Allergen-specific Th2 cells from atopic individuals generally belong to the T helper 2 (Th2) subset producing, among other cytokines, high levels of IL-4, IL-5 and IL-13, but low levels of IL-2 and IFN-γ following activation. Both IL-4 and IL-13 induce IgE synthesis, which is inhibited by IFN-γ. IL-4, but not IL-13, also directs differentiation of naive CD4+ T cells into Th2 cells. Furthermore, IL-5 induces the differentiation of eosinophils and eosinophilia, whereas IL-3, IL-4 and IL-10 produced by Th2 cells, synergize with c-kit ligand in promoting mast cell growth. These observations indicate that allergy is a Th2 cell disease, and that targeting of allergen-specific Th2 cells may provide an efficient way to intervene in allergic inflammation. Three different approaches aimed at inhibiting the function or differentiation of allergen-specific Th2 cells are discussed. It is shown that an IL-4R and IL-13R antagonist inhibits IL-4-driven Th2 cell differentiation and human IgE production both in vitro and in SCID-hu mice. In addition, it is discussed that allergen-specific Th2 cells can be rendered anergic following stimulation with allergen-derived peptides, representing T cell activation inducing epitopes. These anergic Th2 cells fail to produce IL-4, IL-5 and IL-13, to proliferate, and to provide help to B cells for IgE synthesis after rechallenge with allergen- and antigen-presenting cells. Finally, it is shown that IL-4-driven allergen-specific Th2 cell differentiation can be redirected into a Th0 and Th1 cell differentiation pathway by stimulating these IL-4-driven allergen-specific Th cell populations in the presence of IL-12, or by co-stimulating these cells via a novel T cell receptor, designated signalling lymphocyte activation molecule (SLAM). The clinical implications of these approaches are discussed.
Theophylline has been used in the treatment of airway diseases, for more than 50 years with benefit thought to be derived from its ability to elicit bronchodilatation. Recent evidence has, however, suggested that theophylline possesses anti-inflammatory activity. The molecular mechanism of action remains unclear, although inhibition of the phosphodiesterase (PDE) enzyme, an enzyme which catalyzes the breakdown of cAMP and cGMP, has been proposed. Theophylline is a relatively weak inhibitor of PDE although there is evidence to suggest that PDE activity is elevated in leukocytes from patients with atopic disease. Thus, an altered responsiveness to PDE inhibitors may partly explain the mechanism of action of theophylline. The PDE enzyme exists as the least of seven different isoenzyme forms which can be characterized on the basis of a number of criteria including substrate specificity, sensitivity to selective inhibitors and the effect of allosteric modulators. The type IV isoenzyme is the predominant isoenzyme in inflammatory cells although it exists together with the type III isoenzyme in T-lymphocytes. There is considerable evidence from in vitro and in vivo studies suggesting that selective PDE IV inhibitors have anti-inflammatory activity. The following article reviews these studies, together with clinical studies demonstrating that theophylline has anti-inflammatory activity.
A questionnaire on the treatment of asthma was sent to 586 physicians. They consisted of specialists authorized by the Japanese Society of Allergology and councillors of the society who were treating patients with bronchial asthma. Of the total of 306 (52%) respondents, 241 replied to questions relating to adult asthma and 129 to questions relating to childhood asthma (including duplicate replies). For acute treatment, methods most commonly selected by physicians were, in increasing order of popularity, for adults: parenteral aminophylline, oxygen inhalation, parenteral steroids and parenteral adrenaline; for schoolchildren (6-16 years): parenteral aminophylline, inhaled β-stimulant, oxygen inhalation, inhaled β-stimulant + disodium cromoglycate (DSCG), parenteral steroids; and for infants (≤5 years): inhaled β-stimulant, parenteral aminophylline, oxygen inhalation, inhaled β-stimulant + DSCG and parenteral steroids. For maintenance treatment, methods most commonly selected by physicians were, in increasing order of popularity, for adults: oral administration of sustained-release theophylline, inhaled steroids and DSCG inhalation; for schoolchildren (6-16 years): DSCG inhalation, oral administration of sustained-release theophylline, oral administration of antiallergic agent preparation and β-stimulant + DSCG inhalant. The questionnaire results clearly showed that different drugs were selected for the treatment of asthma in adults, schoolchildren and infants.
Histamine plays an important role in the development of asthmatic symptoms. Diamine oxidase (DAO histaminase), which inactivates histamine, is located in the intestine and kidney and is released into plasma. Plasma DAO activity in asthmatic children was measured by a recently developed high performance liquid chromatographic method using histamine as the DAO substrate. Diamine oxidase activity was higher in severely asthmatic children than in those with mild asthma. A time course study during the acute exacerbation phase revealed that DAO activity rose during acute asthmatic attacks and then decreased gradually over several days. Although the mechanisms of plasma DAO activity increase during acute asthmatic attacks could not be explained, data showed that plasma DAO activity is an important index of histamine metabolism in asthmatics and may relate to some mechanisms of acute exacerbation of airway inflammation. Consequently, fluctuations in plasma DAO can be used as one of various indices of instability in management of asthma.
Atopic diseases in children often develop in series and atopic dermatitis usually occurs first. To clarify the serial development of atopic dermatitis and bronchial asthma in atopic children in Japan, the present and/or past history of atopic dermatitis in patients with bronchial asthma was examined. Patients (n=280) with bronchial asthma in five prefectures in Japan were examined at a mean (±SD) age of 8.2 (±4.5) years and asked about prior and/or concurrent atopic dermatitis. The mean (±SD) age of the patients at the onset of bronchial asthma was 3.0 (±2.3) years. There was a present or past history of atopic dermatitis in 54% of the patients, and 47 and 72% of those had developed atopic dermatitis within the first 6 and 12 months of life, respectively. In 86% of the patients with both bronchial asthma and atopic dermatitis, atopic dermatitis developed first. The mean (±SD) duration from the onset of atopic dermatitis to the time of examination was 7.3 (±4.3) years, and atopic dermatitis had been cured in 49% of the patients within this period regardless of the therapy used. Patients with atopic dermatitis had a higher rate of atopic dermatitis in their families (43%) compared with those without atopic dermatitis (23%). These data show that half of the children with bronchial asthma first develop atopic dermatitis in early infancy and that it is relatively easily cured.
The efficacy and safety of budesonide nasal powder (Rhinocort Turbuhaler®) in seasonal allergic rhinitis when given only at the onset of symptoms during the pollen season or when also given before the pollen season, were compared. The study was carried out in 364 patients from 14 centres in Italy as a randomized, double-blind, parallel-group, placebo- controlled comparison of five alternative treatment regimens given for 4 weeks during the pre-pollen and early pollen season (PPS) and for 6 weeks during the pollen season (PS). It was concluded that either 200μg or 400μg of budesonide given once daily PPS provides significant control of symptoms experienced during PPS. The 400μg dose, however, also provides additional prophylactic protection against symptoms during early PS. When the pollen season is established, the dose of budesonide may be reduced to 200μg.
We examined the IgE and IgG antibody responses in Japanese cedar pollinosis patients before and after the pollination season for 2 years. The sera from 90 patients in 1990 and 87 in 1991, living in five regions in the Tokyo area, were obtained before and after the pollination season. In all patients, changes (increase then decrease) in specific IgE levels were detected after natural pollen exposure. Total IgE and specific IgG concentrations also changed. However, the degree of change in specific IgE was greater than those in total IgE and specific IgG. Then, the geometric means of specific and total IgE levels were compared among the five regions. These levels were found to be highest in the region where the pollen count was the highest. These findings suggest that IgE antibody production is more stimulated after natural pollen exposure compared to IgG antibody production, and is dependent on the amount of allergens.