Intraepithelial γδ T cells appear to be an essential regulatory T cell subset for the induction and regulation of humoral and cellular immune responses in the mucosa-associated tissues. These cells form a mucosal internet and intranet with epithelial cells which lead to a reciprocal regulation for activation and cell growth. Removal of the TCR gene (γδ^-/- mice) results in a reduction of epithelial cell turnover and downregulates the expression of major histocompatibility complex class II molecules on epithelial cells. Epithelial cells are capable of producing interleukin (IL)-7 and stem cell factor which can activate mucosal γδ T cells expressing IL-7R and c-kit. Further, cell surface immunoregulatory molecules expressed on epithelial cells inhibit the proliferation and cytokine synthesis of γδ T cells stimulated via the TCR-CD3 complex. Thus, direct cell-to-cell interactions between mucosal γδ T cells and epithelial cells occur via their secreted cytokines and their cell surface immunoregulatory molecules to maintain the homeostatic regulation of the mucosal immune system. γδ^-/- mice possess significantly lower numbers of immunoglobulin A (IgA) producing cells in mucosa-associated tissues, including intestinal lamina propria and salivary glands, when compared with normal control mice. Furthermore, the levels of antigen- specific IgA B cell responses in γδ^-/- mice decreased when they were immunized orally. Mucosal γδ T cells possess an ability to maintain an IgA response in the presence of systemic tolerance. These results clearly indicate that γδ T cells play an important role in the regulation of antigen-specific mucosal IgA responses. Taken together, a triad mucosal lymphocytes intranet which connects among γδ T cells, αβ T cells and IgA B cells is necessary for the induction and regulation of IgA antibody responses in mucosal areas.

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T-helper (Th) 2 cells, which produce interleukin (IL)-4, IL-5, IL-10 and IL-13 upon stimulation of their T cell receptors, play an important role in the development of human allergic diseases. However, the precise mechanism involved in the differentiation of Th2 cells is not well understood compared with that of Th1 cells. The selective differentiation of Th1 or Th2 subsets is established during priming under the influence of a variety of factors. Prostaglandin E₂ (PGE₂) is one of those factors. Prostaglandin E₂ produced by antigen presenting cells directly affects the naive CD4⁺ T cells, causing them to differentiate into Th2 cells. This effect is mediated by the elevation of cyclic adenosine monophosphate (cAMP) at the early stage of T cell activation. IL-4 and PGE₂ lead naive CD4⁺ T cells to differentiate into Th2 cells cooperatively, by distinct signal transduction. Both PGE₂ and IL-4 inhibit the hypomethylation of the proximal regulatory regions of the genomic IFN-γ gene, whose hypomethylation has been suggested as being important for the IFN-γ production by CD4⁺ T cells stimulated through their antigen receptors. Prostaglandin E₂ facilitates Th2 differentiation of naive CD4⁺ T cells by acting not only on T cells directly but also on antigen presenting cells by inhibiting their IL-12 production. The production of PGE₂ by monocytes is increased significantly in allergic patients. These results, taken collectively, suggest that PGE₂ plays an important role in facilitating the differentiation of Th2 cells in vivo.

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Food allergy, triggered by an aberrant immune response elicited by orally ingested food allergens, is generated through a complicated mechanism because the allergen interacts with the mucosal immune system (the gut- associated lymphoid tissue, GALT) and the resulting immune response affects the generation of allergy. This review will describe the process by which antigens or allergens are recognized by the GALT and the characteristic immune responses induced thereafter. Orally administered antigens induce distinct immune responses in the Peyer's patches, lamina propria and the intestinal epithelium. In addition to these local immune responses in the gut, ingested antigens are known to affect sys- temic immunity. These may induce a suppressed state of systemic immune responsiveness, which is called oral tolerance, or in some cases they may elicit a systemic IgE antibody response which may lead to allergic reactions. Information on the regions on food allergens recognized by T cells and IgE antibodies is important in understanding the fates of food allergens after being recognized by the GALT. The structure of T and B cell epitopes on food allergens and the possibility of modulation of allergic reactions by amino-acid substituted analogs of allergen-derived peptides will also be discussed.

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Nitric oxide (NO) is produced within the airways and has a variety of actions on the airway function. Nitric oxide is a potent bronchodilator, and NO released from airway epithelial cells and inhibitory nonadrenergic non-cholinergic nerve terminals may attenuate airway hyperresponsiveness. However, a large amount of NO produced by inducible NO synthase may facilitate airway inflammation, which then leads to airway hyperresponsiveness. Although the role of NO remains controversial, the measurement of exhaled NO may well be of value in the clinical management of asthma.

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This paper presents a short overview of the diagnostics and background of type I allergy to natural rubber latex proteins and makes recommendations for preventing corresponding allergic diseases in the future. These recommendations and prevention strategies are based on the current knowledge of latex allergy presented in the literature and are addressed to legislative bodies; manufacturers; directors of hospitals; those working at nursing facilities and physicians' and dentists' practices; as well as to other health service employees. Primary prevention is the focus but advice is also given on secondary prevention. The major preventive aim is the elimination of causative protein allergens in all latex devices and thus, the minimization of latex-related health problems.

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Eosinophils are the key effector cells for allergic inflammation. In order to clarify drugs which can regulate eosinophil function, we investigated the direct effect of pemirolast potassium (anti-allergic drug) and FK506 (immunosupressant) on eosinophil degranulation and cytokine production. Eosinophil degranulation induced by granulocyte-macrophage colony stimulating factor and/or platelet activating factor was inhibited from 10^-4 to 10^-6 mol/L pemirolast (inhibitory effect 66 and 33%, respectively) and 10^-8 mol/L FK506 (inhibitory effect 45%). Pemirolast and FK506 also inhibit interleukin (IL)-8 production by eosinophil. Our data suggest that both pemirolast potassium and FK506 possess direct regulatory effects on human eosinophils and a potential to suppress allergic inflammation.

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A high molecular weight allergen, M-177, was recently discovered in the house dust mite, Dermatophagoides farinae (D. farinae). The aims of this study were to develop a conventional purification procedure for M-177 and then to analyze some of the immunochemical properties of M-177. Mite extracts obtained from purified mite bodies were a suitable material for preparing M-177, because the purified mite extract contained large amounts of M-177. The purification of this allergen from the extract was achieved by ethanol fractionation, anion exchange chromatography, and gel filtration chromatography. The purified antigen was immunochemically equivalent to that of a preparation obtained by a previous affinity method using an anti-Mag 3-immobilized column. The yield of this purification procedure was 36.8% of the initial amount of M-177 in the extract, 40-fold greater than that of the previous immunoaffinity method. Our purification method was useful for preparing this allergen. The purified M-177 reacted in skin tests in 11 of 16 mite-allergic patients, compared to 10 of 16 with Der f 2. The amount of M-177 in the purified mite extract determined by enzyme-linked immunosorbent assay inhibition was as much as 0.95% of the total protein, which was higher than the amounts of Der f 1 (0.52%) and Der f 2 (0.32%). The potent allergenic activity and large amount of M-177 in the mites indicate that it is an important mite allergen.

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This study was designed to examine the effects of adrenomedullin (AM) on airway epithelial cells. Primary cultures of guinea-pig tracheal epithelial cells and the human bronchiolar epithelial cell line NCI-H441 were used. Intracellular cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), prostaglandin E₂ (PGE₂), and stable end-products of nitric oxide were assayed. Adrenomedullin (10^-6 mol/L) stimulated cAMP production in guinea-pig epithelial cells. Indomethacin (10^-5 mol/L) significantly decreased the basal level of intracellular cAMP in guinea-pig epithelial cells, but not in NCI-H441 cells. However, AM did not stimulate production of PGE₂, a major product that can increase cAMP formation. In the case of NCI-H441 cells, AM (10^-8 - 10^-6 mol/L) did not significantly affect intracellular cGMP levels or nitrite content in conditioned medium. Adrenomedullin and calcitonin gene-related peptide (CGRP) each stimulated cAMP production in NCI-H441 cells, but AM-stimulated cAMP production was antagonized by the CGRP fragment CGRP_8-37. These findings suggest that AM stimulates cAMP production and functionally competes with CGRP for binding sites in airway epithelial cells, at least in human epithelial cells, but that it does not stimulate the release of PGE₂ and nitric oxide. Though cyclooxygenase products contribute to some extent to cAMP formation in guinea-pigs, AM independently stimulates intracellular cAMP formation in airway epithelial cells.

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To elucidate the mechanisms of cationic protein-induced airway hyperresponsiveness (AHR), the airway response to methacholine, and the concentrations of thromboxane B₂ (TXB₂) and 6-keto-PGF₁α in the bronchoalveolar lavage fluid (BALF) of guinea-pigs were measured after inhalation of poly-L-lysine (P-L-L). The airway responsiveness (AR) was evaluated by specific airway resistance. The inhalation of P-L-L significantly enhanced AR to methacholine, and increased TXB₂ and 6-keto-PGF₁α in the BALF. The enhanced AR and the increase of TXB₂ and 6-keto-PGF₁α were both significantly inhibited by pretreatment with low molecular weight heparin (LMWH; anionic protein; 10 mg/mL for 6 min inhalation). Furthermore, thromboxane (TX) synthase inhibitor (ozagrel), thromboxane A₂ (TXA₂) receptor antagonist (ONO-3708), and bradykinin B₂ receptor antagonist (BBRA; Nα-adamantaneacetyl-D-Arg [Hyp³, Thi^5,8, D-Phe⁷]-bradykinin) inhibited the cation-induced AHR. BBRA significantly inhibited the increase of those mediators in the BALF. The data suggest that TXA₂, which is newly generated by the stimulation of the bradykinin B₂ receptor after inhalation of cationic proteins, plays an important role in cationic protein-induced AHR in guinea pigs.

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The objective of this study was to identify the risk factors for sensitization to Japanese cedar pollen (JCP) and house dust mite (HDM). The purpose was to clarify how children become sensitized to JCP and HDM and to evaluate the risk factors for sensitization to those antigens. A cohort of 267 children aged 6-11 years was surveyed using a self-administered questionnaire for symptoms and environmental factors such as passive smoking and the condition of the subject's home in 1994. A serum examination of JCP- and HDM-immunoglobulin E was also conducted every year from 1994 to 1997. A total of 35% of the children were positive to JCP in the first survey and a further 19% were positive in at least one of the subsequent three annual surveys. Twenty-seven percent of the children were sensitized to HDM in the first survey and a further 12% were sensitized in at least one of the subsequent three annual surveys. The incidence of JCP sensitization in any one year was proportional to the pollen count. No other environmental factors could be associated with the prevalence of either sensitization or the incidence of JCP sensitization, but HDM sensitization was more common in less well-ventilated houses (relative risk (RR) = 3.42, 95% confidence interval (CI) = 1.0311.38) and among those who use kerosene stoves (RR = 3.42, 95% CI = 1.269.23). The susceptibility to an antigen varies continuously and cannot be divided in a dichotomous manner. The children who had already been sensitized when they were enrolled in this study were of such strong susceptibility to the antigen that they could be sensitized by the minimum exposure to the antigen regardless of the environmental factors. Those with weak susceptibility could be sensitized by an extraordinarily high exposure to the antigen or by environmental risk factors during school age.

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We reported a 15-year-old Japanese girl with possible eosinophilic pneumonia (EP) from inhaled Alternaria. She presented with a fever, cough and general fatigue and with a moderate infiltrate in the right lower to middle lung fields on a chest roentgenogram one week previously. On admission, the above infiltrate had disappeared, while a left upper infiltrate had appeared. Eosinophilic pneumonia (EP) was diagnosed by a cytological study of bronchoalveolar lavage fluid and histology of a transbronchial lung biopsy. Skin test to and specific serum IgE antibody against Alternaria were both positive. An inhaled Alternaria challenge test showed both immediate and late phase allergic reactions as evidenced by %FEV1. In addition, Alternaria was significantly detected in all places of the patient's house. Alternaria could be a causative organism of EP and should always be considered one of its etiologic agents.

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The efficacy of the addition of inhaled oxitropium bromide in combination with inhaled corticosteroids in the treatment of elderly asthmatic patients whose asthma is not well controlled was evaluated. A randomized, open-label cross-over trial comparing 4-week treatment periods with and without regular inhalation of 200 µg of oxitropium bromide four times per day was performed. Twenty-four patients (mean age ± SD: 62 ± 7 years) completed the study. The dose of beclomethasone dipropionate in this patient group was 1300 ± 800 µg/day. Forced expiratory volume in 1 second (FEV₁) was significantly improved after treatment with regular inhalation of oxitropium bromide when compared with FEV₁ after treatment without oxitropium (1.73 ± 0.60 vs 1.63 ± 0.68). Both morning and evening peak expiratory flow rates were significantly greater during the treatment period with regular inhalation of oxitropium bromide. The score for dyspnea/chest tightness was also significantly improved during the oxitropium bromide period. There was no statistically significant improvement in forced vital capacity, scores for other symptoms or the frequency of rescue inhalation of fenoterol. The results of this study demonstrated that the addition of regular inhalation of oxitropium bromide is beneficial in elderly asthmatics whose asthma is not well controlled, even when treated with high-dose inhaled steroids.

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