What is the mechanism of action of calcineurin inhibitors?

Mechanism of Action of Calcineurin Inhibitors

Calcineurin inhibitors block the phosphatase activity of calcineurin, which impairs the activation and translocation of nuclear factors important in the transcription of interleukin (IL)-2, thereby inhibiting T-cell activation and proliferation. 1

Primary Mechanism of Action

Calcineurin inhibitors (such as cyclosporin and tacrolimus) work through the following mechanism:

1. Initial binding:

   • Tacrolimus binds to an intracellular protein called FKBP-12 2
   • Cyclosporin binds to cytoplasmic cyclophillin 1

2. Complex formation:

   • These drug-protein complexes interact with calcium, calmodulin, and calcineurin
   • This interaction inhibits the phosphatase activity of calcineurin 1

3. Downstream effects:

   • Blocked dephosphorylation and translocation of transcription factors:
     • Nuclear factor of activated T cells (NFAT)
     • Nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB) 2, 3
   • Inhibited production of multiple cytokines including:
     • IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10
     • Gamma interferon
     • Tumor necrosis factor-alpha
     • Granulocyte macrophage colony-stimulating factor 2

Cellular Impact

The inhibition of calcineurin creates deficiencies in the production of IL-2, which:

• Inhibits cell cycles necessary for proliferation of activated lymphocytes
• Blocks mobilization of cell-mediated immune responses 1
• Suppresses T-helper (Th) cell responses (both Th1 and Th2) 1
• Inhibits IL-2 receptor expression and nitric oxide release
• Induces apoptosis and production of transforming growth factor beta 2

Beyond NFAT Inhibition

Recent research has revealed that calcineurin inhibitors also:

• Prevent calcineurin-mediated dephosphorylation of LckS59, an inhibitory modification that affects TCR-proximal signaling 4
• Inhibit antigen-specific T cell/dendritic cell adhesion and clustering in lymph nodes 4
• Suppress NF-κB phosphorylation in CD3+, CD4+, and CD8+ T cells by approximately 55% 3

Additional Immunomodulatory Effects

Calcineurin inhibitors also:

• Inhibit the function of antigen-presenting cells
• Inhibit the release of mast cell mediators including histamine and prostaglandins
• Inhibit keratinocyte proliferation and cytokine secretion 1

Clinical Implications

The potent immunosuppressive effects make calcineurin inhibitors valuable for:

• Organ transplantation to prevent rejection
• Treatment of steroid-refractory acute graft-versus-host disease (aGVHD) 1
• Management of autoimmune hepatitis, especially for refractory disease 1
• Treatment of immune-mediated skin conditions like psoriasis and atopic dermatitis 1

Important Considerations

• Calcineurin inhibitors have a narrow therapeutic index requiring careful monitoring
• Major adverse effects include nephrotoxicity and hypertension 1
• They may have paradoxical autoimmune effects through impaired negative selection and apoptosis of autoreactive lymphocytes 1
• Long-term use requires monitoring for toxicities including neurotoxicity 1

Understanding this complex mechanism of action explains both the efficacy and side effect profile of these powerful immunosuppressive agents.