On to the mechanism of #CNI. Calcineurin inhibitors bind to the "immunophiliins" for which they are named. Cyclosporine (CsA) binds cyclophilin and tacrolimius(FK506) binds FK binding protein.
The CNI-immunophilin complex is the superhero which then inhibits calcineurin
Meet calcineurin, whose superpower is a calcium-dependent PHOSPHATASE: enzyme that uses H2O to cleave phosphoric acid into a phosphate ion and an alcohol (read: removes phos)
Normally, calcineurin dephosphorylates NFAT - allowing it to freely swim into the nucleus.
Almost there. NFAT (nuclear factor of activated T-cells), clearly needs to be in the nucleus to activate T-cells! In the nucleus, NFAT ⬆️ transcription of genes required for T-cell activation.
With #CNI: NFAT keeps its phos, TRAPPED in cytoplasm, 🚫 T-cell activation
So let's summarize. Calcineurin inhibitors bind immunophilins, which then inhibit the phosphatase calcineurin.
NFAT then remains phosphorylated and can't get into the nucleus for the transcription of T-cell activation genes.
By interfering with NFAT signaling in pancreatic b-cells, #CNI may contribute to new diabetes mellitus after transplant. FK506 is usually more to blame than CsA - which may be explained by the higher concentration of FK binding protein in b-cells relative to cyclophilin.
There's more! Hypertrichosis associated with CsA use may be related to abnormal NFAT signaling in follicular keratoctyes. Oral CsA has even been used to treat alopecia areata!
Interestingly, FK use is associated with hair loss...though the mechanism is unknown.
Let's stop there for now, though #CNI can bombard patients with MANY toxicities including:
Acute and chronic nephrotoxicities
Numerous electrolyte abnormalities
The take home message here: it's all about the NFAT!