Calcineurin inhibitors (cyclosporine and tacrolimus) are used for immunosuppression after solid organ transplantation. What is the mechanism of action of cyclosporine?

• A Blocks mTOR pathway, inhibiting T-cell proliferation in response to IL-2
• B Binds cyclophilin, and the complex inhibits calcineurin, preventing IL-2 gene transcription ✓
• C Blocks IL-2 receptor (CD25), preventing T-cell activation signal 3
• D Inhibits inosine monophosphate dehydrogenase (IMPDH), reducing purine synthesis

Explanation

Cyclosporine binds to the cytoplasmic protein cyclophilin; the cyclosporine-cyclophilin complex then inhibits calcineurin (a phosphatase). Calcineurin normally dephosphorylates NFAT (nuclear factor of activated T-cells), allowing it to enter the nucleus and transcribe the IL-2 gene. By blocking calcineurin, cyclosporine prevents IL-2 production and T-cell activation and proliferation. Tacrolimus has a similar mechanism via FK-binding protein (FKBP12). Sirolimus/everolimus blocks mTOR. Basiliximab blocks IL-2 receptor. Mycophenolate blocks IMPDH.

Reference: Bailey & Love's Short Practice of Surgery, 27th ed.

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