TY - JOUR
T1 - The effect of dexamethasone, cyclosporine, and rapamycin on T-lymphocyte proliferation in vitro
T2 - Comparison of cells from patients with glucocorticoid-sensitive and glucocorticoid-resistant chronic asthma
AU - Haczku, Angela Franciska
AU - Alexander, Andrew
AU - Brown, Peter
AU - Assoufi, Basil
AU - Li, Baiqing
AU - Kay, A. Barry
AU - Corrigan, Christopher
PY - 1994
Y1 - 1994
N2 - Inhibition of T-lymphocyte activation may provide a useful approach to the treatment of chronic severe asthma. We compared rapamycin, a novel immunosuppressive drug, with cyclosporine and dexamethasone for its effects in inhibiting proliferation of T lymphocytes from patients with glucocorticoid-resistant and glucocorticoid-sensitive asthma. Phytohemagglutinin-stimulated peripheral blood T lymphocytes from 11 patients with clinically glucocorticoid-resistant and 8 patients with glucocorticoid-sensitive chronic asthma were tested for sensitivity to these drugs in a highly reproducible proliferation assay. All drugs inhibited proliferation in a dose-dependent manner (10-6 to 10-10 mol/L). T lymphocytes from the patients with glucocorticoid-resistant asthma were significantly less sensitive (p < 0.01) to dexamethasone than those of patients with glucocorticoid-sensitive asthma over a wide concentration range. In contrast, cyclosporine and rapamycin inhibited cells from both patient groups to an equivalent extent. The presence of exogenous interleukin-2 abrogated the inhibitory effect of dexamethasone but not that of cyclosporine or rapamycin, suggesting that dexamethasone may act principally by inhibition of interleukin-2 production, whereas the latter drugs exert distinct or additional inhibitory effects. Stimulation of peripheral blood T lymphocytes with phytohemagglutinin for 24 hours before addition of the drugs abolished the inhibitory effect of dexamethasone and significantly reduced that of cyclosporine. The inhibitory effect of rapamycin was, however, unaltered. These data suggest that dexamethasone and cyclosporine exert their effects only at an early stage of T-lymphocyte activation, whereas rapamycin is able to inhibit lymphoblasts. The fact that the inhibitory mechanisms of these drugs are different might explain why cyclosporine and rapamycin are effective in inhibiting T lymphocytes from both patients with glucocorticoid-sensitive and those with glucocorticoid-resistant asthma. The data further suggest that cyclosporine and rapamycin may be effective for the therapy of glucocorticoid-resistant asthma.
AB - Inhibition of T-lymphocyte activation may provide a useful approach to the treatment of chronic severe asthma. We compared rapamycin, a novel immunosuppressive drug, with cyclosporine and dexamethasone for its effects in inhibiting proliferation of T lymphocytes from patients with glucocorticoid-resistant and glucocorticoid-sensitive asthma. Phytohemagglutinin-stimulated peripheral blood T lymphocytes from 11 patients with clinically glucocorticoid-resistant and 8 patients with glucocorticoid-sensitive chronic asthma were tested for sensitivity to these drugs in a highly reproducible proliferation assay. All drugs inhibited proliferation in a dose-dependent manner (10-6 to 10-10 mol/L). T lymphocytes from the patients with glucocorticoid-resistant asthma were significantly less sensitive (p < 0.01) to dexamethasone than those of patients with glucocorticoid-sensitive asthma over a wide concentration range. In contrast, cyclosporine and rapamycin inhibited cells from both patient groups to an equivalent extent. The presence of exogenous interleukin-2 abrogated the inhibitory effect of dexamethasone but not that of cyclosporine or rapamycin, suggesting that dexamethasone may act principally by inhibition of interleukin-2 production, whereas the latter drugs exert distinct or additional inhibitory effects. Stimulation of peripheral blood T lymphocytes with phytohemagglutinin for 24 hours before addition of the drugs abolished the inhibitory effect of dexamethasone and significantly reduced that of cyclosporine. The inhibitory effect of rapamycin was, however, unaltered. These data suggest that dexamethasone and cyclosporine exert their effects only at an early stage of T-lymphocyte activation, whereas rapamycin is able to inhibit lymphoblasts. The fact that the inhibitory mechanisms of these drugs are different might explain why cyclosporine and rapamycin are effective in inhibiting T lymphocytes from both patients with glucocorticoid-sensitive and those with glucocorticoid-resistant asthma. The data further suggest that cyclosporine and rapamycin may be effective for the therapy of glucocorticoid-resistant asthma.
KW - Asthma
KW - glucocorticoid resistance
KW - immunosuppressants
KW - T lymphocytes
KW - therapy
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U2 - 10.1016/0091-6749(94)90361-1
DO - 10.1016/0091-6749(94)90361-1
M3 - Article
C2 - 8120277
AN - SCOPUS:0028289245
VL - 93
SP - 510
EP - 519
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 2
ER -