The modes of action of topical cyclosporin A were studied in rabbits. Immunorejection of corneal allografts was provoked by placing the grafts eccentrically, in contact with the limbus. Topical application of cyclosporin A five times daily for 28 days prevented the rejection of corneal allografts. All grafts were rejected in the control animals. The seven rabbits of the cyclosporin A group were subsequently treated for six months with a lower dosage of cyclosporin A 1%. In six rabbits the graft remained clear. One rabbit treated with two drops a day showed an allograft reaction that could be suppressed by increasing the dosage. After six months, discontinuation of the therapy resulted in rejection of all grafts within four weeks. Cyclosporin A could be detected in the plasma and aqueous humour of both eyes at the end of the treatment, raising the question whether the immunosuppressive effect of topically applied cyclosporin A was due to local or systemic action. Cyclosporin A 1% was therefore applied to the fellow eye five times daily following transplantation, and this treatment, producing similar plasma levels of cyclosporin A, failed to delay the rejection of eccentric corneal allografts. Consequently the suppression of the allograft rejection by topical cyclosporin A is primarily a local immunosuppressive effect, though systemic influence is not ruled out.
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