The mainstay of chronic asthma management consists of using pharmacological agents that induce broncho-dilatation, such as short-acting β-adrenergic receptor agonists (bronchodilators or relievers), and that control the chronic inflammatory process, such as cortico-steroids (anti-inflammatory or controllers). Short-acting β-adrenergic receptor agonists are the best relievers, whereas inhaled corticosteroids, by inhibiting eosino-philic and lymphocytic inflammation and mediator/cytokine expression, remain the mainstay chronic treatment of asthma. Long-acting β-adrenergic receptor agonists are best used in conjunction with inhaled corticosteroids, providing additive bronchodilatation, better asthma control and reduced exacerbation rates in patients with moderate to severe asthma. Slow-release theophylline combines bronchodilator and some anti-inflammatory effects and is best used in combination with inhaled corticosteroids. Leukotriene inhibitors, by either inhibiting the effects of cysteinyl leukotrienes or reducing their production, also cause some bronchodilator effects with inhibition of eosino-philic inflammation. They are effective in mild-to-moderate asthma, but low-dose inhaled steroids are more efficacious; leukotriene inhibitors also provide additive effects in combination with inhaled steroids. Increased understanding of the immunology and inflammatory responses has led to the identification of novel targets and to the development of potentially new therapies. These include immunologic targets, such as those against T cells and T cell-related targets, anti-cytokine therapies and anti-IgE approaches. New effective therapies are particularly needed for patients with severe asthma who do not respond to currently avail-able treatments.

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Triggering of the antigen-specific T cell receptor (TCR) can lead to various functional outcomes, such as activation and proliferation, anergy or cell death. This differential signaling is mainly determined by the quality and quantity of TCR signals, the nature of accessory signals and the differentiation/maturation status of the T cell. In this regard, T cell development and differentiation of the two major T helper (Th) subsets, namely Th1 and Th2 cells, can also be viewed as examples of differential signaling. In the present report, we review two T cell-selective signaling molecules (protein kinase C (PKC) θ and SLAT), which we have studied extensively and that appear to play important roles in the process of differential signaling. The novel PKC isoform PKCθ is selectively expressed in T lymphocytes and is essential for TCR-triggered activation of mature T cells via activation of the nuclear factor-κB and activator protein-1 pathways. Productive engagement of T cells by antigen-presenting cells (APC) results in recruitment of PKCθ to the T cell-APC contact area, the immunological synapse (IS), where it interacts with several signaling molecules to induce activation signals essential for productive T cell activation and interleukin-2 production. These events are associated with PKCθ translocation to membrane lipid rafts, which also localize to the IS. The Vav/Rac pathway promotes the recruitment of PKCθ to the IS or lipid rafts as well as its activation. SLAT is a novel adapter protein, which we isolated recently. It is selectively expressed in Th2 lineage cells, where it is found associated with the TCR-coupled protein tyrosine kinase ZAP-70. Our initial characterization of SLAT indicates that, by regulating the overall strength of TCR signaling, it may play an important role in differential signaling processes, which promote the differentiation and activation of allergy promoting and anti-inflammatory Th2 cells.

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Background: Both a recombinant soluble form of the high-affinity IgE receptor α subunit (rsFcεRIα) and anti-IgE antibody have been shown to be involved in the regulation of IgE synthesis. However, the mechanisms of IgE regulation by two such IgE-binding agents remain unclear. In the present study, we investigated whether rsFcεRIα and anti-IgE antibody modulated IgE synthesis in an identical or different manner.
Methods: Normal human B cells stimulated with interleukin (IL)-4 plus anti-CD40 antibody were analyzed for the regulatory effects of rsFcεRIα and anti-IgE antibody on the expression of Cε transcipts, the autocrine production of IL-6 and the induction of apoptosis.
Results: Both rsFcεRIα and anti-IgE antibody inhibited mature Cε transcription, without affecting germline Cε transcription. In addition, rsFcεRIα was effective in decreasing IL-6 production at a later stage when IgE-expressing B cells were generated, whereas F(ab')₂, but not the Fab fragment, of anti-IgE antibody induced apoptosis in the cells. Although these three agents almost equally recognized IgE expressed on B cells, rsFcεRIα was unable to induce apoptotic cell death and the Fab fragment was similarly ineffective in the regulation of IL-6 production. The addition of IL-6 to cultures containing rsFcεRIα significantly restored its suppressive effect on IgE synthesis.
Conclusions: These results indicate that regulation of IgE synthesis by rsFcεRIα differs from that by anti-IgE antibody.

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Background: Asthmatics are considered to be at high risk for pulmonary complications during general anesthesia with tracheal intubation. The purpose of the present study was to determine the usefulness of perioperative corticosteroids for mild asthmatics in preventing perioperative exacerbation of asthma.
Methods: Airway hyperresponsiveness to inhaled methacholine was determined in patients with intermittent (n = 27) and mild persistent (n = 48) asthma before general anesthesia who underwent surgery between January 1990 and January 1999. All patients were treated with corticosteroids during the perioperative period, consisting of a course of oral prednisolone 10-20 mg/day for 1-2 days pre-operatively, methylprednisolone 80-125 mg 2 h before the operation, followed by 80 mg methylprednisolone just after the operation. The incidence of perioperative bronchospasm was evaluated based on medical records. Airway hyperresponsiveness to inhaled methacholine was determined in six other asthmatics before and after a similar regimen of perioperative corticosteroids treatment.
Results: Only three cases (4.0%) developed mild asthma during the perioperative period. No evidence of adverse effects of corticosteroids was noted in any case. The use of the same therapeutic regimen in another six asthmatics significantly suppressed airway hyperresponsiveness to inhaled methacholine.
Conclusions: Our results suggest that perioperative corticosteroids are effective in preventing perioperative bronchospasm in stable asthmatics during surgery under general anesthesia by suppressing airway hyperresponsiveness.

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Background: A number of recent studies have clarified the characteristics of major allergens of Cryptomeria japonica, such as the locality, molecular weights of Cry j 1 and Cry j 2 and cross-reactivity with some other species of pollen. However, in order to plant C. japonica forests with low allergen levels, there is still a shortage of fundamental data for forest breeding.
Methods: To obtain the some fundamental data concerning Cry j 1, three items were investigated: (i) variations in weight and Cry j 1 content per single pollen grain among 117 clones; (ii) environmental factors affecting Cry j 1 content; and (iii) genotype variations of Cry j1.
Results: Although the variation in weight per single pollen grain among 117 clones was relatively small (mean (±SD) 10.2 ± 0.1 ng), the Cry j 1 content was found to vary widely from 0.26 to 7.54 pg. The expression level of Cry j 1 was higher in samples collected from lower altitudes. Using western blotting, it was shown that there were two Cry j 1 genotype variations.
Conclusions: From these results, we have concluded that immunologic determination of Cry j 1 by individual pollen grain levels provides useful data, especially for forest breeding to prevent pollinosis.

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Background: Although β-adrenergic receptor agonists inhibit antigen-induced release of histamine, leukotrienes and prostaglandin D₂ from human lung fragments, dispersed human lung mast cells and human skin mast cells, subcellular mechanisms for the inhibition of histamine release by β-adrenergic receptor agonists are not well delineated. The aim of the present study was to investigate the inhibitory mechanisms of β-adrenergic receptor agonists for human mast cell histamine release using human cultured mast cells.
Methods: Human mast cells were obtained by culturing umbilical cord blood CD34⁺ cells in the presence of stem cell factor and interleukin-6. Cultured mast cells were sensitized with human myeloma IgE and stimulated with antihuman IgE.
Results: Stimulation of mast cells induced the elevation of intracellular cytosolic free Ca²⁺ concentrations ([Ca²⁺]_i) and the translocation of protein kinase C (PKC) from the cytosol to the cell membrane, followed by the release of stored histamine. Isoproterenol, salbutamol and dibutyryl cAMP inhibited both the histamine release and PKC translocation, whereas they failed to affect the elevation of [Ca²⁺]_i. H-89, a protein kinase A (PKA) inhibitor, abrogated the inhibition.
Conclusions: The present results suggest that PKA activation induced by β-adrenergic receptor agonists plays a crucial role in inhibiting IgE-mediated histamine release from human cultured mast cells through suppressing PKC translocation.

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Background: Allergens that cause food allergy vary considerably according to race, environment, dietary habits and age. However, data on the actual situation of food allergy in young adult students are limited in Japan. The aim of the present study was to investigate the actual situation of food allergy in young adults.
Methods: Food allergy was examined, along with the presence or absence of allergic rhinitis, atopic dermatitis and bronchial asthma complicating food allergy, in 2053 Japanese university students.
Results: Food allergy was noted in 5.2% of subjects, with a higher prevalence in female students. In terms of the causative allergen, the rank order of incidence was egg, buckwheat, shrimp, crab, mackerel, milk, yam, beef fat, shellfish and other foods. In comparison with Western countries, the incidence of allergy to buckwheat and seafood tended to be higher. Among students with a food allergy, the proportion of those with allergic rhinitis, atopic dermatitis and bronchial asthma was 45.8, 29.0 and 12.1%, respectively, showing higher prevalences than in students without any food allergy.
Conclusions: In the future, the number of young adults with food allergy complicated by other allergic diseases will increase and measures against this issue seem to be necessary.

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