In vivo effects of glucocorticoids on IgE production.

Recent in vitro investigations have demonstrated that corticosteroids in combination with interleukin-4 induce the synthesis of IgE. Corticosteroids are increasingly being used to treat the inflammatory component of asthma. This has raised concern over the potential in vivo effects of corticosteroids on IgE production and the correlation of IgE-enhancing effects with clinical effects on asthma. In this study 10 patients with asthma were given a 7-day course of 20 mg of prednisone, administered orally two times a day. All of the patients had a rise in serum IgE levels after the course of prednisone (p = 0.005). Detection of specific IgE to pollen and perennial allergens demonstrated that the rise in serum IgE was polyclonal. Peripheral blood mononuclear cells from patients treated with prednisone produced increased levels of IgE in vitro when exogenous IL-4 was added to their cultures. Peripheral blood mononuclear cells obtained from patients before and after administration of prednisone revealed a significant decrease in interferon-gamma synthesis (p = 0.005), but not in interleukin-4 (p = 0.6), after the course of prednisone. These findings were paralleled by a significant decrease in the frequency of interferon-gamma (p = 0.03), but not interleukin-4 (p = 1.0) expressing cells. Despite the increase in IgE synthesis, there was a significant increase in forced expiratory volume in 1 second after the course of prednisone (p = 0.01). These data suggest that the observed rise in IgE production associated with prednisone treatment is not clinically deleterious but reflects the immunomodulatory effects of corticosteroids on T lymphocytes.

Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy.

The current study examined whether alterations in glucocorticoid receptor (GR) binding contribute to poor response to glucocorticoid therapy in asthma. 29 asthma patients with forced expiratory volume in 1 s (FEV1) < 70% predicted were studied. Patients were classified as steroid sensitive (SS) if their morning FEV1 increased > 30% after a 1-wk course of oral prednisone 20 mg twice daily and steroid resistant (SR) if they failed to increase > 15%. PBMC obtained from these two groups, 17 SR and 12 SS, as well as 12 normal controls were analyzed. SR patients had two distinguishable GR binding abnormalities: 15 of the 17 SR patients demonstrated a significantly reduced GR binding affinity, as compared with SS patients (P = 0.0001) and normal controls (P = 0.0001). This defect was localized to T cells and reverted to normal after 48 h in culture media. However, incubation with a combination of IL-2 and IL-4 sustained this abnormality. The other two SR patients had an abnormally low GR number with normal binding affinity that was not limited to T cells. Furthermore, GR number failed to normalize after incubation in media alone or IL-2 and IL-4. Therefore, SR asthma may be due to more than one abnormality, the majority related to a reversible cytokine-induced reduction in GR binding affinity and the second related to an irreversible reduction in GR number. These findings may have important implications for the design of alternative treatment approaches for recalcitrant asthma.