Autoimmune diseases as well as type-I allergic diseases have markedly increased in the past 30 years. Environmental estrogens or endocrine disruptors are possibly involved in the etiology of the increase in autoimmune diseases as one of environmental factors. In aged BWF1 mice, a murine model for SLE, B lymphocyte chemoattractant (BLC/CXCL13) is ectopically and highly expressed in target organs such as the thymus and kidney. B1 cells, a specialized cell population that are distinguished from conventional B cells (B2 cells) by their origin, cell surface phenotype, unique tissue distribution, self-reactivity, etc., preferentially migrate towards BLC. Aberrant B1 cell trafficking to the target organs may result in activation of autoreactive CD4 T cells, autoantibody production, and impaired mucosal immunity in the gut during the development of SLE. Interestingly, B1 cells show a higher sensitivity to environmental estrogens than conventional B (B2) cells to produce autoantibodies. Thus, B1 cell can be a useful target for evaluating the pathological significance of environmental estrogens in the development of autoimmune diseases.

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It is well-known that many isoforms of toll-like receptors (TLRs) function as Th1 adjuvant receptors. Thus, the ligands induce Th1 differentiation in an antigen non-specific manner. During the past few years, not only Th1, but also Th2 adjuvants have been reported. Allergy-inducing materials, such as parasites, first stimulate dendritic cells (DCs) to change their character as professional antigen-presenting cells. Such a DC population (DC2) can stimulate naive CD4T cells to induce differentiation into Th2. In some instances, DCs that can stimulate regulatory T cells are also induced. Interestingly, many of such substances are glycolipids or phospholipids that mammalian species do not usually carry. In this paper, we show a cellular and molecular basis for Th2 adjuvants.

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Intestinal microbiota play a crucial role in the development of mucosal tolerance and adaptation. Perturbations in microbiota composition are strongly associated with allergies and asthma in westernized countries. There has been accumulating evidence that the administration of probiotics, "live microbial supplements that exert a beneficial effect on human health," may be effective in the treatment and/or prevention of allergic diseases. Although it has been shown that part of the effect of probiotics arises from its interaction with the host immune system, the precise mechanisms remain to be determined. In addition, future studies are necessary to define appropriate species and strains, optimum dose, frequency, and duration for the treatment of allergic diseases.

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Background: It is still unclear how early exposure to pets is related to the risk of developing atopy-related diseases in children. There are few reports on this pet-allergy relationship in Japan although much controversial data have been reported in Europe and the USA.
Methods: A questionnaire on pet-keeping and allergic diseases was distributed to parents of children 3—6 years of age who belonged to 4 kindergarten and 2 nursery schools in Gifu city and surrounding areas. A total of 1185 questionnaires were analyzed statistically.
Results: Bronchial asthma (11.6%), atopic dermatitis (16.5%), and allergic rhinitis (16.5%) were reported. Dogs, cats, hamsters, rabbits, and birds were kept by 21.6%, 5.5%, 10%, 1.5%, and 2.6% of all families, respectively. Indoor pets with fur resulted in a significantly higher prevalence of atopic dermatitis (OR = 1.82, 95%CI 1.26-2.63) using univariate analysis and also in multivariate logistic regression analysis. We also found a significantly higher prevalence of atopic dermatitis in subjects who started keeping dogs and/or cats indoors after 1 year of age, compared to subjects who kept neither dogs nor cats, using both univariate analysis (OR = 2.26, 95%CI 1.13—4.54) and multivariate logistic regression analysis (OR = 2.17, 95%CI 1.09-4.32).
Conclusions: We found no evidence that pet-keeping protects people from developing various allergies. Conversely, indoor pets with fur have a slightly increased prevalence of atopic dermatitis.

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Background: Asthma patient education has been recognized as an important component of asthma control. The aim of the present study was to carry out a cost-effectiveness analysis of patient education in patients with mild to moderate asthma during 6 months of follow up.
Methods: We randomly allocated asthma patients who were covered by health insurance to a control group (group C) or a self-management group (group S). Self-management consisted of measurement of peak expiratory flow (PEF) and monthly individual education and advice by a specialist. Effectiveness was evaluated on the basis of PEF, quality of life, and mean total cost of medical expenses. Furthermore, we asked the patients about symptom improvement and their level of satisfaction with this program.
Results: PEF values in group S gradually increased at 3 months after the self-management program and remained at high levels. The total costs decreased by 30% from baseline in group S, whereas they increased by 15% in group C. The cost of one-day visits showed no difference between the two groups, but the frequency of visits to general practitioners decreased in group S as compared with group C. Furthermore, the number of episodes of asthma attacks decreased in group S but not in group C, and 94% of the group S patients replied that they considered the self-management program to have been useful.
Conclusions: We conclude that an individual self-management program is not only a safe and effective aid in the treatment of mild to moderate asthma but can also reduce medical expenses.

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Background: The aim of this study was to identify the predictive factors, among laboratory test data and patient background variables, of an efficient response to the anti-allergic agent suplatast tosilate in patients with moderate to severe bronchial asthma.
Methods: The subjects were 44 patients with moderate to severe bronchial asthma on inhaled steroid therapy who were enrolled in a phase II clinical trial of suplatast (300 and 600 mg/day). Improvements in respiratory function parameters and symptom scores during the first 4 weeks of administration of suplatast were assessed to evaluate the response to the drug. Logistic regression analysis was used to relate the response to the independent variables. Secondly, to test whether these results were applicable to clinical practice, we examined the data from a phase III clinical trial of suplatast.
Results: Twenty-two patients were assessed as responders according to our criteria. The percentage of blood eosinophil (%EOS, P = 0.015) and basophil (%BASO, P = 0.019) counts were identified as significant variables to predict responders. When cut-off levels for %EOS and %BASO were set at 7.5 and 1.2, respectively, the sensitivity for prediction of responders with lower %EOS and %BASO was 81.8% (18/22). Furthermore, when we applied the same cut-off levels to subjects of a phase III clinical trial of suplatast, the sensitivity of prediction was found to be as high as 75.0% (6/8).
Conclusions: These results indicate that %EOS and %BASO are good candidates to predict the response to suplatast among patients with moderate to severe bronchial asthma on inhaled steroid therapy. These predictors may contribute, in combination with genomic information, to stratified medical treatment tailored to the individual needs of patients.

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Background: We evaluated the characteristics of late-onset asthma in elderly patients with asthma, particularly concerning the relationship of IgE mediation and response to treatment.
Methods: This study included asthma patients aged 60 or older who were hospitalized under a clinical pathway that provided the treatment of asthma exacerbation, thorough examination, and patient education simultaneously. The patients were divided into two groups, those in whom asthma developed at age 60 or older (late-onset group) and those in whom asthma developed before age 60 (early-onset group). Both groups received step-down therapy with fluticasone dry powder after discharge, and asthma severity was compared between two time points: at 1 year and 2 years after the start of treatment.
Results: One-third of all patients with asthma were aged 60 or older, and half of these had late-onset asthma. There was an inverse correlation between serum IgE levels and the age of onset. The positive rates of specific IgE antibodies to Japanese cedar pollen or house dust mite were significantly lower in the late-onset group than in the early-onset group. Pulmonary functions were equivalent between the two groups. However, asthma severity on admission was lower in the late-onset group. Response to treatment was better in the late-onset group, especially at 1 year of treatment.
Conclusions: Asthma in elderly patients may be divided into early-onset persistent asthma and late-onset asthma with short duration. Late-onset asthma is less IgE-mediated, less severe, and has a better prognosis after appropriate treatment with inhaled fluticasone, and patients are more likely to drop out. For elderly patients with asthma, early detection, repetitive patient education and early intervention with inhaled corticosteroid therapy are important.

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Background: Not only monotherapy with inhaled corticosteroids (ICS) but also the concurrent use of other antiasthmatic agents, including leukotriene receptor antagonists (LTRA), play an important role in the management of asthma. However, few studies have focused on compliance with these drugs and on the relation between drug compliance and drug usage.
Methods: Data were derived from a survey of pharmacists dispensing antiasthmatic drugs to adults with asthma who visited participating pharmacies from October through November 2002. The patients were limited to regular users of ICS whose medication had not been changed for at least 6 months before the survey. Drug compliance and the daily administration frequency of antiasthmatic agents were evaluated on the basis of pharmaceutical records.
Results: Completed data were received for 322 patients. ICS compliance was lower than compliance with oral sustained-released theophylline (OSRT) and compliance with LTRA. ICS compliance significantly correlated with OSRT compliance and with LTRA compliance. There were no significant differences of ICS compliance among ICS alone, ICS + LTRA, ICS + OSRT and ICS + LTRA + OSRT group, while the daily inhalation frequency in ICS + OSRT or ICS + OSRT + LTRA group were higher than those in ICS alone group. Although there was a significant negative correlation between ICS compliance and daily inhalation frequency, neither OSRT compliance nor LTRA compliance significantly correlated with the tablet or capsule numbers per day. These findings indicate that OSRT may increase the compliance of concomitant ICS, and that the compliance of OSRT or LTRA is independent of the numbers of tablets taken per day.
Conclusions: These unique characteristics should be considered in the treatment and guidance of patients with bronchial asthma.

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Background: Because bronchial inflammation was recognized as a basic component of bronchial asthma, the strategy for asthma management has changed in the last two decades. In Japan there are few clinico-epidemiological reports of changes in the management of bronchial asthma in actual practice.
In this study, we analyzed practical asthma management in Japan, and examined changes in the prevalence of asthma medication and relation between these changes and the level of asthma control and management.
Methods: From 1998 to 2002, questionnaires on asthma control, asthma related emergent episodes and satisfaction in daily life. Questionnaires were distributed to adult asthmatic patients. Questionnaires about the patients' profiles and medication were also given to the patients' doctors.
Results: The total number of patient responders was approximately 2500—3300 per year. The rate of peak flow meter (PEFM) use was under approximately only 40% and plateaued from 2000 to 2002. The percentage of inhaled corticosteroid use and leukotriene receptor antagonist use increased, from 62.0%, 27.2% to 77.4%, 40.6% respectively. Indicators for asthma control, including presence of attacks and sleep disturbance, were significantly improved. Limited to PEFM users, there was an improvement hospitalization, ambulance use or ED visits and in satisfaction in daily life based on a Quality of Life (QOL) indicator.
Conclusions: These results indicate that the prevalence of anti-inflammatory agents, including inhaled corticosteroids and leukotriene receptor antagonist, was associated with an adequate improvement in asthma control in clinical practice. In asthma management in clinical practice, prevalence of PEFM may play an important role in the improvement of asthma related emergent episodes or QOL.

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Background: Epinastine hydrochloride (epinastine) is a second-generation histamine H₁-receptor antagonist widely used as an anti-allergic and anti-pruritic. To explore possible new aspects of the anti-pruritic mechanism of epinastine, in particular any effects on the peripheral nervous system, we examined epinastine's effects on sensory neurons using cultured murine dorsal root ganglion (DRG).
Methods: We performed a quantitative assessment of neurite growth and substance P (SP) release from isolated DRG in the presence versus the absence of epinastine. Mechanism(s) of epinastine's effects on sensory neurons were detected by examining its neurotoxicity, inhibitory action on nerve growth factor (NGF), and modulatory function on NGF receptors.
Results: The percentage of DRG with outgrowing neurites, total number of neurites, and average extension length of neurites were decreased by epinastine in a concentration-dependent manner. Epinastine did not exhibit any evidence of neurotoxicity on sensory neurons, degradation and inactivation ability on NGF, or effects on expression of NGF receptors. Also, no effects on neural progenitor cells of the central nervous system in culture were observed. Epinastine suppressed capsaicin-induced SP release from DRG neurons in a dose-dependent fashion.
Conclusions: The results demonstrate that epinastine has inhibitory effects on sensory neuronal growth, which may explain its clinical effects including potent anti-pruritic activity.

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Background: Avoidance of allergens is one of the most effective treatments of allergenic diseases, including pollinosis. Although various masks and goggles for pollinosis sufferers are commercially available, little work has been done on preventing adhesion of pollen to the human body and clothes. We have examined the effect of polymer coating on adhesion of cedar pollen to skin, hair and fabrics, and found that a lecithin polymer (LP), containing both cationic and anionic sites, is highly effective in reducing adhesion levels.
Methods: We evaluated the changes in electrostatic charge and frictional coefficient of sample surfaces after coating with an anionic polymer (AP), a cationic polymer (CP), a nonionic polymer (NIP), or LP (each applied by spraying 0.10% polymer solution in ethanol/water). Pollen adhesion level was evaluated by observation of the number of cedar pollen particles on video microscope (VMS) images and by quantification of cedar pollen antigen Cry j1 with a sandwich ELISA system. Adhesion of pollen to human skin or hair was also examined by VMS observation.
Results: LP-coated samples showed a significant reduction in electrostatic charge level and frictional coefficient. We presumed that these properties are closely related to the significant reduction in the adhesion level of cedar pollen or Cry j1 compared with CP, AP or NIP-coated samples. A similar effect was seen on LP-treated skin, and LP-treated waxed hair.
Conclusions: Our results suggest that coating with LP could help in the management of pollinosis by reducing the contact level of patients with cedar pollen antigens.

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Background: Background data on the allergic constitutions of a general population of Japanese children may provide important information regarding environmental factors that contribute to the increased incidence of allergic diseases and suggest clues for their prevention.
Methods: Serum samples were obtained from a general population of 3-year-old children (612 samples) in the Kanto area and Asahikawa city. The serum levels of total and specific IgE antibodies against food allergens (egg white, milk, soybean, wheat), indoor airborne allergens (house dust, mite, cat dandruff), and outdoor airborne allergens (Japanese cedar or white birch pollen allergens) were determined and analyzed, along with the results of a questionnaire regarding medical history, and allergy-related subjective symptoms.
Results: The mean total IgE level of all subjects was 34.7 IU/ml, while that for the Kanto and Asahikawa areas was 44.7 and 22.5 IU/ml, respectively. Twenty six percent of the 612 children were judged positive for indoor airborne allergen-specific IgE, and 6.7% were positive for food allergen-specific IgE. Cedar allergen-specific IgE was detected in 15.6% of the children living in the Kanto area. The total IgE level was strongly correlated with the number of allergens to which the child was sensitized.
Conclusions: A relatively large number (28.4%) of 3-year-old children possessed allergen-specific IgE antibodies. The basic data obtained in the general population in these two areas of Japan will be valuable for further evaluations of environmental influences on allergic disease.

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Background: A self-recorded instrument for children with asthma needed to be developed to measure their quality of life (QOL). Therefore, the JSCA-QOL questionnaire was revised into a briefer third version, consisting of 5 domains (25 questions) and a summative scale. The purpose was to examine the possibility of identifying children with poor QOL requiring medical or social support, and to devise a practical form of evaluating a nationwide investigation using this instrument.
Methods: Doctors at hospital and clinics throughout Japan distributed the JSCA-QOL to 5308 10- to 18-year-old children with asthma. The questionnaires were returned by mail, after having been filled out by the subjects, who authorized their participation in the investigation by signing the questionnaire.
Results: A total of 2097 children with asthma, who fully completed the questionnaire, were included in the study. As a result of analysis, it was clear that the characteristics of the low score group (under the 10th percentile of QOL scores) were noticeably different from those of the other groups, in the following ways: (i) many children had moderate to severe asthma, (ii) the answers showed different distributions from those of the other groups, (iii) the answers in most "feeling level" questions showed a significantly different distribution. A radar chart was developed for efficient evaluation of children's QOL profiles.
Conclusions: It was very useful to separate the low score group (LSG) with the 10th percentile of the QOL score to distinguish the children who needed special support. The evaluation of the QOL profile was simplified by using the radar chart concept.

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Background: The increase in the incidence of allergic disorders especially in developed countries may be explained by the hygiene hypothesis. A novel therapeutic approach that causes a Th1-dominant response under conditions of Th2-skewed immunity has been investigated. Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a widely used anti-tuberculosis vaccine that strongly induces a Th1-predominant immune response. A potential role for BCG in the treatment of allergic diseases has been reported. In the present study, we investigated whether subcutaneous inoculation with a low dose (1 × 10⁵) of BCG vaccine can attenuate allergic inflammation of the airway in a murine model of asthma.
Methods: Female BALB/c mice were vaccinated on day 0 with a subcutaneous. injection of 1 × 10⁵ CFU of BCG, and sensitized to ovalbumin (OVA, i.p., with alum) on day 7 and 14, respectively. After a 2-week interval, they were exposed to aerosolized OVA (1%). In another experiment, BCG-sensitized splenic CD4⁺ T cells were adoptively transferred before sensitization.
Results: We found that BCG-vaccinated mice had fewer eosinophils in BALF and less severe allergic inflammation. The expression of IL-4 as well as Eotaxin and TARC was down-regulated in the vaccinated mice, while that of both IL-12 and IFN-γ was up-regulated. Moreover, the transfer of splenic CD4⁺ T cells from vaccinated mice into naïve mice before OVA-sensitization prevented the development of allergic inflammation. These splenic CD4⁺ T cells produced much IFN-γ.
Conclusions: The subcutaneous administration of (low-dose) BCG vaccine suppressed allergic inflammation via Th1-skewed immunity and might have clinical applications in immunotherapy for asthma.

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Background: Regulated on activation, normal T expressed and secreted (RANTES) has been known to be deeply involved in the pathophysiology of atopic dermatitis (AD). To examine whether a -401A/G polymorphism in the RANTES promoter gene is associated with the susceptibility to AD in Japanese, we determined the genotypes of the polymorphism in 145 Japanese students and 65 patients with AD.
Methods: DNA was isolated from the mononuclear cells by using SepaGene (Sanko) and analyzed by the polymerase chain reaction (PCR) technique.
Results: The frequency of -401A allele was 0.39 in the healthy subjects without AD. This was not significantly different from that in the patients with AD (0.41). We also failed to show association between the polymorphism in the RANTES promoter gene and the production of IgE.
Conclusions: These results suggest that the -401A/G polymorphism in the RANTES promoter gene does not determine the susceptibility to AD in Japanese, although larger studies could explore the exact role of the polymorphisms in AD, or Japanese might have other susceptibility genes more potent than the RANTES promoter gene.

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Background: Tulobuterol tape is the first long-acting transdermal preparation of a β₂-agonist designed to release tulobuterol in an optimal fashion over a 24-hour period. We investigated the additive effect of tulobuterol tape in adult asthma patients treated with inhaled corticosteroids.
Methods: A randomized, double-blind, double-dummy, parallel-group, multicenter trial was conducted. Male and female patients with a diagnosis of asthma requiring inhaled short-acting β₂-agonists despite treatment with inhaled corticosteroids took tulobuterol tape (1 mg or 2 mg) and corresponding placebo tapes for 4 weeks.
Results: Mean morning peak expiratory flows (PEF) in the 1 and 2 mg/day groups were significantly increased from the baseline value by 23.8 and 35.9 L/min at week 4, respectively. The increase in mean morning PEF in the 2 mg/day group was significantly higher than that in the 1 mg/day group. The mean evening PEF was significantly increased in both treatment groups compared with baseline values. Although the increase in mean evening PEF in the 2 mg/day group was greater than that in the 1 mg/day group, the difference between groups was statistically significant only at week 1. The safety profiles of the two treatments were similar.
Conclusions: In patients with persistent asthma who require inhaled short-acting β₂-agonists while receiving inhaled corticosteroids, transdermal tulobuterol significantly improved PEF in a dose-dependent manner, i.e., greater effect with 2 mg than with 1 mg per day.

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Background: There is evidence that neutrophils are increased in the airway of severe disease or acute exacerbations of asthma. The mechanisms by which neutrophils are recruited to the airways and contribute to the pathophysiology of asthma remain to be elucidated. Tumor necrosis factor (TNF-α), which can induce both tissue accumulation and activation of neutrophils and eosinophils, has been shown to be increased in the airways of severe asthma. The objective of this study is to evaluate whether TNF-α is associated with neutrophilic inflammation in asthma.
Methods: Following an inhalation of hypertonic saline, induced sputum was obtained from 9 healthy controls, 9 mild persistent asthma patients who were treated with low-dose inhaled corticosteroids; and 7 severe persistent asthma patients who were treated with combinations of drugs including high-dose inhaled corticosteroids, oral prednisolone, bronchodilators, and leukotriene receptor antagonist. After 0.1% dithiothreitol (DTT) homogenization, they were examined for total cell count, cellular differentiation, and the concentrations of TNF-α and myeloperoxidase (MPO).
Results: The concentration of TNF-α was not correlated with neutrophils in healthy controls or mild asthma patients. In sputum from severe asthma patients, however, the concentration of TNF-α is significantly correlated with both the percentage of neutrophils and the concentration of MPO. The concentration of TNF-α is not correlated with the percentage of eosinophils in healthy controls, mild asthma patients, or severe asthma patients.
Conclusions: TNF-α may be a contributing molecule for both accumulation and activation of neutrophils in the airways of severe asthma.

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Background: We developed an in vitro system to diagnose allergy using an allergen microarray and photo-immobilization technique. Photo-immobilization is useful for preparing the allergen microarray because it does not require specific functional groups of the allergen and because any organic material can be immobilized by a radical reaction induced by photo-irradiation.
Methods: To prepare the plates, allergen solutions were mixed with polymer and a bis-azidophenyl derivative, a photo-reactive cross-linker, the mixtures were micro-spotted on the plate, and the droplets were dried. The plate was irradiated with an ultraviolet lamp for immobilization. For the assay, human serum was added to the microarray plate.
Results: Allergen-specific immunoglobulin E (IgE) adsorbed on the micro-spotted allergen was detected by peroxidase-conjugated anti-IgE antibody. The chemiluminescence intensities of the substrate decomposed by the peroxidase were detected with a sensitive CCD camera.
Conclusions: All allergens were immobilized by this method and used to screen allergen-specific IgE.

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Background: Pranlukast and Montelukast are Cysteinyl leukotriene receptor antagonists with almost the same pharmacological activity. However, I will describe a case in which these drugs showed different therapeutic effects on clinical symptoms during the daytime and eosinophilic inflammation in the peripheral airway.
Methods: A 70-year-old male patient with non-atopic bronchial asthma who was treated with 400 μg/day of Budesonide Turbuhaler^® (BUD-TH) changed from Pranlukast (225 mg, twice daily) to Montelukast (10 mg, one tablet before sleeping), resulting in worsening clinical symptoms consisting of sputum and cough in the daytime, mainly at lunch time. Due to the fact that the symptoms did not improve sufficiently, instead of increasing the dose of BUD-TH, we investigated the clinical symptoms and pulmonary functions as well as measured the mean eosinophil count, eosinophil cationic protein (ECP) and eotaxin in the hypertonic saline-induced sputum prior to administration of Pranlukast, and 4 and 8 weeks after the re-administration of Pranlukast from Montelukast.
Results: Following the re-administration of Pranlukast, the clinical symptoms disappeared within a few days and pulmonary function improved within 4 weeks. Eosinophils in the induced sputum almost completely disappeared for 4 weeks. The sputum ECP and eotaxin before and 4 weeks after the re-administration of Pranlukast changed from 700 μg/l to 192 μg/l, and 69.9 pg/ml to 30.6 pg/ml, respectively. After 8 weeks, no sputum induction was found.
Conclusions: The clinical difference between these two similar antagonists may be caused by the time difference relating to when and how often each drug is administered, suggesting the existence of the lunchtime dip.

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