A patient with acute severe ulcerative colitis not responding to IV methylprednisolone is started on cyclosporine. The mechanism by which cyclosporine suppresses T-cell-mediated colonic inflammation is:

• A Binds cyclophilin, forming a complex that inhibits calcineurin and blocks NFAT-mediated IL-2 transcription ✓
• B Binds FK-binding protein (FKBP12), inhibiting mTOR and blocking T-cell proliferation in G1 phase
• C Alkylates DNA at N7 of guanine, preventing T-lymphocyte DNA replication and clonal expansion
• D Inhibits dihydroorotate dehydrogenase, depleting pyrimidine nucleotides required for T-cell proliferation

Explanation

Cyclosporine binds to the intracellular immunophilin cyclophilin (CyP). The cyclosporine-cyclophilin complex then inhibits calcineurin, a phosphatase that normally dephosphorylates NFAT (nuclear factor of activated T cells). Inhibition of calcineurin prevents NFAT translocation to the nucleus, blocking transcription of IL-2 and other cytokines (IL-4, TNF-α) needed for T-cell activation and clonal expansion. Option B describes the mechanism of tacrolimus (FK506)—which also inhibits calcineurin but via FKBP12. Option B describes tacrolimus/sirolimus: sirolimus inhibits mTOR via FKBP12. Alkylation is the mechanism of cyclophosphamide. Dihydroorotate dehydrogenase inhibition is the mechanism of leflunomide.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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