Calcineurin Inhibitor
A class of immunosuppressive drugs that block calcineurin, a phosphatase essential for T cell activation. Cyclosporine is the primary peptide-based calcineurin inhibitor, used for transplant rejection prevention and autoimmune disease treatment. Tacrolimus (a non-peptide) is the other major calcineurin inhibitor.
Technical Context
Calcineurin is a calcium/calmodulin-dependent serine-threonine phosphatase essential for T cell activation: TCR signalling → calcium influx → calmodulin binds calcineurin → calcineurin dephosphorylates NFAT → NFAT translocates to nucleus → IL-2 gene transcription → T cell proliferation. Cyclosporine mechanism: cyclosporine binds cyclophilin (an immunophilin) → cyclosporine-cyclophilin complex binds and inhibits calcineurin → NFAT remains phosphorylated in cytoplasm → IL-2 not produced → T cell activation blocked. Tacrolimus (FK506, a macrolide not a peptide) inhibits calcineurin through a different immunophilin (FKBP12) but the downstream effect is identical. Calcineurin inhibitor toxicities: nephrotoxicity (dose-dependent, both acute — afferent arteriolar vasoconstriction, and chronic — tubulointerstitial fibrosis; the major limitation of long-term use), neurotoxicity (tremor, seizures), hypertension, hyperlipidaemia, and hyperglycaemia. Therapeutic drug monitoring (trough levels) is essential for cyclosporine.