Effects of cyclosporin A administered into the airways against antigen-induced airway inflammation and hyperreactivity in the rat

The immunosuppressant cyclosporin A given orally has anti-asthma properties but carries an undesirable risk of systemic effects. We administered cyclo sporin A to Brown Norway rats tither orally (p.o.) or topically by intratra cheal(i.t.) instillation into the airways before inhaled antigen. Cyclospor in A suppressed the antigen-induced accumulation of activated (CD25(+)) CD4 (+) T lymphocytes and eosinophils in the lung, interleukin-5 mRNA expressio n in lung tissue and airway hyperreactivity. Intratracheal cyclosporin A su ppressed cell accumulation at a 10-fold lower dose than that required orall y. Minimum effective doses were 3 mg kg(-1) i.t. and 30 mg kg(-1) p.o. Intr atracheal administration reduced the plasma concentration and systemic expo sure compared with an equieffective oral dose, but the reduction (4-5-fold) was not as large as anticipated. Our data suggests that although topical a dministration to asthmatics would provide some potential for an improved sa fety margin, it may not offer any major advantage over existing oral therap y. However, the data clearly demonstrate that a novel immunosuppressant wit h similar anti-inflammatory properties but reduced potential for systemic e ffects would offer an attractive therapy for severe asthma. (C) 2001 Elsevi er Science B.V. All rights reserved.