IMMUNOMODULATION BY THEOPHYLLINE IN ASTHMA

Theophylline is the most widely used anti-asthma drug worldwide and is classified as a bronchodilator, although there is increasing evidence that it may have immunomodulatory effects. We have investigated the effects of theophylline withdrawal under placebo control in 27 asthmatic patients (25 to 70 yr) treated with long-term theophylline who were also treated with high dose inhaled corticosteroids. We measured asthma symptoms (diary card), lung function (spirometry and home records of peak expiratory flow), and peripheral leukocyte populations using dual color flow cytometry. In eight of these patients, we examined fiberoptic bronchial biopsies by immunocytochemistry. We also studied peripheral blood lymphocytes in eight asthmatic patients who have never received theophylline. Mean steady state plasma theophylline concentrations during theophylline therapy were 8.6 +/- 0.9 mg/L. Theophylline withdrawal was associated with a significant increase in asthma symptoms, particularly at night, and a fall in spirometry and morning peak flow. This was accompanied by a significant fall in peripheral blood monocytes (CD14(+), activated CD4(+) T-lymphocytes (CD4(+)/CD25(+)) and activated CD8(+) T-cells (CD8(+)/HLA-DR(+)) in patients with a plasma theophylline > 5 mg/L. The lymphocyte populations in theophylline-naive patients were similar to those found after theophylline withdrawal. Bronchial biopsies showed a mirror image of the peripheral blood with an increase in CD4(+) and CD8(+) lymphocytes in the airway. Chronic treatment with theophylline, even at low plasma concentrations, controls asthma symptoms and has effects on T-lymphocyte populations in the peripheral blood which are the inverse of those observed in the airways. This indicates that theophylline has immunomodulatory effects and that its place in asthma therapy should be reassessed.