In solid organ transplantation, calcineurin inhibitors (tacrolimus, cyclosporine) prevent acute rejection by which primary mechanism?

• A Inhibiting mTOR pathway, preventing T-cell proliferation in G1 phase
• B Depleting circulating T-lymphocytes by complement-mediated lysis
• C Blocking co-stimulatory CD28-B7 signaling, inducing T-cell anergy
• D Binding to intracellular immunophilins and inhibiting calcineurin phosphatase, preventing IL-2 transcription ✓

Explanation

Calcineurin inhibitors (tacrolimus binds FKBP12; cyclosporine binds cyclophilin) form drug-immunophilin complexes that inhibit calcineurin phosphatase, preventing dephosphorylation and nuclear translocation of NFAT (nuclear factor of activated T-cells), thus blocking IL-2 gene transcription — the primary growth factor for T-lymphocyte proliferation. mTOR inhibitors (sirolimus, everolimus) act downstream in the IL-2 receptor signaling pathway at G1/S phase. CD28 blockade is the mechanism of belatacept.

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

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