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Background: The essential role of Th cells and T cell cytokines in eosinophilic inflammation has been established., Methods: To determine whether Th cells are sufficient for the development of airway eosinophilic inflammation, ovalbumin-reactive murine Th clones were established and infused into unprimed mice., Results: Eosinophilic infiltration into the lung was induced upon antigen inhalation in parallel with the rise in bronchoalveolar lavage fluid (BALF) eosinophil peroxidase activity. Neither IgG, IgA, nor IgE antibodies were present in this model. Pathological examination showed swelling and desquamation of epithelial cells, mucous plugs, and goblet cell hyperplasia, all of which well resemble human asthma. Fluorescent probe labeled Th clones migrated into the lung prior to the eosinophil accumulation. Bronchial hyperresponsiveness (BHR) was clearly induced upon antigen inhalation. Anti-IL-5 monoclonal antibody abrogated the responses. Dexamethasone and cyclosporin A suppressed cytokine production by Th cells both in vitro and in vivo, BALF eosinophilia, and BHR. The number of eosinophils recovered in the BALF correlated with the intensity of BHR., Conclusion: The results clearly indicated that monoclonal Th cells are sufficient for the development of both airway eosinophilia and BHR. Agents capable of downregulating IL-5 production seem promising for the treatment of bronchial asthma.

Background: We have recently demonstrated that allergic eosinophilic inflammation is transferred to unprimed mice by infusing IL-5-producing CD4+ T cells. The contribution of mast cells to the development of eosinophilic inflammation is controversial., Methods: To clarify the possible different roles of CD4+ T cells and mast cells in eosinophilic inflammation, we compared antigen-induced airway eosinophilia between mast-cell-deficient mice (WBB6F1-W/W(v)) and their congenic normal littermates (WBB6F1-+/+)., Results: The time course study indicated that equivalent numbers of eosinophils were recruited into the airway of both +/+ and W/W(v) mice 6, 24, 96, and 216 h after antigen challenge, whereas the number of eosinophils 48 h after antigen challenge was significantly lower in W/W(v) compared to +/+ mice. Administration of either anti-CD4 or anti-IL-5 monoclonal antibody almost completely inhibited antigen-induced eosinophil recruitment in W/W(v) mice 48 h after antigen challenge. In contrast, the inhibitory effect of these antibodies in +/+ mice were partial (approximately 50% inhibition). Anti-CD4 and anti-IL-5 antibodies equally suppressed airway eosinophilia in both +/+ and W/W(v) mice 96 h after antigen challenge., Conclusion: Our study indicates that CD4+ T cells are crucially involved in the development of allergic eosinophilic inflammation, while mast cells may play a supplemental role depending on the kinetics of the response.

We have recently demonstrated that airway eosinophilic inflammation can be transferred to unprimed mice by infusion of IL-5-producing T cell clones. In this study, we investigated the effects of dexamethasone and cyclosporin A on the airway eosinophilic inflammation in mice transferred with T cell clones. An ovalbumin-reactive T cell clone, KW29, produced IL-5 as well as IL-2 and IL-4 upon stimulation with relevant antigen. Dexamethasone and cyclosporin A dose-dependently suppressed the production of these cytokines in vitro. The number of eosinophils recovered in the bronchoalveolar lavage fluid and the airway responsiveness to acetylcholine were increased in KW29-transferred mice after antigen provocation. Both responses were dose-dependently suppressed by the administration of dexamethasone or cyclosporin A in vivo. We concluded that airway eosinophilic inflammation can be controlled by agents capable of downregulating IL-5 production in T cells.

Background: The Lewis rat among highly inbred strains exhibits significant airway hyperresponsiveness (AHR) following intravenous administration of Sephadex G-200 (Sephadex). The aim of this study was to investigate the association of Sephadex-induced AHR with changes in airway inflammation in Lewis rats., Methods: A suspension (0.5 mg/ml/rat) of Sephadex was intravenously administered to male Lewis rats on days 0, 2 and 5. Measurement of airway responsiveness to serotonin, bronchoalveolar lavage (BAL) and histological study were performed on day 2-11., Results: Significant AHR induced by Sephadex was recognized on day2 (p < 0.05), and AHR reached a maximum on day 7 (p < 0.001). In the BAL study, eosinophils increased on day2 (p < 0.01) with a peak on day 5 (p < 0.05). In the histological study, we found Sephadex beads trapped in small arteries of the lung and granulomatous arteritis on day 2 or later. Pulmonary granulomas, horseshoe-shaped multinuclear giant cells, eosinophils and goblet cell hyperplasia were observed on day 2, and the degree became intense on day 5-7. GCC-AP0341 (10 mg/kg, i.p. x 3) inhibited the recruitment of eosinophils in BAL fluid and in lung tissue, but it did not inhibit AHR. The compound also inhibited pulmonary granulomas and goblet cell hyperplasia., Conclusion: The mechanism of Sephadex-induced AHR may not be directly associated with inflammatory changes such as recruitment of eosinophils, pulmonary granulomas and hyperplasia of goblet cells in rats.

Type IV phosphodiesterase (PDE IV) is expressed in many tissues including airway smooth muscle and inflammatory cells, suggesting that this isozyme has a regulatory role in the pathogenesis of bronchial asthma. We investigated the effect of a novel selective PDE IV inhibitor, T-440, on immediate asthmatic reaction (IAR), late reaction (LAR) and leukocyte infiltration into the airways after allergen challenge in guinea pigs. Inhalation of ovalbumin by sensitized guinea pigs induced an immediate increase in specific airway resistance that peaked at 15 min. LAR was only produced in combination with chronic treatment with metyrapone, an inhibitor of the biosynthesis of adrenocortical steroids, and was suppressed by administration of dexamethasone, suggesting that the expression of LAR is dependent on an intrinsic steroid hormone. These reactions were accompanied by increases in the number of eosinophils and neutrophils recovered in bronchoalveolar lavage fluid. Oral administration of T-440 significantly inhibited IAR, LAR and the infiltration of eosinophils, whereas it suppressed neutrophil accumulation with relative low potency. These findings imply that the inhibition of PDE IV activity is a reasonable target for the management of obstructive airway diseases associated with airway inflammation such as asthma.

The effect of T-440, a selective type IV phosphodiesterase (PDE IV) inhibitor on interleukin (IL)-5 production by peripheral blood mononuclear cells (PBMCs) of atopic asthmatic subjects was investigated. PBMCs produced IL 5 following challenge with specific allergen in vitro. T-440 suppressed allergen-induced IL-5 production significantly at a concentration of 1 microgram/ml. T-440 inhibited cyclic AMP-phosphodiesterase (PDE) activity in a concentration dependent manner and raised the intracellular cyclic AMP level of PBMCs significantly. Dibutyryl cyclic AMP suppressed IL-5 production by PBMCs in a similar way to T-440, suggesting that the increase of intracellular cyclic AMP caused by T-440 reduces IL-5 production. T-440 may be an effective agent to treat atopic diseases associated with eosinophilic inflammation, e.g. asthma and atopic dermatitis.