Calcineurin inhibitors (ciclosporin, tacrolimus) prevent transplant rejection primarily by inhibiting which pathway?

• A mTOR pathway, preventing T-cell proliferation in response to IL-2
• B Calcineurin phosphatase activity, preventing NFAT dephosphorylation and IL-2 transcription ✓
• C JAK-STAT signalling downstream of IL-2 receptor
• D CD28 co-stimulatory pathway of T-cell activation

Explanation

Calcineurin inhibitors (ciclosporin via cyclophilin; tacrolimus via FKBP12) form drug-protein complexes that inhibit calcineurin phosphatase. This prevents dephosphorylation of NFAT (Nuclear Factor of Activated T cells), keeping NFAT in the cytoplasm and blocking transcription of IL-2 and other cytokines required for T-cell activation and clonal expansion. mTOR inhibitors (sirolimus, everolimus) act downstream to block IL-2-driven proliferation. Belatacept blocks CD28 co-stimulation.

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

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