Individual variations in lymphocyte-responses to glucocorticoids in patients with bronchial asthma: comparison of potencies for five glucocorticoids.
Glucocorticoids (GCs) are known to be effective for bronchial asthma, however, a considerable number of asthma patients fail to respond to GC despite the onset of serious side effects. Here we examined individual sensitivities to five clinically-used GCs in 40 asthma patients and 100 healthy subjects. Peripheral-blood mononuclear cells (PBMCs) were isolated from these subjects, and their in vitro sensitivities to hydrocortisone, prednisolone, methylprednisolone, dexamethasone, and betamethasone were determined with a mitogen-assay procedure. The number of PBMCs positive to IL-2 receptors (IL-2Rs) as well as soluble IL-2R (sIL-2R) levels in serum were concomitantly measured in asthma patients, and relationships between these cytokine indices and PBMC-sensitivities to GCs were also examined. Large individual variations in GC IC50s have been observed in PBMCs from asthma subjects, especially in prednisolone IC50s (ranged from 1 to 10,000 ng/ml). When compared with healthy subjects, asthma patients tend to show PBMC-resistance to prednisolone (p < 0.05). Moreover, potencies of methylprednisolone on PBMC-blastogenesis were > 10 times higher than those of prednisolone in both healthy subjects and asthmatics (p < 0.01). In asthma patients, IC50s of hydrocortisone, prednisolone and betamethasone against PBMC-blastogenesis were significantly correlated with elevated percentages of IL-2R-positive PBMCs (p < 0.05), while the IC50 of methylprednisolone showed no such correlation. sIL-2R levels did not correlate with IC50s of any of the GCs examined. Thus, the results showed that a part of asthma patients exhibited PBMC-resistance to GCs, especially to prednisolone. Methylprednisolone potency was unexpectedly higher (> 10 times) than prednisolone potency. Our results also raised the possibility that PBMC-resistance to prednisolone in asthma may correlate with an increase in IL-2R positive PBMCs.
Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Science, Hachioji, Japan. hiranot@ps.toyaku.ac.jp
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Hirano
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Homma
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Oka
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Tsushima
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Niitsuma
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Hayashi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D003907:Dexamethasone / Q000627:therapeutic use; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use; D008875:Middle Aged; D011239:Prednisolone / Q000627:therapeutic use; D015375:Receptors, Interleukin-2 / Q000097:blood*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D018927:Anti-Asthmatic Agents; D005938:Glucocorticoids; D015375:Receptors, Interleukin-2; D003907:Dexamethasone; D011239:Prednisolone; D006854:Hydrocortisone; D008775:Methylprednisolone