In vitro and in vivo characterization of the anti- inflammatory effects of cyclosporin A

Cyclosporin A (CsA), a cyclic undecapeptide extracted from Tolypocladium inflatum Gams, is effective in the prevention/treatment of graft rejection and in an increasing number of autoimmune and inflammatory disorders. The immunosuppressive effect of CsA was initially attributed to inhibition of lym- phokine mRNA transcription. We have demonstrated that pharmacological concentrations of CsA (10-100 ng/ml) also inhibit the in vitro immunologic release of preformed (histamine) and de novo synthesized (leukotriene C₄ and prostaglandin D₂) mediators of inflammatory reactions from human basophils and mast cells. Furthermore, the administration of a single dose of CsA (7 mg/ kg) to 8 normal donors caused a rapid and significant (20-40%) inhibition of histamine release from basophils obtained ex vivo from these subjects and challenged in vitro with anti-IgE, f-Met-Leu-Phe and A23187. The inhibitory effect of CsA peaked at 1-5 h, slowly decreased up to 13 h, and was associated with a sharp increase in blood CsA levels. Thus, CsA exerts remarkable anti-inflammatory effects on the immunologic release of mediators from human basophils and mast cells - properties that may contribute to the drug’s ther-apeutic effects.