Japanese cedar pollinosis (JCPsis) is a major national health problem in Japan. The present review provides an update on information on JCPsis based on clinical data from our research group, through the support of the Department of Health and Welfare (Japanese Government), during the period from 1988 to 1997, because this disease is infrequently documented internationally despite a large number of publications from Japan. The information on JCPsis presented here may be of use in the management of various kinds of pollinosis prevalent in other countries. The prevalence rates of JCPsis vary from district to district and also depend on the age of the subjects, the method of analysis and the year of examination in population. Yet, on an average, the incidence of JCPsis is presumed to be 10—20% in adults and 5—10% in children. The risk factors for sensitization and the onset of symptoms seem to be dependent on the amount of air-borne pollen, the age of school children, hereditary disposition, including human leukocyte antigen type and the high levels of specific IgE in childhood. Because pollen counts also vary depending on many factors, such as the type of pollen samplers used, yearly variations, the number of pollen count stations, the atmospheric temperature and solar radiation in the previous year of the season, accurate predictions of daily and seasonal pollen counts are rather difficult. Commercial crude extracts and purified allergenic substances Cry j I and II correlate well with the skin test and the radioallergosorbent test. Japanese cedar pollen has an allergenic component that is cross-reactive with Japanese cypress. In many patients, the onset of symptoms occurs on the day when the air-borne pollen count is 10/cm² (the Durham method) and, if severe symptoms occur due to intense exposure to pollen, the symptoms will last for a long time despite variations in the pollen count (priming effect). Eye glasses, face masks and keeping windows and doors of the house closed are useful measures for pollen avoidance. Symptom control during the season is not difficult by the continuous use of new anti-allergic drugs during the season. If medication is started 1—2 weeks prior to the onset of the season, more satisfactory results can be obtained. Specific immunotherapy can not only control symptoms, but can reduce the amount of medication and, after completion of the regimen, long-term remission without medication can be expected.

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The present study was performed in order to investigate the mechanism(s) involved in eotaxin-induced normal human eosinophil chemotaxis using a 48-well microchemotaxis chamber assay. Eotaxin, at a wide range of doses, induced eosinophil chemotaxis with optimal activity at 100 ng/mL. To elucidate the role of Ca²⁺ as a second messenger, eosinophils were depleted of intracellular Ca²⁺ which, per se, did not modify eosinophil chemotaxis. To gain insight of the possible intracellular signal transduction, we blocked pertussis toxin (PTX)-sensitive G_i proteins as well as several protein kinases. It was found that the inhibition of tyrosine kinase with herbimycin A and the inhibition of mitogen-activated protein kinase (MAPK) with MEK-1 inhibitor (PD98059) significantly blocked chemotaxis; however, inhibition of protein kinase C with staurosporine, protein kinase A with H-89 and G_i proteins with PTX did not affect chemotaxis. These results suggest a signal transduction pathway(s) involving Ca²⁺-independent tyrosine kinase and MAPK activities.

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To investigate effects of endotoxin on allergic airway diseases, we studied bronchial responsiveness to histamine (HI) and substance P (SP) in actively sensitized and non-sensitized guinea pigs 24 h after exposure to endotoxin (75 μg/mL; 40 min) and its vehicle, saline. Bronchial responsiveness to HI and SP was assessed by calculation of -log PC₂₅₀ HI and -log PC₂₅₀ SP, respectively, where the PC₂₅₀ is the provocative concentration producing a 250% increase in lung resistance. Endotoxin increased bronchial responsiveness to SP but not to HI and caused airway inflammation characterized by accumulation of neutrophils in bronchoalveolar lavage fluid (BALF) without increasing SP-induced airway microvascular leakage assessed by the extravasation of Evans blue dye. The actively sensitized animals showed a tendency to increase the value of -logPC₂₅₀ SP (P < 0.1) compared with that of non-sensitized control animals. To elucidate the mechanisms underlying preferential bronchial hyperresponsiveness to SP, neutral endopeptidase (NEP) activities in the airways were measured. Neutral endopeptidase activities were significantly decreased in actively sensitized animals and were further decreased in endotoxin-exposed animals. There was a significant inverse correlation between NEP activity and bronchial responsiveness to SP (r = -0.55; P < 0.001), while no such relationship was observed for HI. These data suggest that NEP mediates endotoxin-induced bronchial hyperresponsiveness to SP and that active sensitization may affect bronchial responsiveness to SP in guinea pigs.

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In a 1993 survey, allergic rhinitis was identified as the most common allergic disease in Hong Kong, affecting 29.1% of schoolchildren. Recently (1995), the International Study of Asthma and Allergies in Childhood (ISAAC) also reported 44.5% current rhinitis among Hong Kong teenagers. Our objective was to study the aetiology of allergic rhinitis in Hong Kong using serological tests of allergen sensitization. In 57 allergic rhinitis patients and in the same number of age- and sex-matched controls the following were measured: serum total IgE, mixed aeroallergen IgE (Phadiatop^TM) and specific IgE versus house dust mite (HDM), cockroach, cat and dog dander, mould mixture (Penicillium, Cladosporium, Aspergillus and Alternaria species) and four local pollens (Bermuda grass, Timothy, ragweed and mugwort). Compared with controls, allergic rhinitis patients (26 males, 31 females; mean (± SD) age 25 ± 11 years) had a significantly elevated serum total IgE concentration (mean ± SEM: 496 ± 88 vs 179 ± 38 kU/L) and an increased proportion of positive Phadiatop (95 vs 33%) and specific IgE tests versus HDM (90 vs 44%) and cockroach (42 vs 9%; Mann—Whitney U-test and χ² tests all P < 0.005). There was no significant difference in sensitization to other allergens tested. House dust mite and cockroach are ubiquitous in Hong Kong with a warm, humid climate and crowded living conditions. Their identification as aetiological agents of allergic rhinitis should help in the development of environmental strategies for reducing the inhalant allergen load to prevent and control this prevalent and costly health problem in our community.

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Bronchial asthma (BA) is characterized by infiltration of the respiratory tracts by eosinophils. A wide variety of adhesion molecules is involved in the binding of eosinophils to the vascular endothelium and their subsequent transmigration from the circulation to the airways, while little is known about CD44 expression on eosinophils. In the present study we introduce a novel staining combination with which surface markers on eosinophils can be analyzed without purification prior to staining and examined whether the expression of CD44 on peripheral blood eosinophils could be monitored as a marker of the control of BA. Staining of eosinophils with anti-CD16 and anti-VLA-4 monoclonal antibodies enabled us to delineate eosinophils as VLA-4^highCD16^- cells from other leukocyte populations in the whole blood. CD44 was constitutively expressed on resting eosinophils and expression increased following cytokine-mediated activation. In all BA patients examined, CD44^high eosinophils were enriched in sputum relative to peripheral blood, indicating that eosinophils in sputum were more activated than those in the blood. By comparing the extent of CD44 expression on blood eosinophils from poorly controlled and well-controlled asthma patients, we unexpectedly found that the density of CD44 expression is lower on blood eosinophils from the poorly controlled group. Thus, the extent of CD44 expression on blood eosinophils defined as VLA-4^highCD16^- cells is a novel marker indicative of the management of BA.

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The effect of interleukin (IL)-4 on eosinophil chemotactic lymphokine (ECL) production from peripheral blood mononuclear cells (PBMC) stimulated with purified protein derivative (PPD) was examined. The PBMC stimulated with PPD in the absence of IL-4 failed to produce evident ECL. However, PPD-induced eosinophil chemotactic activity (ECA) production was markedly enhanced in a dose-dependent manner by pretreatment of PBMC with IL-4. The most potent enhancement was induced by IL-4 at a concentration of 30 U in tuberculin-sensitive PBMC. Short-term pretreatment (30 min to 3 h) was sufficient for the enhancement, whereas longer-term treatment was less effective. Eosinophil chemotactic lymphokine was found to be a CD4⁺ T cell-derived factor with an isoelectric point of approximately pH 7.0 and without heparin affinity, unlike chemokines such as RANTES and eotaxin. The effect of IL-4 on the production of other cytokines, such as interferon (IFN)-γ, IL-5, RANTES (regulated on activation, normal T expressed and secreted), and granulocyte—macrophage colony stimulating factor (GM-CSF) was also examined. Peripheral blood mononuclear cells produced all these cytokines when they were treated with PPD, even in the absence of IL-4. When PBMC were pretreated with IL-4, interestingly not only IFNγ but also IL-5 production was suppressed by pretreatment with IL-4, although ECL production was enhanced by the pretreatment. In the case of RANTES and GM-CSF, significant amounts of these cytokines were produced, even without antigenic stimulation, and IL-4 pretreatment did not result in an enhancement of their production. It is thus suggested that IL-4, existing in allergic lesions, plays a crucial role in eosinophil accumulation mediated by the T cell-derived ECL.

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To investigate the relationship between local responsiveness and allergic symptoms, bronchial and nasal responsiveness were measured in the following four groups of subjects: (i) bronchial asthma patients with serum house dust mite (HDM)-specific IgE antibody; (ii) allergic rhinitis patients with serum HDM-specific IgE antibody; (iii) normal control subjects with HDM-specific IgE antibody; and (iv) normal control subjects without IgE antibody specific for 10 common aero-allergens. Bronchial hyperresponsiveness was detected in all subjects with asthma (group 1) and in some subjects from groups 2 and 3, but not in subjects from group 4. Nasal hyperresponsiveness was found in all subjects with allergic rhinitis (group 2) and in some subjects from groups 1 and 3, but not in subjects from group 4. These findings indicate that local hyperresponsiveness of the non-diseased organ is influenced by an individual's atopic status. Interleukin (IL)-4 and IL-5 production by peripheral blood mononuclear cells (PBMC) was measured after stimulation with HDM in groups 1, 2 and 3 and was found to be similar in all three groups. A correlation between bronchial hyperresponsiveness and in vitro cytokine production was noted in asthma patients. These results suggest that the capacity of IL-4 or IL-5 production by PBMC may reflect local hyper-responsiveness in case of asthma.

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The allergenic activity of 60 kDa antigen of Brugia malayi adult worm, due to its ability to release histamine from mast cells, has been previously reported by us. To determine the roles of protein kinase C (PKC) and calmodulin in this process, histamine release from passively sensitized lung and peritoneal mast cells was investigated in the presence of W-7 and trifluoperazine, used as calmodulin inhibitors, and H-7, used as a PKC inhibitor. The results show that H-7 is able to inhibit histamine release from both lung and peritoneal mast cells, thus suggesting a vital role of PKC in histamine release. However, lung and peritoneal mast cells exhibited a differential response to the calmodulin inhibitors. The calmodulin inhibitors prevented histamine release from peritoneal mast cells, but not from lung mast cells, thus suggesting that calmodulin is not essential for histamine release by lung mast cells.

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In some clinical studies performed in patients with perennial allergic rhinitis, ramatroban, a new thromboxane A₂ receptor antagonist, significantly improved nasal symptoms. As yet the mechanism of action of this drug has not been fully elucidated. In the present study we investigated the effects of ramatroban on changes in nasal reactivity and levels of inflammatory cells and mediators in nasal lavage fluid after allergen challenge. Ramatroban was administered orally at a daily dose of 150 mg (b.i.d.) for 4 weeks to 11 patients with perennial allergic rhinitis exhibiting positive responses to nasal allergen challenge with house dust mite. Analysis of variance revealed that there was a significant decrease in eosinophil counts and eosinophil cationic protein levels in nasal lavage fluid when compared with values immediately before allergen challenge before and after ramatroban treatment. Histamine, tryptase and albumin levels were significantly decreased in analysis of variance before and after ramatroban treatment. The degree of nasal reactivity to histamine was also significantly decreased after the ramatroban treatment. These findings indicate that ramatroban decreases important pathogenic factors in allergic rhinitis, resulting in an improvement in nasal symptoms.

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