Low-dose theophylline modulates T-lymphocyte activation in allergen-challenged asthmatics

Jaffar, ZH; Sullivan, Paul; Page, Clive; Costello, John

doi:10.1183/09031936.96.09030456

Cited by 70 publications

(34 citation statements)

References 37 publications

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“…Values are calculated as 100 -(cytokine expression with PHA/PMA and dexamethasone/cytokine expression with PHA/PMA only)6100. the number of CD4+ lymphocytes in bronchoalveolar lavage (BAL) fluid and a corresponding elevation of these cells in peripheral blood [27]. Moreover, the authors in the latter study [27] found that theophylline therapy appeared to be associated with a reduction in the absolute numbers of BAL CD4+ T-cells expressing activation markers but not a decrease in the proportion of these cells. In other words, the drug may have modulated the movement both of activated and nonactivated lung CD4+ Tcells rather than acting directly to inhibit the activated status of CD4+ cells.…”

Section: ±10mentioning

confidence: 81%

Effects of theophylline, dexamethasone and salbutamol on cytokine gene expression in human peripheral blood CD4+ T-cells

Choy¹,

Ko²,

Li³

et al. 1999

Eur Respir J

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CD4+ T-cells are considered as pivotal in orchestrating the airway inflammation in asthma through the actions of their cytokines. Current hypothesis suggests that the anti-asthma effect of theophylline may be due to its anti-inflammatory actions, although the exact mechanisms remain unclear.The in vitro effect of theophylline on cytokine gene expression in peripheral blood CD4+ T-cells in normal subjects was compared with that of dexamethasone and salbutamol. CD4+ T-cells were cultured with phytohaemagglutin and phorbol myristate acetate in the presence of different concentrations of theophylline (10 -8 ±10 -3 M or 0.0018±180 mg . mL -1 ) in one group of subjects (n=8), dexamethasone (10 -9 ±10 -6 M or 0.39±390 ng . mL -1 ) in a second group (n=8) and salbutamol (10 -9 ±10 -4 M or 0.00058±58 mg . mL -1 ) in a third group (n=8). Gene expression of interleukin (IL)-3, IL-4, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon (IFN)-c was semiquantified by reverse transcription-polymerase chain reaction.Suppressed expression of IL-3 (36.9%), IL-4 (38.8%), GM-CSF (24.6%) and IFN-c (37.7%), but not of IL-5, was only seen with theophylline at a concentration of 10 -3 M (180 mg . mL -1 ) (p<0.05) and not at lower concentrations. In contrast, dexamethasone caused a dose-dependent suppression of transcription of all cytokines, with 39.5% for IL-3, 84.4% for IL-4, 40.6% for IL-5, 50.9% for GM-CSF and 31.8% for IFN-c at 10 -6 M (390 ng . mL -1 ) (p<0.05±0.001). Salbutamol did not suppress gene expression of any of the cytokines at the concentrations examined.These data suggest that cytokine gene expression of CD4+ T-cells is not affected at therapeutic concentrations of theophylline and salbutamol, but its suppression is likely to be an important mechanism underlying the therapeutic effect of corticosteroids in asthma.

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Section: ±10mentioning

confidence: 81%

Effects of theophylline, dexamethasone and salbutamol on cytokine gene expression in human peripheral blood CD4+ T-cells

Choy¹,

Ko²,

Li³

et al. 1999

Eur Respir J

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“…A small study demonstrated a partial inhibition of the LAR but little effect on the induced AHR (87). There are few studies addressing airway inflammation; however, one study showed no inhibition of allergeninduced airway eosinophilia while noting a reduction in activated T cells (88).…”

Section: Bronchodilatorsmentioning

confidence: 99%

The allergen bronchoprovocation model: an important tool for the investigation of new asthma anti‐inflammatory therapies

Gauvreau

et al. 2007

Allergy

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Allergen bronchoprovocation tests have been used for more than two decades in the investigation of respiratory allergic diseases such as asthma and rhinitis. These bronchial challenges are now well standardized and can offer key information on the therapeutic potential of new agents and on their anti‐inflammatory effects on the airways. Both standard and low‐dose allergen provocations are safe when performed by experienced investigators and do not lead to persistent worsening of asthma or change in airway function. The evaluation of new therapeutic agents by these methods can also provide important information on the mechanisms of development and persistence of airway diseases.

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“…In man, theophylline inhibits the allergeninduced late asthmatic response (LAR) and associated hyperresponsiveness [5,6]. Six weeks of treatment with theophylline has been shown to reduce the number of activated eosinophils recruited to the airway following allergen challenge, and decrease the numbers of activated CD4+ cells in bronchoalveolar lavage (BAL) fluid postchallenge [7,8]. In another study, withdrawal of theophylline treatment in asthmatic patients was accompanied by a fall in activated CD4+ cells in the peripheral blood and a concomitant increase in T-cells within the bronchial epithelium [9].…”

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confidence: 99%

The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects

Harbinson

MacLeod²,

Hawksworth³

et al. 1997

Eur Respir J

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115

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Recent studies have suggested that theophylline, a nonspecific phospho-diesterase inhibitor, has useful anti-inflammatory actions in asthma. Phosphodiesterase 4 (PDE4) represents the predominant PDE isoenzyme present in inflammatory cells. PDE4 inhibitors might, therefore, have beneficial effects in asthma. Sideeffects, specifically nausea, have limited the use of existing agents. CDP840 is an orally active, potent and selective PDE4 inhibitor. We have examined the effect of CDP840 on the allergen-induced asthmatic response, its possible modes of action, and its tolerability at therapeutic doses.A total of 54 patients were recruited to three double-blind, placebo-controlled studies. The first study examined the effect of CDP840 (15 mg b.i.d. for 9.5 days) on the allergen-induced asthmatic response in patients with known dual response to allergen. A second study examined the effect of CDP840 (15 mg b.i.d. for 9.5 days) on airway responsiveness to histamine. A third study examined whether single dose CDP840 (15 and 30 mg) had significant bronchodilatory effects.In all studies, CDP840 was well-tolerated, with no patients reporting nausea. CDP840 did not lead to changes in baseline forced expiratory volume in one second (FEV1) as compared to placebo. The late asthmatic response (LAR) to allergen, expressed as area under the curve at 3-8 h (AUC3-8h), was inhibited by 30% (p=0.016), an effect which persisted to the end of the observation period. The early asthmatic response (EAR) was unaffected, and there was no bronchodilatory effect at the doses used. Treatment with CDP840 did not affect bronchial hyperresponsiveness to histamine.In conclusion, CDP840 significantly attenuated the late asthmatic response to allergen challenge in the absence of any bronchodilatory or histamine antagonist effect. This suggests that CDP840 may exert its effects via an anti-inflammatory mechanism.

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Low-dose theophylline modulates T-lymphocyte activation in allergen-challenged asthmatics

Cited by 70 publications

References 37 publications

Effects of theophylline, dexamethasone and salbutamol on cytokine gene expression in human peripheral blood CD4+ T-cells

Effects of theophylline, dexamethasone and salbutamol on cytokine gene expression in human peripheral blood CD4+ T-cells

The allergen bronchoprovocation model: an important tool for the investigation of new asthma anti‐inflammatory therapies

The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects

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