Matsunobu Suko

Food-dependent, exercise-induced anaphylaxis : a study on 11 Japanese cases

Eleven patients with food-dependent, exercise-induced anaphylaxis were studied. Seven patients experienced anaphylactic symptoms only after eating certain foods, such as shellfish, wheat, and grape before exercise. In the remaining four patients, no specific food could be identified, but the act of eating itself predisposed to anaphylaxis. Their anaphylactic symptoms were all clearly distinguished from cholinergic urticaria by history. Patients who developed anaphylactic symptoms before 20 years of age (N = 7) were atopic themselves or had atopic first-degree relatives. Six patients had increased serum IgE levels, and IgE antibodies against the causative food allergens were detected by the skin prick test or RAST in four cases. In contrast, patients who developed the symptoms after 30 years of age (N = 4) appeared to have a less atopic background, and IgE levels were within normal range except in one case. Three of four patients in the latter group developed symptoms after ingesting food made of wheat followed by exercise. All patients were sensitive to wheat as determined by the skin prick test. In six of 11 patients, a considerable rise in plasma histamine concentration was observed after exercise challenge with treadmill alone, and food intake followed by exercise induced a further increase in one patient.

Increased IL‐6 and IL‐8 in bronchoalveolar lavage fluids (BALF) from patients with sarcoidosis: correlation with the clinical parameters

A variety of cytokines have been implicated in the pathogenesis of pulmonary sarcoidosis, but the exact roles of IL‐6 and IL‐8 are not yet clear. We studied these cytokine levels in BALF from patients with pulmonary sarcoidosis, idiopathic pulmonary fibrosis (IPF), systemic screlosis (SSc) with interstitial lung disease and control subjects. IL‐6 and IL‐8 levels were significantly elevated in sarcoidosis, IPF and SSc with interstitial lung disease compared with control subjects. Subjects with sarcoidosis had significantly increased levels of both cytokines compared with controls when the cytokine values were corrected by the total albumin content and the two cytokine levels correlated with each other (r=0.876). BALF IL‐6 levels correlated with percent lymphocytes and percent CD3+ cells. Moreover, when sarcoidosis patients were divided into three groups, those who needed steroid therapy or had progressive disease showed increased cytokine levels in BALF over stable or improved patients. These observations suggest that locally derived IL‐6 and IL‐8 were increased in sarcoidosis and correlated with activity of this granulomatous lung disease.

Regulation of interleukin-5 production by peripheral blood mononuclear cells from atopic patients with FK506, cyclosporin A and glucocorticoid.

Upon stimulation with phorbol ester and ionomycin, peripheral blood mononuclear cells (PBMC) of atopic patients with moderate eosinophilia produced significantly higher amounts of IL-5 compared to that of normal subjects. This finding renders further support to the notion that T cell-eosinophilic inflammation plays a central role in allergic disorders. IL-5 induction in vitro was completely inhibited by immunosuppressant FK506, cyclosporin A and dexamethasone. FK506 applied in vivo effectively suppressed clinical symptoms of atopic dermatitis and IL-5 production of PBMC. FK506 and cyclosporin A may become a better therapeutic modality against allergic diseases.

Experimental hypersensitivity pneumonitis in the mouse: Histologic and immunologic features and their modulation with cyclosporin A☆

A murine model of hypersensitivity pneumonitis (HP) was established with transnasally administered Thermoactinomyces vulgaris (Tv) bacilli. Bronchoalveolar lavage (BAL) of experimental animals revealed marked increase in the total cell, lymphocyte, and macrophage numbers; the findings were similar to those in human HP. The BAL lymphocytes were mostly Thy 1.2 positive. Lyt-1 positive cells predominated Lyt-2 positive cells. Anti-Tv IgG antibodies and delayed-type hypersensitivity footpad reactions against Tv were detected in animals with HP. Cyclosporin A (CyA), a potent immunosuppressive drug, had marked effects on the development of HP in this model. When CyA was administered throughout the course of Tv inoculations, the granulomatous pneumonitis was markedly suppressed, and an increase in BAL lymphocytes, Thy 1.2 positive cells, was suppressed. When CyA was administered only during the first half period of the Tv treatment, suppression of the disease was minimal; when CyA was administered in the latter half, both the HP lesions and the increase in BAL cell lymphocyte numbers were significantly suppressed. These results indicate that a series of transnasal administration of Tv in mice may provide a good model for human HP.

T-Cell-Dependent Accumulation of Eosinophils in the Lung and Its Inhibition by Monoclonal Anti-Interleukin-5

The transnasal administration of an extract of the parasite Ascaris suum to C57BL/6 mice for 3 weeks produced marked eosinophilia in the bronchoalveolar lavage (BAL) fluid. The oral administration of ciclosporin significantly suppressed the pulmonary eosinophilia. Athymic C57BL/6-nu/nu mice failed to develop pulmonary eosinophilia. These data indicate that the pulmonary eosinophilia caused by this parasite extract is T-cell-dependent. Genetically mast-cell-deficient (WB x C57BL/6) F1-W/Wv (W/Wv) mice developed marked eosinophilia in the BAL, which shows that mast cells are not necessary in the formation of lung eosinophilia in this model. Monoclonal antimurine interleukin-5 injected intraperitoneally clearly inhibited the infiltration of eosinophils in the lung, suggesting that T-cell-derived interleukin-5 is essential.

Cellular and molecular mechanisms of IL-5 synthesis in atopic diseases: A study with allergen-specific human helper T cells ☆ ☆☆ ★

BACKGROUND Cytokines produced by helper T cells are intimately involved in chronic allergic diseases associated with eosinophilic inflammation. OBJECTIVE We investigated the production of IL-5, a potent growth factor and chemotactic factor for eosinophils, by CD4+ T lymphocytes in patients with asthma. METHODS Allergen-specific T cell clones and T cell hybridomas were established from the peripheral blood lymphocytes of patients with asthma, and the responses to various stimuli were determined. RESULTS After nonspecific stimulation, IL-5 production by CD4+ T cells from both atopic and nonatopic subjects with asthma was significantly enhanced compared with that by cells from healthy controls. Peripheral blood mononuclear cells from atopic asthma patients both proliferated and produced IL-5 after incubation with mite allergen, suggesting that mite-specific helper T cells were involved in the eosinophilic inflammation of atopic asthma. A human IL-5 promoter/enhancer luciferase gene construct transfected into IL-5-producing T cell clones was clearly transcribed after stimulation, indicating that the 515 base pair IL-5 gene segment upstream of the coding region was sufficient to respond to activating signals in human helper T cells. The same gene segment was not transcribed in IL-5-nonproducing T cell clones, suggesting that human T cell IL-5 synthesis is regulated at the transcriptional level. Experiments with T cell hybridomas confirmed these findings and suggested that a unique transcription factor may be essential for human IL-5 gene transcription. CONCLUSION Enhanced IL-5 production by helper T cells seems to cause the eosinophilic inflammation of both atopic and nonatopic asthma. Elucidation of IL-5-specific regulatory mechanisms may facilitate the development of novel treatments for allergic diseases associated with eosinophilic inflammation.

Hyposensitization to allergic reaction in rDer f 2-sensitized mice by the intranasal administration of a mutant of rDer f 2, C8/119S.

C8/119S is a mutant of recombinant Der f 2 (rDer f 2), and lacks a disulphide bond possessed by wild‐type rDer f 2. In humans and mice, C8/119S has a very weak IgE‐binding capacity compared with the wild‐type, but possesses a T cell reactivity comparable to that of the wild‐type. C8/119S may thus be a safe immunotherapeutic agent for house dust mite allergy. The aim of the present study was to evaluate whether the intranasal administration of C8/119S could suppress an immediate allergic reaction in mice sensitized with wild‐type rDer f 2, possessing an allergic activity comparable to native counterparts purified from mite extract. Seven‐week‐old male A/J mice were immunized with wild‐type rDer f 2 four times, and then intranasally administered 0.2–2 μg of wild‐type, 0.2–20 μg of C8/119S, or PBS alone, three times a week for 4 weeks. Seven days after the last administration, the mice were examined for an immediate allergic reaction. The animals administered 2 μg of C8/119S (C2.0 group) showed significantly reduced immediate bronchoconstriction provoked by the i.v. injection of 1 and 10 μg of wild‐type rDer f 2, compared with the PBS‐treated mice. Similar results were obtained when we examined mice 10 weeks after the last administration. The reactions in the other groups given wild‐type or C8/119S also tended to decrease in severity in comparison with the animals of the PBS group. The allergic phenotypes of the T cells, B cells, and basophils in the C2.0 group were shifted to that of naive mice without immunization. We conclude that C8/119S has hyposensitizing activities in mice sensitized with wild‐type rDer f 2. C8/119S may be useful for immunotherapy of house dust mite allergy.

Bronchial Responsiveness to Mite Allergen in Atopic Dermatitis without Asthma

Eight patients with atopic dermatitis (AD) without a history of asthmatic episodes and 8 patients with mite-allergic bronchial asthma (BA) were subjected to bronchial inhalation challenge with a nonspecific stimulus (acetylcholine) and an immunologically specific stimulus (house dust mite allergen). AD patients had a significantly greater concentration of IgE (p less than 0.01) and antimite IgE antibody (p less than 0.05) than BA patients. Nonspecific bronchial hyperreactivities of AD patients distributed from normal to asthmatic range. After allergen challenge, all 8 AD patients and all 8 BA patients showed an immediate asthmatic response (IAR). The mite extract concentration to induce an IAR was significantly (p less than 0.01) greater in AD patients than in BA patients. A late asthmatic response was observed in 6 out of 8 BA patients, whereas it was not observed in any AD patient. Our results showed that AD patients are less reactive to a specific mite allergen than BA patients in spite of greater concentrations of antimite IgE antibody. They suggest that this difference in the bronchial reactivity to the allergen concerns the difference in the onset of clinical symptoms and that a certain level of bronchial hyperreactivity to the allergen is a prerequisite for the development of asthmatic symptoms.

Oral Immunotherapy May Induce T Cell Anergy

Recently, the induction of T cell anergy has been considered as a sophisticated form of immunotherapy. However, the multiplicity of T cell allergen epitopes discourages the practical use of this method. Since orally administered antigen proteins are digested to peptides and absorbed into the circulation, oral administration of antigen might be an apparently primitive but practically very useful therapeutic approach. Freeze-dried body extract of Dermatophagoides farinae mite in tight capsules was orally administered at 0.5-3 mg/day to 17 adult male mite-sensitive asthmatic patients for 12 weeks. Marked and moderate improvement of clinical symptoms judged by symptom scores and peak expiratory flow was observed in 47% (8/17) of the patients. Bronchial provocation tests carried out before and after oral immunotherapy showed a statistically significant improvement especially in the late asthmatic response. The peripheral blood eosinophil count decreased significantly after oral immunotherapy. Interleukin-5 spontaneously produced by patient peripheral mononuclear cells decreased significantly (p < 0.05) after the oral immunotherapy. These results suggest that T cell anergy might be achieved by oral immunotherapy.

Allergen-Specific Human T Cell Clones Produce lnterleukin-5 upon Stimulation with the Th1 Cytokine lnterleukin-2

CD4+ T cell clones specific for Der fII (a major allergen of the house dust mite) were established from peripheral blood mononuclear cells of atopic patients. All of the T cell clones were classified as having the Th0 phenotype, since they produced both interleukin (IL)-2 and IL-4 upon stimulation. Some of the clones produced IL-5 upon antigenic stimulation. Human recombinant IL-2 induced these T cell clones to express IL-5 mRNA and produce IL-5 protein in a dose-dependent manner. IL-2 did not induce IL-4 production, indicating a discrete signal requirement for IL-4 versus IL-5 production by T cells. Moreover, IL-5 production induced by immobilized anti-CD3 monoclonal antibody was completely suppressed by the addition of anti-IL-2 monoclonal antibody, suggesting that IL-5 production, designated as a Th2-type immune response, is dependent on IL-2, a Thl cytokine. IL-2 produced at the site of allergic inflammation may contribute to IL-5 production by T cells in vivo.