GLUCOCORTICOID RESISTANCE IN CHRONIC ASTHMA - PERIPHERAL-BLOOD LYMPHOCYTE-T ACTIVATION AND COMPARISON OF THE LYMPHOCYTE-T INHIBITORY EFFECTS OF GLUCOCORTICOIDS AND CYCLOSPORINE-A

A total of 37 chronic severe asthmatic patients with documented reversible airways obstruction were classified as glucocorticoid sensitive or resistant according to changes in the FEV1 following a course of oral prednisolone. The phenotype and expression of activation molecules on peripheral blood T lymphocytes from these patients just before the course of prednisolone were studied using flow cytometry. The resistant patients had significantly elevated percentages of T lymphocytes expressing the activation molecules IL-2R and HLA-DR compared to the sensitive patients. There were no differences between the patient groups in the percentages of peripheral blood T lymphocytes expressing the phenotypic markers CD4 and CD8. Peripheral blood mononuclear cells (PBMC) from 29 patients were cultured in vitro with the T lymphocyte mitogen PHA in the presence or absence of dexamethasone or cyclosporin A. Dexamethasone (10(-7) mol/L) significantly inhibited the proliferation of T lymphocytes from the sensitive but not the resistant asthmatic subjects. In contrast, cyclosporin A (500 ng/ml) inhibited proliferation of T lymphocytes from both the sensitive and the resistant asthmatic subjects, although the effect was less marked in the latter group. Inhibition of elaboration of interleukin-2 and interferon-gamma by mitogen-stimulated T lymphocytes from sensitive and resistant asthmatic patients was also studied. Dexamethasone (10(-7) mol/L) significantly inhibited the production of interleukin-2 and interferon-gamma by proliferating T lymphocytes isolated from the glucocorticoid-sensitive but not the resistant chronic asthmatic patients. Cyclosporin A (500 ng/ml) inhibited the elaboration of both lymphokines by T lymphocytes derived from both patient groups. These observations demonstrate that ongoing T lymphocyte activation can be detected in the peripheral blood of chronic asthmatic patients who are receiving glucocorticoids but not demonstrating clinical improvement. They also provide further evidence that clinical glucocorticoid sensitivity in asthma correlates with the degree of inhibition of T lymphocyte function by glucocorticoids in vitro. This suggests that activated T lymphocytes may be one target for glucocorticoid therapy in this disease, with the implication that alternative anti-T lymphocyte drugs, such as cyclosporin A, may be of therapeutic value in glucocorticoid-resistant asthmatic patients.