In solid organ transplantation, tacrolimus (FK506) exerts its immunosuppressive effect through which specific mechanism?
- A Binds FK-binding protein 12 (FKBP12); the complex inhibits calcineurin, preventing NFAT dephosphorylation and IL-2 transcription ✓
- B Inhibits inosine monophosphate dehydrogenase, depleting guanosine nucleotides in T cells
- C Blocks CD28-B7 co-stimulatory signaling between T cells and antigen-presenting cells
- D Inhibits mTOR complex 1 (mTORC1), arresting T cell cycle progression from G1 to S phase
Explanation
Tacrolimus binds to the intracellular immunophilin FKBP12 (FK506-binding protein). The tacrolimus-FKBP12 complex inhibits calcineurin (a calcium-calmodulin-dependent phosphatase), which normally dephosphorylates NFAT (nuclear factor of activated T cells), allowing NFAT to translocate to the nucleus and drive IL-2 transcription. By inhibiting calcineurin, tacrolimus prevents IL-2 production and T cell activation and proliferation. Mycophenolate mofetil inhibits IMPDH. Belatacept blocks CD28-B7. Sirolimus (rapamycin) inhibits mTOR via FKBP12 but a different downstream target than tacrolimus.
Reference: Bailey & Love's Short Practice of Surgery, 27th ed.
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