Glucocorticoid resistance in chronic asthma. Peripheral blood T lymphocyte activation and comparison of the T lymphocyte inhibitory effects of glucocorticoids and cyclosporin 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Corrigan
C J
CJ
Department of Allergy and Clinical Immunology, National Heart and Lung Institute, Brompton Hospital, London, England.
Brown
P H
PH
Barnes
N C
NC
Tsai
J J
JJ
Frew
A J
AJ
Kay
A B
AB
D000328:Adult; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D002908:Chronic Disease; D016572:Cyclosporine / Q000494:pharmacology*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005938:Glucocorticoids / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D007376:Interleukin-2 / Q000032:analysis; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000737:chemistry / Q000187:drug effects / Q000276:immunology
D005938:Glucocorticoids; D007376:Interleukin-2; D007371:Interferon-gamma; D016572:Cyclosporine