennial nasal symptoms for 8 years. Serum‐specific IgE and IgG4 in untreated patients with perennial allergic rhinitis never significantly change during the observation period. These data will be of great value for studies in serologic changes following active treatment for atopic diseases. Additionally, our study suggests that a reduction in serum‐specific IgE and an increase in serum‐specific IgG4 following immunotherapy are not the result of an immunotherapy‐independent and age‐related phenomenon but the result of active immunologic modulation by immunotherapy.

Presence of bronchoalveolar lavage fluid necessary for platelet activating factor-induced ciliary depression

Many different mediators have been implicated in allergic responses and allergic diseases of the respiratory tract. The influence of several allergic inflammatory mediators on the ciliary activity has been well studied. However, ciliary responsiveness to platelet-activating factor (PAF) is yet to be established conclusively. Our study concerns the response of normal tracheal cilia from the guinea pig during an in vitro contact with PAF. PAF at concentrations between 10(-10) and 10(-8) M never affected the ciliary activity. On the other hand, such concentrations of PAF inhibited the ciliary activity in a dose-response fashion within 5 min in the presence of alveolar macrophages. Such a ciliary dysfunction should allow allergens and other molecules to easily invade epithelium and submucosa of the airway, resulting in an increased epithelial permeability which might be a mild manifestation of airway hyperresponsiveness and make a significant contribution to further airway hyperresponsiveness.

Influenza A modification of endotoxin-induced otitis media with effusion in the guinea pig

SummaryA total of 120 Hartley strain guinea pigs were used to investigate the possible role of influenza A in endotoxin-induced otitis media with effusion. Intratympanic inoculation of 0.2 ml physiologic saline solution containing 104 plaque-forming units (PFU)/ml of influenza A suspension or 100 ng/ml lipopolysaccharide failed to induce either middle ear effusions or mucociliary pathologies in the tubotymapanum. In contrast, intratympanic inoculation 100 ng/ml endotoxin resulted in prolonged mucociliary dysfunction and middle ear effusions when 0.2 ml 104 PFU/ml of influenza A was inoculated in the tympanic cavity. The inference is drawn that an influenza A infection might predispose the middle ear to endotoxin-induced otitis media with effusion.