Prevention of the effector cell activation via high affinity IgE receptor (FcεRI) is thought to be a straightforward strategy for suppressing the allergic reaction. Among the numerous methods to prevent the activation through FcεRI, three versions are described in this article. The first and second ideas involve inhibition of binding between FcεRI and IgE with a soluble form of the FcεRI α chain and a humanized antibody directed against the α chain, respectively. Both of these paths involve suppression the histamine release from human peripheral blood basophils in vitro. They also inhibited the allergic reaction in vivo. The soluble α inhibited the anaphylactic reaction in rodents and the Fab fragments of the humanized anti-FcεRI α chain antibody suppressed the dermal response in rhesus monkeys. The third idea involves repression of FcεRI expression by suppressing the transcription of the genes encoding the subunits of FcεRI. Although no plausible candidate molecule for actualizing this idea can be identified at present, further analyses of the transcriptional regulatory mechanisms in the human FcεRI α and β chain genes will lead to the discovery of novel targets for developing anti-allergic agents.

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Asthmatic deaths have shown a tendency to decrease in National Fukuoka Hospital. According to our analysis of asthma death and near-fatal asthma, the risk factor for death was considered as follows: low compliance, underestimation of severity (by patient or family), becoming used to attacks through experiencing many attacks, insufficient knowledge about attacks, overuse of β-stimulant metered-dose inhaler, etc. One of the reasons for the decrease in asthma death was thought to be the regular usage of many anti-asthmatic drugs especially inhaled corticosteroid.

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An astounding feature of the DNA sequences termed CpG motifs is the induction of immune and inflammatory responses in a senseless manner. CpG motifs exist abundantly in microbes and evoke innate immunity that constitutes the first line of defense against microbial infections in vertebrates. CpG motifs that essentially work in an antigen-nonspecific fashion, however, turn into novel immunomodulators that can manipulate acquired immunity in an antigen-specific manner if oligodeoxynucleotides containing CpG motifs (CpG ODNs) are directly conjugated to the antigen. CpG ODNs with potent polyclonal Th1-inducing ability show promise for application in immunotherapy whereby neutralization of dominant allergy-prone Th2 cells is achieved by inducing allergen-specific Th1 cells. The underlying mechanisms include an unexpected enhancement of dendritic cell function as a linker between innate and acquired immunity. In the foreseeable future the mainstream therapeutic role of corticosteroids in anti-inflammatory therapy for allergic diseases could possibly be replaced by immunotherapy using CpG ODN-conjugated antigens.

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Asthma is a complex disorder of inflammation and remodelling largely restricted to the conducting airways. It is a disorder where there are major genetics and environmental factors that interact together to initiate and propagate the disease into a chronic relapsing disorder. Until recently the genetic factors involved in disease pathogenesis have been restricted to variants in known molecules involved in the inflammatory or remodelling pathways. In this review evidence is presented for a new susceptibility gene for asthma, ADAM 33, that was identified by positional cloning. It is suggested that ADAM 33 plays a key role in predisposing to reduced lung function and bronchial hyperresponsiveness characteristic of asthma. Through an understanding of the disease-related SNPs (in ADAM 33) it may be possible, not only to identify a gene based diagnostic test, but also to focus attention on developing a new treatment that reverses remodelling changes.

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Physicians are very much concerned that death from asthma has not significantly declined despite modern treatment.Since most asthma deaths take place at home it is mandatory to keep in mind that adequate management should be commenced as early as possible at home when a severe asthmatic attack develops especially in high-risk patients.
For preventive care, the main objective should be to avoid severe hypoxemia with resultant cardiac arrest that may occur during severe asthmatic attacks at home and during transportation.
A total of 97 patients were studied with near-fatal asthmatic attacks requiring mechanical ventilation at least once during the period from January 1979 to November 1993, these patients were seen at Okinawa Chubu Hospital and survived without significant morbidity.
They were considered at high risk for recurrence of life-threatening asthmatic attacks and death and were therefore persuaded to undergo a trial of immediate self-oxygenation at home and during transportation to an emergency department whenever a severe attack developed.
Only 61 patients agreed to our request. Among those who agreed to install home oxygen, 24 subsequently developed severe attacks requiring mechanical ventilation outside hospital during following 15 years.
Sixteen of them immediately started oxygenation at home in addition to the anti-asthma medication, continuing the process all the way to emergency center; all survived.
Eight Patients did not actually take their home oxygen and four of them died (p<0.05).
Among the 36 patients who declined home oxygen trial, 13 experienced recurrences of severe asthmatic attacks outside the hospital; nine of them died.
Long-term follow up disclosed that 8.1 percent of those receiving home oxygen offered to them (n=61) died from an asthmatic attack. On the other hand, 30.5 percent of those who refused to have home oxygen (n=36) died within a 15 years period (p<0.05).

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To evaluate the extent of exposure to airborne mite allergens, we measured major mite allergens in indoor environments with an immunoassay using allergen-specific antibodies. The levels of mite allergens trapped by the sampler were measured with a highly sensitive immunoassay. We found heavy exposure to mite allergens from bedding during sleep. Bedding is likely one of the major reservoirs of mite allergens. When the used bedding was replaced with new allergen-free bedding, we detected a decrease in the airborne allergen levels. The use of new bedding seems to be an effective countermeasure against airborne mite allergen exposure.

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Remodeling in chronic sinusitis and nasal polyps is discussed. In chronic sinusitis, epithelial shedding, which is characteristic of asthma, is not observed in the maxillary sinus. An increase of mirovillous cells, squamous metaplasia, and goblet cells is observed in many patients with chronic sinusitis. The decreased ciliary area increases postoperatively in the maxillary ostium and in the maxillary sinus. There is no significant difference in the number of goblet cells between normal controls and chronic sinusitis. On the other hand, the number of submucosal acinar cells in chronic sinusitis is significantly higher than that in normal controls. Nasal polyps show a diversity of histogical findings. Although squamous metaplasia and goblet cells hypertrophy is observed in many patients, epithelial shedding, which is characteristic of asthma, is not observed in nasal polyps. The most striking finding of glands in nasal polyps is long shape. Histochemical analysis reveals deposition of types I, III, and V collagens in nasal polyps. Myofibroblasts, which are abundant in nasal polyps but rare in nasal mucosa, could be involved in the growth process of nasal polyps by inducing extracellular matrix accumulation. Although accumulation of extracellular matrix is a main feature of nasal polyps, its pathogenesis is not clearly known.

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We summarized the Therapeutic Guidelines for Atopic Dermatitis 2002, and outlined important points with reference to medical care and management of atopic dermatitis.

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Vernal keratoconjunctivitis, a severe form of allergic conjunctival disease, is characterized by the development of various types of corneal lesions in conjunction with proliferative changes in the conjunctiva. Expression of bioactive substances, such as chemokines and adhesion molecules, by corneal fibroblasts likely contribute to the formation of corneal lesions by promoting local infiltration, activation, and survival of immune cells. Proliferation and deposition of extracellular matrix by conjunctival fibroblasts also may provide conditions which support the activation and survival of immune cells. Topical administration of corticosteroids is the principal mode of treatment for conjunctival inflammation in individuals with vernal keratoconjunctivitis. In some individuals, however, the surgical removal of conjunctival giant papillae or of corneal plaques is indicated.

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The health-related quality of life (HRQoL) is assessed using instruments that have been validated scientifically. From the viewpoint of assessment, they are different from other clinical indices because the subjects themselves evaluate their own HRQoL (the patients in many clinical settings). As an index for evaluating health care services or outcomes, the HRQoL is as important as life expectancy. These instruments can be classified into generic and disease-specific instruments. There are numerous disease-specific instruments that can be used for patients with asthma, such as Juniper et al.'s Asthma Quality of Life Questionnaire (AQLQ), the Living with Asthma Questionnaire (LWAQ), the St. George's Respiratory Questionnaire (SGRQ), and Marks et al.'s Asthma Quality of Life Questionnaire (AQLQ). The characteristics of each instrument should be considered in the selection of specific HRQoL questionnaires for clinical research. Generally, the HRQoL is more disturbed in patients with severe asthma, and has been considered to be an important end-point in randomized controlled trials that involve asthma patients. We expect that further studies will also be performed in Japan.

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Interleukin (IL)-9 is a pleiotropic Th2 type cytokine which has been shown to play an important role in the pathogenesis of bronchial asthma. This review will concentrate on the structure, the source, and the effects of IL-9 as well as its induction and inhibition. The signaling of IL-9 through its receptor will be outlined. Moreover the role of IL-9 in airway hyperresponsiveness, mucus overproduction and airway remodeling in bronchial asthma will be discussed. Possible treatment options by blocking IL-9 will be outlined.

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The hygiene hypothesis implies, in immunological terms, that microbial stimulation in early life skews the immune system towards the development of a T helper type 1 (Th1)-type lymphocyte population, and away from a T helper type 2 (Th2)-type development that is associated with atopy. The hygiene hypothesis originally theorized that increased infections protected against atopy. This theory has evolved since harmful infections may not be as critical as exposure to microbial burden because exposure to microbes can occur in the absence of infections. Despite substantial public hygiene measures in modern metropolitan communities, an atopy-protective effect of endotoxin in these metropolitan environments still occurs. This article is a review of clinical and experimental studies concerning the protective effect of endotoxin exposure on the susceptibility to atopic responses. The discussion includes: (1) factors influencing household endotoxin levels; (2) recent developments in the potential use of endotoxin for the prevention of atopy and asthma; (3) association of endotoxin and pets with atopic sensitization and diseases; (4) animal studies on the protective effects of timing of endotoxin exposure on atopy and asthma and (5) animal studies on the protective effects of endotoxin dose on atopy and asthma.

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Clinical choice of β₂-adrenergic receptor agonists (β₂-agonists) is based on the parameter of receptor selectivity, potency, and duration of action. The guidelines for asthma management describe nothing about intrinsic efficacy concerning the use of β₂-agonists. Since intrinsic efficacy refers to the ability to activate β₂-adrenergic receptors independent of agonist concentration, β₂-adrenergic desensitization may be associated with intrinsic efficacy. However, little is currently known whether chronic administration of high intrinsic efficacy drugs interferes with the effects of β₂-agonists as a reliever medication. In this review, the causal relationship between intrinsic efficacy and desensitization to β₂-agonists is examined in tracheal smooth muscle using isometric tension records. Reasonable clinical use of these agonists based on these observations is discussed. When β₂-agonists intrinsic efficacy was measured as relaxation response (the maximum inhibitory effects against 1 μM methacholine-induced contraction), their rank order was: isoproterenol = procaterol = formoterol > salbutamol > salmeterol >> tulobuterol. Next, the subsequent response to short-acting β₂-agonists (procaterol, salbutamol) was examined after continuous exposure to long-acting β₂-agonists (formoterol, salmeterol, tulobuterol). β₂-adrenergic desensitization induced by these long-acting β₂-agonists was enhanced in proportion to their intrinsic efficacies. On the other hand, under the conditions of impairment of β₂-adrenergic receptors, reduced responsiveness to these short-acting β₂-agonists was enhanced in inverse proportion to the intrinsic efficacy. Although the clinical relevance of these results is still unclear, our data may provide evidence that weak partial agonists are useful as a controller medication, whereas full or strong agonists are useful as a reliever medication.

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Background: The bronchodilating action of β-agonists depends on the tone of airway smooth muscle or on spasmogen. To estimate the precise intrinsic activity of β-agonists, relaxation responses should be examined on maximally contracted airway smooth muscle. The aim of this study was to compare the relaxation responses to β-agonists under different tonic conditions of airway smooth muscle.
Methods: We examined the relaxation response to β-agonists on the isolated tracheal ring preparations in guinea-pigs precontracted with different concentrations of carbachol, leukotriene D₄ or substance P, and compared these results with that of spontaneously developed muscle tone.
Results: Relaxation responses to β-agonists were diminished depending on the extent of carbachol-induced tone in the tracheal muscle. The degree of hyporesponsiveness was greatest in treatment with tulobuterol, procaterol and isoproterenol, but least with adrenaline, formoterol and salmeterol. Diminished relaxation responses to β-agonists were partially reversed by pretreatment with AF-DX 116, a muscarinic M₂ receptor antagonist. When the tracheal muscle was precontracted with different concentrations of leukotriene D₄ (1—100nM) or substance P (0.1—10 μM), a diminished relaxation response to procaterol was not observed.
Conclusions: All β-agonists tested were partial agonists for relaxation of the carbachol-contracted guinea-pig tracheal muscle, where adrenaline rather than isoproterenol had the highest intrinsic activity.

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Background: Connective tissue growth factor (CTGF) is known to play a direct role in fibrosis in various organs as a downstream mediator of TGF-β.
Objective: To evaluate a role in subepithelial fibrosis in the asthmatic airway, we investigated CTGF mRNA expression and CTGF producing cells in the airways of a murine asthma model with allergic inflammation.
Methods: After repetitive inhalation challenges with ovalbumin (OVA), cell numbers and TGF-β1 concentrations in bronchoalveolar lavage fluid from immunized mice were measured. Collagen deposition in lung tissue was estimated by measuring hydroxyproline content. CTGF mRNA and GAPDH mRNA levels were determined by quantitative RT-PCR method. Immunohistochemistry for CTGF with anti-CTGF antibody was performed.
Results: Numbers of eosinophils and TGF-β1 concentration increased markedly in BALF on the 7^th day and 14^th day after inhalation challenge with OVA. Hydroxyproline content in lung tissue increased significantly on the 14^th day after inhalation challenge of OVA compared to control. The ratio of CTGF mRNA /GAPDH mRNA in lung tissue in mice exposed to OVA increased 10-fold compared to those exposed to saline. Immunohistochemistry revealed that the number of CTGF-positive cells increased in bronchial submucosa after inhalation challenge of OVA.
Conclusions: Our results suggested that CTGF might be one of the potential molecules involved in subepithelial fibrosis in murine airways with allergic inflammation.

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Background: Based on the fact that site-specific amino acid replacement on peptide antigens stimulated T cell clones to produce increased amount of IFN-γ, we investigated this structure-function relationship, using various peptide analogues.
Methods: We used three human Th0 clones (BC20.7,BC33.5 and BC42.1) that express distinct TCRα and TCRβ chains, but recognize the same TCR ligand; i.e., the same framework of peptide antigen BCGa p84-100 in the context of DRB1^*1405. These T cells were stimulated with various peptide analogues, followed by determination of proliferative responses and IFN-γ production.
Results: Replacement of Leu at peptide position 2 (P2) by amino acids which are less hydrophobic than the wild type (Val, Ala) or those with similar structural or neutral charge (Thr, Ser), induced increased IFN-γ production from T cells. This phenomenon was associated with structural features of TCR, especially the length of CDR3 region of TCRα. Amino acid replacement at the other positions did not induce increased IFN-γ production.
Conclusions: Amino acid substitution at P2 frequently induces increased IFN-γ production in a clone-specific manner, which is associated with the structure of CDR3 in TCRVα chains.

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Background: Early intervention in adult asthma has been evaluated mostly with regard to symptoms, respiratory function and airway hyperresponsiveness, and has rarely been evaluated with regard to airway inflammation. Further, no clinical data concerning prevention of remodeling by anti-inflammatory therapy have been reported. The anti-inflammatory activities of an inhaled steroid and a leukotriene receptor antagonist were compared using sputum induced by inhaled hyperosmotic NaCl solution, and the usefulness of anti-inflammatory treatment for mild intermittent asthma (step 1) was investigated.
Methods: The subjects of the study were patients with mild intermittent asthma (step 1) who had not received steroid treatment and had only been treated with inhaled β2-stimulants as needed. The subjects were divided into two groups: one group received 400 μg/day of budesonide (BUD group; n = 15) and the other group received 10 mg/day of montelukast (MK group; n = 12). The anti-inflammatory activities of BUD and MK were compared by examining respiratory function, exhaled nitric oxide (ENO) concentrations, airway hyperresponsiveness (acetylcholine provocation test) and the sputum induced by inhalation of hyperosmotic NaCl solution at three time points, i.e., before, 1 month after, and 6 months after the start of treatment.
Results: It was shown that even in mild intermittent asthma (step 1) the levels of ENO and sputum eosinophil ratio were elevated, indicating that airway inflammation was clearly present and that airway hyperresponsiveness was elevated. The effects of BUD and MK in improving ENO and sputum eosinophil ratio were almost the same. However, airway hyperresponsiveness in both groups were not significantly improved after 1 and 6 months of treatment.
Conclusions: Anti-inflammatory treatment is necessary even for mild intermittent asthma (step 1). We believe that early intervention with anti-inflammatory drugs is important for the prevention of airway remodeling, exacerbation of disease and progression to intractable asthma. Either of the two types of drugs, low-dose inhaled steroids or leukotriene receptor antagonists, can be selected as anti-inflammatory drugs for mild intermittent asthma.

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Background: Suplatast tosilate is a type 2 (Th2) cytokine inhibitor that blocks the production of IgE antibodies and the invasion of tissues by eosinophils during an allergic reaction. Suplatast tosilate ameliorates asthma symptoms and airway hypersensitivity by inhibiting production of the Th2 cytokines interleukin (IL)-4 and IL-5.
Methods: In the present study, a comparative examination of the therapeutic effects of suplatast tosilate was carried out in patients with mild intermittent and mild persistent asthma by randomly allocating 35 adult patients to a suplatast tosilate group (n = 18; 100 mg suplatast tosilate three times daily) and a beclomethasone dipropionate (BDP) group (n = 17; 200 μg BDP twice daily) for 6 weeks of treatment.
Results: The suplatast tosilate group required more time than the BDP group to show improvement in peak expiratory flow, but at week 6 the change from baseline was nearly the same in both groups. A significant improvement was observed for both groups in the peripheral blood eosinophil ratio, serum eosinophil cationic protein (ECP) levels, induced sputum ECP levels, forced expiratory volume in 1 second, and airway hypersensitivity, but induced sputum ECP level was lower in the BDP group than in the suplatast tosilate group. Total IgE levels decreased in the suplatast tosilate group only.
Conclusions: We conclude that suplatast tosilate may be useful inlong-term management of mild bronchial asthma.

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Background: We have recently shown that early postmenopausal but not premenopausal asthmatic women treated with inhaled corticosteroids demonstrate reduced bone mineral density (BMD) and decreased serum intact osteocalcin levels. Thus, the development of therapeutic approaches would be desirable for the prevention and intervention of BMD reduction in postmenopausal asthmatic women receiving inhaled corticosteroids.
Methods: This study was aimed at examining the effects of etidronate disodium on BMD in 20 postmenopausal asthmatic women with reduced BMD of the lumbar spine (T score; -1.5 or less). These patients had been managed by inhaled beclomethasone dipropionate or inhaled fluticasone propionate, without regular use of oral or parentheral corticosteroids. They were given a 200 mg/day oral dose of etidronate disodium for 14 days every three months. BMD of the lumbar spine was determined at baseline and at 1 or 3 years after the treatment.
Results: The baseline BMD was 0.692 ± 0.018 (SE) g/cm² (T score, -3.0 ± 0.8). The BMD significantly increased by 5.2 ± 2.0% at 1 year (P = 0.022) and by 7.3 ± 2.9% at 3 years (P = 0.037) after the treatment.
Conclusions: Intermittent cyclical treatment with ethidronate improves reduced BMD in postmenopausal asthmatic women on inhaled corticosteroid therapy.

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Background: Lactobacillus paracasei strain KW3110 has been shown by in vitro cytokine secretion analysis to be a potent Th1 inducer and Th2 repressor. Oral administration of L. paracasei strain KW3110 also represses IgE elevation in the ovalbumin sensitized mouse allergy model.
Methods: During pollen season from January to April in 2003, a daily dose of 4 × 10¹⁰ cfu L. paracasei strain KW3110 was fed for 12 weeks as a yogurt to 14 pollen allergy patients (mean age 39.0 years). A yogurt made with Lactobacillus delbrueckii strain B, shown to be a poor Th1 inducer and Th2 repressor in a former study, was also fed at a daily dose of 4 × 10¹⁰ cfu for 12 weeks to 14 pollen allergy patients (mean age, 39.0 years). Blood samples were collected every 4 weeks. Eosinophils, eosinophil cationic protein (ECP), non-specific serum IgE, cedar pollen specific serum IgE, and Th1/Th2 ratios were quantified.
Results: Twelve weeks after ingestion of the yogurts, the group that was fed L. delbrueckii group showed significant reductions in the Th1/Th2 ratios between the first observation in January and last observation in April, representing the four month study period, due to increases in Th2 cells. Significant increases in ECP were also observed in the group fed L. delbrueckii between January and April. In contrast, the group fed L. paracasei had no significant changes in the ECP and Th1/Th2 ratios.
Conclusions: Our results suggest that ingestion of the L. paracasei strain KW3110 is associated with both repression of Th2 cell generation and eosinophil activation. Our data point to the possibility that specific lactic acid bacteria may be useful for allergy therapy.

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Background: Isocyanates have become one of the most important causes of occupational asthma in industrialized countries. Increased exhaled nitric oxide (eNO) levels have been shown to be associated with allergic airway inflammation. The objective of this study was to investigate the influence of isocyanate on eNO levels and to elucidate whether the latter are associated with specific sensitization and/or unspecific bronchial hyperresponsiveness (BHR). Additionally, we wanted to compare eNO changes of smokers and non-smokers.
Methods: We determined eNO during diagnostic isocyanate challenges in workers with suspected isocyanate asthma.
Results: Fourteen of 22 symptomatic isocyanate workers showed BHR and five of these 14 developed an asthmatic response upon challenge with methylene diphenyl diisocyanate (MDI). In comparison with the group without BHR, subjects with BHR had higher basal eNO and a significant increase in eNO 22 hrs after MDI challenge. Four of the asthmatic responders and six of the nine MDI non-responders with BHR revealed an eNO increase of > 30%. There was also a positive association between the eNO change and the increase in airway resistance in isocyanate workers with BHR. The highest eNO change was found in subjects with IgE-mediated sensitization to MDI and low MDI thresholds. Only one of the eight MDI non-responders without BHR exhibited an eNO increase of > 30%.
Conclusions: Isocyanate workers with BHR show increased MDI responses both of airway resistance and of the inflammatory marker eNO. eNO measurement is obviously a new suitable tool for monitoring isocyanate workers under respiratory risk.

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Background: IgG antibody to allergens in the serum of pollinosis patients is not routinely measured, because there are no simple methods for assaying small amounts of specific IgG in the serum; so far only IgE and IgG4 antibodies have been assayed. In this study, we used a reverse-sandwich ELISA for measuring specific non-IgE,-IgG4 (probably, mainly IgG1) to Japanese cedar pollen allergens, and compared the antibody-positive rates and geometric mean antibody titers between pollinosis patients and non-patients (healthy individuals).
Methods: Antibodies to two major allergens of Japanese cedar, Cry j 1 and Cry j 2, were assayed by the following methods: specific non-IgE,-IgG4 was measured by a reverse-sandwich ELISA; specific IgE and IgG4 were measured by indirect ELISAs.
Results: We detected specific non-IgE,-IgG4 in both the patients and non-patients. In comparison to the IgE antibody, which was detected in a small proportion of the non-patients with low titers, the non-IgE,-IgG4 antibody was present in a higher proportion with higher titers among both the patients and non-patients.
Conclusions: Healthy individuals had specific non-IgE,-IgG4 to Japanese cedar allergens in a higher proportion than the specific IgE. The non-IgE,-IgG4 antibody assay may be useful in studies on the prevalence of allergen-specific antibody responders and may help in clarifying the natural history of pollinosis.

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Background: Although subcutaneous immunotherapy may cure allergic diseases, it is not commonly used in Japan because of the pain and risk of anaphylactic shock. Sublingual immunotherapy (SLIT) overcomes these limitations and although it is the most advanced form of local immunotherapy for clinical application, it is not used in Japan nor has it been extensively studied.
Methods: After obtaining approval from the Ethics Committee of Nippon Medical School and informed consent from five patients with cedar pollinosis (one man, four women; age range, 38—66 years), administration of a therapeutic extract was started in July 2001 or later (mean treatment period, 13.4 months). The clinical efficacy of SLIT and its influence on the quality of life, as measured by the Japanese Allergic Rhinitis QOL Standard Questionnaire, and the incidence of side effects were evaluated in 2003.
Results: Between February and April the mean severity score was 1.44 in the patients undergoing SLIT and 1.86 in the patients undergoing pharmacotherapy, and the respective mean QOL total scores during the season were 3.82 and 10.0. Neither systemic nor local side effects occurred during SLIT.
Conclusions: SLIT is safe and effective for Japanese cedar pollinosis.

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