Molecular and biological actions of cyclosporin A and FK506 on T cell development and function

The microbial products cyclosporin A (CsA) and FK506 are potent immunosuppressive agents in experimental and clinical transplantation. Binding of both drugs to intracellular immunophilins results in the inhibition of calcineurin activity and the prevention of interleukin-2 gene transcription and, thus, in the inhibition of T cell receptor-dependent T cell activation. CsA and FK506 also have a profound effect on the structure and function of the thymus with disruption of positive and negative selection of T cells. These influences on thymic microenvironment and T cell ontogeny disrupt the induction or maintenance of self-tolerance (or both) and are thus of relevance to clinical transplantation immunology.