Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma:effect on mucosal inflammation and in vitro sensitivity to glucocorticoidsof mitogen-induced T-cell proliferation

The authors have investigated whether the steroid-sparing effect of methotr exate (MTX) in severe orally glucocorticoid-insensitive asthmatics may be a ccounted for by the ability of this drug to increase the T-cell responsiven ess sensitivity to dexamethasone in vitro. In addition the authors have inv estigated whether low-dose MTX treatment is associated with anti-inflammato ry effects in peripheral blood and the bronchial mucosa. In eight patients with severe atopic asthma, using greater than or equal to 15 mg.day(-1) prednisolone, the inhibitory effect of dexamethasone on mito gen stimulated peripheral blood mononuclear cells (PBMC) in vitro was teste d before and after 8 weeks of uncontrolled treatment with MTX. Endobronchia l biopsies were taken before and after MTX therapy in seven subsequent pati ents, and analysed using immunohistochemistry. In eight patients, serum was drawn for measuring levels of free interleukin (IL)-8. The in vitro sensitivity of PBMC to dexamethasone (at 1.6X10(-9) and 3.2X10 (-10) mol.L-1) was significantly lower in the asthmatics before treatment w hen compared with the control subjects (p=0.03 and =0.001) but increased si gnificantly after MTX treatment (p=0.04 and =0.02) to normal responsiveness . This was not associated with a decrease in peripheral blood T-cell number s or activation. Except for a significant increase in the numbers of CD3+ ( p=0.04), no significant numerical changes in activated T-cells, eosinophils , or mast cells were found (p>0.05). However, MTX treatment was associated with a significant fall in serum levels of free IL-8 (p=0.03). It is hypothesized that the steroid-sparing effect of methotrexate originat es from increased sensitivity of lymphocytes to the inhibitory effects of g lucocorticoids. The absence of an inhibitory effect on inflammatory cells i n blood and mucosa suggests that this effect is achieved by modulating cell function rather than cell number.