The mechanisms regulating the differentiation of naive CD4 T cells into Th1/Th2 subsets have been intensively investigated in the mouse. This report summarizes the current knowledge regarding naive human CD4 T cell maturation in vitro. The Th1/Th2 dichotomy is less absolute in human than in mouse T cells; indeed, unlike their murine counterparts, human Th2 cells retain the capacity for responding to and of inducing the production of interleukin (IL)-12. When adequately stimulated, naive CD4 T cells release not only IL-2, but also high levels of type 1 cytokines (interferon (IFN)-γ, lymphotoxin and tumor necrosis factor (TNF)-α) as well as low levels of type 2 cytokines (IL-4, IL-13 and IL-10). Interleukin-4 may be produced by every single naive T cell at very low levels that are sufficient to promote the acquisition of a Th2 phenotype upon repetitive stimulation in the absence of exogenous cytokine. Interleukin-12 primes naive T cells for increased production of IFN-γ, decreased production of IL-4 and IL-5 and increased responsiveness to IL-12. The effects of IL-12 on IFN-γ and IL-5 as well as on IL-12 responsiveness are prolonged, whereas those on IL-4 are transient. However, repetitive stimulation in the presence of IL-12 leads to Th1 effectors. Thus, IL-12 is required not only for the induction but also for the development and maintenance of a Th1 response. Upon interaction with dendritic cells (DC), naive T cells produce several cytokines (IL-4, IFN-γ) and express CD40L, which triggers IL-12 production by DC. The balance between these endogenously produced cytokines determines the lymphokine-producing phenotype of primed cells, this balance depending upon the genetic background, the nature and the strength of the T-cell-receptor-mediated signal and the activation state of DC.

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The T-cell hypothesis of asthma, particularly chronic asthma, is based around the concept that the disease is ‘driven’ and maintained by the persistence of a specialized subset of chronically activated T-memory cells, sensitized against an array of allergenic, occupational or viral antigens that ‘home’ to the lung after appropriate antigen exposure or viral infection. Allergens induce a CD4 T-helper (Th) cell response, whereas viruses recognize CD8⁺ cytotoxic (Tc) cells. In the asthmatic airways there appears to be both CD4⁺ and CD8⁺ cells with a type 2 cytokine phenotype (i.e. Th2- and Tc2-types). These cells produce interleukin (IL)-5, IL-3 and granulocyte/macrophage-colony stimulating factor, which recruit, mobilize and activate eosinophils for subsequent mucosal tissue damage, and IL-4, an essential co-factor for local or generalized immunoglobulin (Ig) E production. This in turn leads to ‘eosinophilic desquamative bronchitis’ with epithelial shedding, mucus hypersecretion and bronchial smooth muscle contraction. Thus, although the eosinophil is believed to produce airway damage, function appears to be under T cell control. Support for this hypothesis includes the observations that activated T cells and their products can be identified in biopsies from the major variants of the disease (atopic, non-atopic (‘intrinsic’) and occupational asthma), the colocalization of mRNA for type 2 cytokines to CD4⁺ and CD8⁺ cells in atopic and non-atopic asthma, the presence of chronically activated cytokine-producing T cells in corticosteroid-resistant asthma, the association of disease severity with type 2 cytokines, particularly IL-5, and the efficacy of cyclosporine A in chronic steroid-dependent disease. Inhibitors and/or antagonists directed against more precise T cell-associated molecular targets hold promise for the future treatment of chronic asthma.

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Bronchial asthma (BA) often develops in children with atopic dermatitis (AD). To clarify the usefulness of AD in infants as a predictor for the later development of BA, we examined the prevalence of and the risk factors for the later development of BA in infants with AD in four prefectures in Japan. We registered 157 infants with AD (100 boys and 57 girls) for the study and 151 infants (95 boys and 56 girls) were successfully followed up for a mean duration of 1 year. Atopic dermatitis was cured and improved in 23 and 70% of the patients, respectively, during the follow-up period. Boys developed mite allergy more frequently than did girls during the follow-up period (P<0.05). Twelve boys and two girls were diagnosed as having BA during the period, without any correlation with the outcome of the AD, and 12 boys developed wheezing but were not diagnosed as having BA by a physician. Male sex, a positive family history of BA, but not that of AD, and the appearance of mite-specific IgE during the follow-up period were identified as significant risk factors for the development of BA. The combination of a positive family history of BA and mite-specific IgE and the same combination in the boys had high specificity (55 and 56%, respectively) and sensitivity (60 and 50%, respectively) as risk factors. The data suggest the involvement of genetic factors in the early development of BA in young children with AD and indicate that AD in infants and young children with these risk factors is a useful predictor for the development of BA within a short period.

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To study the function and mechanism of eosinophils via the low affinity IgE receptor (Fc∈Rll), we examined the production of O₂ metabolites by measuring the luminol-dependent chemiluminescence (LDCL) response and the generation of cysteinyl leukotrienes. Eosinophils obtained from guinea pig peritoneal fluid sensitized with horse serum were purified. Luminoldependent chemiluminescence was induced by stimulation with monoclonal anti-CD23 antibody, but not by mouse serum (controls). The mean (±SEM) value of LDCL was 20.6±1.3×10³c.p.m. This reaction consisted of an initial rapid phase and a propagation phase and ended within 10min. Guinea pig eosinophils were histochemically stained with monoclonal anti-CD23 antibody. The major product generated in the LDCL response was superoxide, as determined by the measurement of superoxide by cytochrome c reduction and the complete inhibitory effect of superoxide dismutase on the LDCL response. Pretreatment with either pertussis toxin or cholera toxin inhibited the LDCL reaction. Depletion of bivalentions by EDTA inhibited this response and the protein kinase C inhibitor D-sphingosin inhibited both 1-oleoyl-2-acetyl-glycerol-induced and Fc∈Rll-mediated LDCL. These findings suggest that the NADPH-protein kinase C pathway may be involved in the Fc∈Rll-mediated LDCL response in guinea pig eosinophils.

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Suppression of antigen-induced late airway obstruction associated with neutrophilic inflammation by selective and non-selective phosphodiesterase (PDE) inhibitors was investigated in mice. Respiratory resistance (Rrs) increased in sensitized BDF1 mice 4-6 h after antigen provocation, whereas no obvious immediate reaction was observed. This reaction was associated with marked airway neutrophilia without significant infiltration of eosinophils. A selective PDE IV inhibitor, T-440 (10-30mg/kg), and a non-selective PDE inhibitor, theophylline (10mg/kg), significantly inhibited airway obstruction and neutrophilia when administered orally. An anti-allergic drug, ketotifen (1mg/kg), caused slight inhibition of airway obstruction, whereas it did not affect airway neutrophilia. These results suggest that neutrophilic inflammation plays a role in the airway obstructive reaction and that PDE has a regulatory role in obstructive airway disease associated with airway inflammation.

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We evaluated the anti-asthmatic effects and mechanism of action of TMK-688, a potent 5-lipoxygenase inhibitor, on the dual-phase asthmatic response and on airway inflammation in conscious guinea pigs sensitized with ovalbumin (OA). TMK-688 inhibited both the immediate and the late asthmatic response (LAR) after administration of a single oral dose of 3.2 or 10mg/kg 2h before OA challenge. Pretreatment with TMK-688 also inhibited airway hyperresponsiveness to acetylcholine. The increase in eosinophils in bronchoalveolar lavage fluid and the production of reactive oxygen, an index of cell activation during LAR, was also suppressed by TMK-688. These findings suggest the following inhibitory mechanism of LAR by TMK-688: (i) a reduction of eosinophil accumulation in airways; (ii) the inhibition of the immediate asthmatic response; (iii) the inhibition of airway hyperresponsiveness; and (iv) the suppression of the generation of reactive oxygen from bronchoalveolar lavage cells.

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Scratching behavior observed after epicutaneous challenge with the antigen 2,4-dinitrofluorobenzene (DNFB) in the ear of BALB/c mice passively sensitized with anti-dinitrophenol (DNP). Immunoglobulin (Ig) E was characterized pharmacologically and compared with that caused by compound 48/80. Although DNFB application itself caused scratching behavior in non-sensitized mice, the number of scratchings apparently increased in sensitized mice from 60min after antigen application in comparison with non-sensitized control mice. Prednisolone, cyproheptadine, dibucaine and naloxone significantly inhibited the DNFB-induced scratching behavior, whereas the histamine H₁-receptor antagonists HSR-609, cetirizine and terfenadine only showed a tendency to inhibit scratching. Injection of 48/80 into the rostral part of the back also caused scratching. The first scratching was observed within 10min after injection and lasted intermittently for 30min. The 48/80-induced scratching was markedly inhibited by cyproheptadine, dibucaine and naloxone, but not by prednisolone and the histamine H₁-receptor antagonists. Ear edema caused by DNFB application in sensitized mice was markedly inhibited by prednisolone, HSR-609, cetirizine, terfenadine and cyproheptadine, whereas dibucaine and naloxone failed to affect ear edema. These results indicate that scratching behavior could be induced in mice in association with an IgE- mediated allergic cutaneous reaction and that the reaction is pharmacologically similar, but not identical, to that caused by 48/80. Although histamine is considered to participate in the formation of ear edema, it may not play an important role in the generation of scratching.

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The efficacy of oral amphotericin B (ApB) was studied in 125 cases of refractory atopic dermatitis (AD). Indications for ApB therapy were positive CAP-RAST (Pharmacia & Upjohn Co. Ltd)-class to Candida albicans and several food allergens and a high intake of sweets or alcoholic beverages together with recalcitrant symptoms of AD, such as facial erythema and eruptions refractory to topical steroids. Good or excellent results were obtained in 56.8% of 125 cases. Assessment of improvement in the 125 subjects was statistically compared with that in 55 controls who were not treated with ApB. There were no significant differences in the background between the two study groups. Cases treated with oral ApB showed significantly greater improvement (P<0.01) than did the controls, who were not treated with ApB, over 3 and 6 month periods. Treatment with ApB helped patients to discontinue or to reduce the frequency of topical steroid use or to change from high-dose steroids to lower-dose steroids. Treatment of patients with oral ApB resulted in improvements in laboratory data, including CAP-RAST to C. albicans and several food allergens. Good results were associated with restricting the intake of food allergens. A poor response was recognized in patients with a significantly high titer of CAP-RAST levels to Dermatophagoides farinae. Controlling environmental allergens and limiting exposure to food allergens was necessary to achieve success with ApB treatment.

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