MOLECULAR AND BIOLOGICAL ACTIONS OF CYCLOSPORINE-A AND FK506 ON T-CELL DEVELOPMENT AND FUNCTION

The microbial products cyclosporin A (CsA) and FK506 are potent immuno suppressive agents in experimental and clinical transplantation. Bindi ng of both drugs to intracellular immunophilins results in the inhibit ion of calcineurin activity and the prevention of interleukin-2 gene t ranscription and, thus, in the inhibition of T cell receptor-dependent T cell activation. CsA and FK506 also have a profound effect on the s tructure and function of the thymus with disruption of positive and ne gative selection of T cells. These influences on thymic microenvironme nt and T cell ontogeny disrupt the induction or maintenance of self-to lerance (or both) and are thus of relevance to clinical transplantatio n immunology.