Cyclosporin in immunology: Past, present and future

The discovery of cyclosporin in 1972 was a major advance in immunopharmacology. Cyclosporin specifically modifies the immune response, without lymphotoxicity, and inhibits graft rejection. Cyclosporin is a cyclic peptide isolated from the fungus Tolypocladium inflatum. It acts principally on T lymphocytes by binding to cyclophilin, a member of the family of isomerases known as the immunophilins. Other immunosuppressive agents such as tacrolimus (FK-506) and sirolimus (rapamycin) also act by binding to immunophilins; the combination of cyclosporin and sirolimus has been shown to have synergistic properties. Cyclosporin has anti-inflammatory effects in chronic inflammation, and at high doses prevents chronic rejection. The future aims of immunosuppressive therapy should be to (i) induce allograft tolerance, (ii) permit discontinuation of corticosteroids, (iii) reduce adverse effects, (iv) avoid long term immunosuppression with high doses of agents, and (v) allow treatment of chronic rejection. Experimental studies with combinations of cyclosporin and other agents appear promising. Future immunosuppressive strategies will probably use successive combinations of synergistic drugs at low doses, allowing induction of allograft tolerance without serious adverse effects or the need for life-long therapy.