No abstract

Inhibition of T-lymphocyte activation may provide a useful approach to the treatment of chronic severe asthma. We compared rapamycin, a novel immunosuppressive drug, with cyclosporine and dexamethasone for its effects in inhibiting proliferation of T lymphocytes from patients with glucocorticoid-resistant and glucocorticoid-sensitive asthma.Phytohemagglutinin-stimulated peripheral blood T lymphocytes from 11 patients with clinically glucocotiicoid-resistant and 8 patients with glucocorticoid-sensitive chronic asthma were tested for sensitivity to these drugs in a highly reproducible proliferation assay. All drugs inhibited proliferation in a dose-dependent manner (10e6 to 10-l' mol/L). T lymphocytes from the patients with glucocorticoid-resistant asthma were significantly less sensitive (p < 0.01) to dexamethasone than those of patients with glucocorticoid-sensitive asthma over a wide concentration range. In contrast, cyclosporine and rapamycin inhibited cells from both patient groups to an equivalent extent. The presence of exogenous interleukin-2 abrogated the inhibitory effect of dexamethasone but not that of cyclosporine or rapamycin, suggesting that dexamethasone may act principally by inhibition of interleukin-2 production, whereas the latter drugs exert distinct or additional inhibitory effects. Stimulation of peripheral blood T lymphocytes with phytohemagglutinin for 24 hours before addition of the drugs abolished the inhibitory effect of dexamethasone and significantly reduced that of cyclosporine. The inhibitory effect of rapamycin was, however, unaltered. These data suggest that dtzcamethasone and cyclosporine exert their effects only at an early stage of T-lymphocyte activation, whereas rapamycin is able to inhibit lymphoblasts. The fact that the inhibitory mechanisms of these drugs are different might explain why cyclosporine and rapamycin are effective in inhibiting T lymphocytes from both patients with glucocorticoid-sensitive and those with glucocotiicoid-resistant asthma. The data further suggest that cyclosporine and rapamycin may be effective for the therapy of glucocotiicoid-resistant asthma. {J ALLERGY CLIN IMMUNOL 1994;93:510-19.)

Conclusions -Interleukin S is detectable in the serum ofa proportion ofboth atopic and non-atopic patients with chronic severe asthma, and concentrations in these patients were higher than in normal controls. These observations are compatible with the hypothesis that IL-5 release occurs in these patients during a period of stable asthma despite systemic glucocorticoid therapy. (Thorax 1994;49:1231-1233 There is increasing evidence that the eosinophil-rich bronchial inflammation characteristic of asthma is orchestrated, at least partly, by cytokine products of activated CD4 T lymphocytes. Of these, interleukin (IL)-5 is particularly implicated because, together with IL-3 and granulocyte/macrophage colony stimulating factor, it promotes the differentiation, priming, and survival of eosinophils in vitro.' Interleukin 5 has also been clearly implicated in the pathogenesis of asthma from in vivo studies. Increased IL-5 mRNA expression was observed in bronchial mucosa2 and in bronchoalveolar lavage fluid cells' from mild atopic asthmatics compared with controls. The degree of expression correlated with disease severity and symptomatology.We have previously shown that peripheral blood CD4 T lymphocyte activation is accompanied by raised serum concentrations of IL-5 in a proportion of both atopic and nonatopic patients with acute severe asthma, but that IL-5 was not detectable in the same patients following oral glucocorticoid therapy, or in normal controls.4 Others have reported raised plasma concentrations of soluble IL-2 receptor in oral glucocorticoid-dependent asthmatics compared with patients controlled without oral glucocorticoids, suggesting that ongoing T lymphocyte activation is associated with severe chronic disease despite maintenance prednisolone.5 The aim of this study was to investigate whether IL-5 may be implicated in the pathogenesis of oral glucocorticoid-dependent chronic severe asthma. Methods Documented chronic asthmatic subjects aged 18-65 years with FEV, and/or PEFR below 75% of the predicted value and >20% reversibility to f2 agonist were considered for the study if they required long term maintenance treatment with 5-20 mg oral prednisolone daily, in addition to maximal tolerated and effective other therapy including high dose inhaled glucocorticoids. Written informed consent was obtained from each patient and the study was approved by the ethics committee of the Royal Brompton National Heart and Lung Hospitals.A total of 1 1 men and 18 women aged 21-62 (mean 49) years who had had asthma for 5-54 (mean 29) years and had received continuous treatment with oral prednisolone for 0-5-26 (mean 9 7) years were enrolled. Mean (SE) daily dosage of prednisolone was 8-6 (0 8) mg and of inhaled glucocorticoid was 1630 (99) jg; median (range) total serum IgE concentration was 76 (6-1250) IU/ml and peripheral blood eosinophil count 0-2 (0-1 2) x 109/1. Twenty of the patients studied were atopic (as defined by one or more positive skin prick tests to 1231 on 12 May 2018 by guest. Protected by copyright.

The 147-nm gas phase photolysis of dimethylsilane yields ten retrievable products in addition to a solid polymeric material. The nature of the competing, simultaneous primary steps, their quantum yields, and secondary reactions of the primary radicals were deduced from the observed products and the effect of pressure, exposure time, added scavengers, and deuterium labeling on product yields. At least 11 primary steps are required to explain the experimental observations. The major mode of decomposition is molecular elimination and, although the 147-nm photolysis line lies in the Si-H absorption region, Si-C cleavage predominates.Three silylene diradicals, S1H2, S1HCH3, and Si(CH3)2, are implicated in the reaction. They all readily insert into the Si-H bonds of the substrate to give vibrationally excited methylated silanes but neither one reacts with nitric oxide or ethylene. The presence of primary and secondary H/D kinetic isotope effects in the primary decomposition was established by a detailed analysis of the kinetic data.