Tacrolimus

Abstract

Tacrolimus, also known as FK-506, is produced by Streptomyces tsukubaensis and was discovered in Japan in 1984. The major target of tacrolimus is the T lymphocyte, by inhibiting T cell activation and cell proliferation via suppressing production of growth factor interleukin 2 (IL-2) and subsequent downregulation of IL-2 receptor on cell surface. T cells become activated following ligation of the T cell receptor (TCR) in the immunological synapse generated by receptor-ligand interactions including MHC molecules and co-accessory molecules on antigen-presenting cells (dendritic cells, macrophages and B cells). Subsequent signalling events in T cells include activation of cytoplasmic calcineurin. Calcineurin dephosphorylates and activates the transcription factor NF-AT, which regulates the production of proteins required for T cell activation and differentiation, e.g. cytokines, in particular IL-2. This process can be inhibited by blocking the phosphatase activity of calcineurin by a complex consisting of tacrolimus bound to the immunophilin protein FKBP12 (FK-506 binding protein). This mechanism of action is similar to cyclosporine A with the only difference being the cytoplasmic binding partner. In addition to the inhibition of T cell signalling, tacrolimus appears to affect dendritic cell function by interfering with MHC class II-restricted antigen presentation after binding to another FKBP. There are various isoforms of FKBP with a cell type-specific expression pattern, which might also explain the side effect profile of tacrolimus.