1 To clarify the involvement of Th2 responses in the development of allergen-induced airway remodelling, we investigated the e ect of anti-CD4 monoclonal antibody (mAb) and anti-CD8 mAb, and the responses of IL-4 gene-knockout (KO) mice in a murine model of allergic asthma. 2 Mice were immunized twice by intraperitoneal injections of ovalbumin (OA), and exposed to aeroallergen (OA, 1% w v 71 ) for 3 weeks. Twenty-four hours after the ®nal challenge, airway responsiveness to acetylcholine was measured, and bronchoalveolar lavage (BAL) and histological examinations were carried out. 3 Anti-CD4 mAb (1 mg kg 71 ) clearly inhibited allergen-induced increases in airway responsiveness to acetylcholine, the number of eosinophils in BAL¯uid, serum OA-speci®c IgE levels, IL-13 and transforming growth factor-b1 levels in BAL¯uid, and amount of hydroxyproline in the lung by 100, 99, 100, 100, 84, and 60%, respectively. Furthermore, the antibody (1 mg kg 71 ) also attenuated allergen-induced goblet cell hyperplasia in the epithelium and subepithelial ®brosis by 72 and 83%, respectively. In contrast, anti-CD8 mAb (1 mg kg 71 ) showed no e ect on each parameter. Furthermore, all these parameters were attenuated in IL-4KO mice by 57, 93, 100, 45, 84 and 60%, and also 72 and 83%, respectively. 4 These ®ndings suggest that Th2 responses play a critical role for the development of allergeninduced airway remodelling, and that the inhibition of Th2 responses, e.g. using anti-CD4 mAb, is a therapeutic approach for the treatment of airway remodelling in asthma.

Here we report the cellular arachidonate (AA)-releasing function of group IIF secretory phospholipase A 2 (sPLA 2 -IIF), a sPLA 2 enzyme uniquely containing a longer C-terminal extension. sPLA 2 -IIF increased spontaneous and stimulus-dependent release of AA, which was supplied to downstream cyclooxygenases and 5-lipoxygenase for eicosanoid production. sPLA 2 -IIF also enhanced interleukin 1-stimulated expression of cyclooxygenase-2 and microsomal prostaglandin E synthase. AA release by sPLA 2 -IIF was facilitated by oxidative modification of cellular membranes. Cellular actions of sPLA 2 -IIF occurred independently of the heparan sulfate proteoglycan glypican, which acts as a functional adaptor for other group II subfamily sPLA 2 s. Confocal microscopy revealed the location of sPLA 2 -IIF on the plasma membrane. The unique C-terminal extension was crucial for its plasma membrane localization and optimal cellular functions. sPLA 2 -IIF expression was increased in various tissues from lipopolysaccharidetreated mice and in ears of mice with experimental atopic dermatitis. In human rheumatoid arthritic joints, sPLA 2 -IIF was detected in synovial lining cells, capillary endothelial cells, and plasma cells. These results suggest that sPLA 2 -IIF is a potent regulator of AA metabolism and participates in the inflammatory process under certain conditions.

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Abstract. The development of non-human primate models of asthma requires a period of time (e.g., 0.5 -1 year). To develop the models in a short period, male cynomolgus monkeys were sensitized with dinitrophenyl-Ascaris suum (DNP-As) allergen by intraperitoneal and intramuscular injection and by intratracheal inhalation. All sensitized animals developed positive intradermal skin reaction to DNP-As. Sensitization elevated allergen-specific IgE levels in serum, the number of CCR4-positive T helper lymphocytes in peripheral blood, and IL-4 and IL-5 releases from phorbol 12-myristate 13-acetate-and ionomycin-stimulated peripheral blood. In addition, allergen challenge induced increases in lung resistance, airway inflammation, and hyperresponsiveness to inhaled methacholine. Next, animals were sensitized with house dust mite extracts (HDM) under the similar procedure. In these animals sensitized with DNP-As or HDM, inhaled fluticasone propionate and oral prednisolone inhibited the allergen-induced airway hyperresponsiveness. Taken together, monkey asthma models were successfully developed by sensitization with DNP-As or HDM under a short-term protocol (within 7 weeks). These models should be useful for the evaluation of anti-inflammatory drugs for asthma treatment.

Group IID secretory phospholipase A 2 (sPLA 2 -IID), a heparin-binding sPLA 2 that is closely related to sPLA 2 -IIA, augments stimulus-induced cellular arachidonate release in a manner similar to sPLA 2 -IIA. Here we identified the residues of sPLA 2 -IID that are responsible for heparanoid binding, are and therefore essential for cellular function. Mutating four cationic residues in the C-terminal portion of sPLA 2 -IID resulted in abolition of its ability to associate with cell surface heparan sulfate and to enhance stimulusinduced delayed arachidonate release, cyclooxygenase-2 induction, and prostaglandin generation in 293 cell transfectants. As compared with several other group II subfamily sPLA 2 s, which were equally active on A23187-and IL-1-primed cellular membranes, sPLA 2 -IID showed apparent preference for A23187-primed membranes. Several human colon carcinoma cell lines expressed sPLA 2 -IID and sPLA 2 -X constitutively, the former of which was negatively regulated by IL-1. sPLA 2 -IID, but not other sPLA 2 isozymes, was expressed in human cord blood-derived mast cells. The expression of sPLA 2 -IID was significantly altered in several tissues of mice with experimental inflammation. These results indicate that sPLA 2 -IID may be involved in inflammation in cell-and tissue-specific manners under particular conditions.