In solid organ transplantation, calcineurin inhibitors (tacrolimus, cyclosporine) act on which intracellular target to prevent T-cell activation?
- A mTOR, blocking IL-2 receptor signaling downstream
- B Inosine monophosphate dehydrogenase (IMPDH), depleting guanosine nucleotides
- C Calcineurin phosphatase, preventing dephosphorylation of NFAT and subsequent IL-2 gene transcription ✓
- D Purine synthesis de novo pathway, arresting T-cell proliferation
Explanation
Tacrolimus (FK506) and cyclosporine bind intracellular immunophilins (FKBP-12 and cyclophilin respectively), and the drug-immunophilin complex inhibits calcineurin phosphatase. Calcineurin normally dephosphorylates NFAT (nuclear factor of activated T cells), allowing it to enter the nucleus and drive IL-2 transcription. Blockade prevents IL-2 production and T-cell proliferation. mTOR is the target of sirolimus/everolimus. IMPDH is inhibited by mycophenolate. De novo purine synthesis is blocked by azathioprine (via 6-mercaptopurine). Understanding these distinct mechanisms explains why combinations such as tacrolimus + mycophenolate have synergistic immunosuppression.
Reference: Bailey & Love's Short Practice of Surgery, 27th ed.
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