Effect of cyclosporin A on the allergen-induced late asthmatic reaction.
BACKGROUND
The allergen-induced late asthmatic reaction (LAR) is associated with mucosal inflammation involving several cell types including activated T lymphocytes and eosinophils. In contrast, the early asthmatic reaction (EAR) is considered to results from rapid allergen-induced release of bronchoconstrictor mediators from IgE sensitised mast cells. Cyclosporin A has efficacy in chronic severe corticosteroid-dependent asthma and is believed to act principally by inhibiting cytokine mRNA transcription in T lymphocytes. However, it has effects on other cell types in vitro, including the inhibition of exocytosis/degranulation events in mast cells. It was therefore hypothesised that cyclosporin A would attenuate both the EAR and LAR in subjects with mild asthma.


METHODS
Twelve sensitised atopic asthmatic subjects with documented dual asthmatic responses were studied in a double blind, placebo controlled, crossover trial. On two separate study visits subjects received two oral doses of either cyclosporin A or matched placebo before inhaled allergen challenges. The forced expiratory volume in one second (FEV1) was measured half hourly for eight hours and blood eosinophil counts were analysed three, six, and 24 hours after the challenge. Treatment effects on blood eosinophil counts as well as the EAR and LAR, respectively defined as the areas under the curve (AUC) of FEV1 changes from baseline between 0-1 and 4-8 hours after challenge, were compared by non-parametric crossover analysis.


RESULTS
Cyclosporin A reduced both the LAR (median AUC -41.9 1.h (interquartile range -82.7 to -12.4) for cyclosporin A and -84.5 1.h (-248.9 to -39.1) for placebo; p = 0.007) and the late increase in blood eosinophils (median 0.2 x 10(9)/1 (0.15 to 0.4) for cyclosporin A and 0.4 x 10(9)/1 (0.25 to 0.55) for placebo; p = 0.024) but had no effect on the EAR. The reduction of the LAR by cyclosporin A correlated significantly with prechallenge blood concentrations of cyclosporin A (r = 0.6, p = 0.028).


CONCLUSIONS
These data are consistent with the concept that cyclosporin A has anti-inflammatory actions in asthma resulting from inhibition of mRNA transcription of eosinophil-active cytokines, predominantly in T lymphocytes. Cyclosporin A, possibly in its inhaled form, or other agents which prevent cytokine gene transcription may therefore have potential in ameliorating the inflammatory component of asthma.
Sihra
B S
BS
Imperial College School of Medicine, National Heart and Lung Institute, London, UK.
Kon
O M
OM
Durham
S R
SR
Walker
S
S
Barnes
N C
NC
Kay
A B
AB
D000328:Adult; D001249:Asthma / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000097:blood / Q000627:therapeutic use*; D004311:Double-Blind Method; D004804:Eosinophils; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D006969:Hypersensitivity, Immediate / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D007166:Immunosuppressive Agents / Q000097:blood / Q000627:therapeutic use*; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged
D007166:Immunosuppressive Agents; D016572:Cyclosporine