Which immunosuppressant drug acts primarily by inhibiting calcineurin and preventing the dephosphorylation of NFAT (Nuclear Factor of Activated T cells)?

Explanation

## Calcineurin Inhibitors and NFAT Signalling ### Mechanism of Tacrolimus **Key Point:** Tacrolimus (FK-506) binds to FKBP12 (FK-binding protein 12) and the resulting complex inhibits calcineurin phosphatase activity. This prevents dephosphorylation and nuclear translocation of NFAT, blocking IL-2 and other pro-inflammatory cytokine transcription. ### Comparison of Immunosuppressants | Drug | Mechanism | Target | Clinical Use | |------|-----------|--------|---------------| | **Tacrolimus** | Calcineurin inhibition | NFAT dephosphorylation | Organ transplant, autoimmune disease | | **Cyclosporine** | Calcineurin inhibition (via cyclophilin) | NFAT dephosphorylation | Organ transplant, atopic dermatitis | | **Mycophenolate mofetil** | IMPDH inhibition | Guanosine synthesis in T/B cells | Organ transplant, lupus nephritis | | **Azathioprine** | Purine antagonist | DNA synthesis | Organ transplant, autoimmune disease | | **Sirolimus** | mTOR inhibition | mTOR signalling | Organ transplant, renal cell carcinoma | **High-Yield:** Tacrolimus is 10–100 times more potent than cyclosporine on a molar basis and does not require hepatic metabolism to the same extent, making it the preferred calcineurin inhibitor in modern transplantation. **Clinical Pearl:** Tacrolimus is associated with **post-transplant diabetes mellitus (PTDM)** more frequently than cyclosporine, likely due to direct pancreatic β-cell toxicity. **Mnemonic:** **FKBP** = FK-506 Binding Protein — remember that FK-506 (tacrolimus) requires FKBP12 to exert its effect, whereas cyclosporine binds cyclophilin.