What are the effects of Calcineurin (CN) inhibitors, such as Cyclosporin (Cyclosporine) and Tacrolimus, on the immune system?

From the Guidelines

Calcineurin inhibitors, such as Cyclosporin and Tacrolimus, significantly suppress the immune system by inhibiting the enzyme calcineurin, which prevents T-cell activation and proliferation, thereby reducing the risk of organ rejection, but also increasing the risk of nephrotoxicity, hypertension, neurotoxicity, and other side effects 1. The two main calcineurin inhibitors are tacrolimus (Prograf, FK506) and cyclosporine (Neoral, Sandimmune, Gengraf). These medications work by inhibiting the enzyme calcineurin, which prevents T-cell activation and proliferation, thereby suppressing the immune response.

Key Points

• Tacrolimus is typically dosed at 0.1-0.15 mg/kg/day divided into two doses, while cyclosporine is usually started at 8-12 mg/kg/day divided into two doses, with subsequent dosing guided by therapeutic drug monitoring 1.
• Common side effects include nephrotoxicity, hypertension, neurotoxicity, hyperkalemia, hyperglycemia, and increased risk of infections and malignancies.
• Regular monitoring of drug levels is essential as these medications have narrow therapeutic windows and significant drug interactions, particularly with medications metabolized by cytochrome P450 enzymes.
• Patients should maintain consistent timing with food when taking these medications, as food can affect absorption, and should be monitored regularly for renal function, electrolytes, blood pressure, and glucose levels.
• The use of tacrolimus is associated with a significant reduction in mortality, graft loss, and rejection compared to cyclosporine, making it the preferred choice for immunosuppression in liver transplant patients 1. Some of the key differences between tacrolimus and cyclosporine include:
• Tacrolimus is more frequently associated with diabetes, while cyclosporine is more commonly associated with dyslipidemia and gingival hyperplasia 1.
• Tacrolimus has a more favorable efficacy profile, with a lower incidence of acute rejection and steroid-resistant rejection 1.
• A prolonged-release formulation of tacrolimus has been developed, allowing for once-daily dosing with similar efficacy and safety to the twice-daily formulation 1.

From the FDA Drug Label

Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed, after which the phosphatase activity of calcineurin is inhibited Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB) Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony-stimulating factor Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation, as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

The effects of Calcineurin (CN) inhibitors, such as Tacrolimus, on the immune system are:

• Inhibition of T-lymphocyte activation and proliferation
• Inhibition of T-helper-cell-dependent B-cell response
• Immunosuppression 2

From the Research

Effects of Calcineurin Inhibitors on the Immune System

The effects of Calcineurin (CN) inhibitors, such as Cyclosporin (Cyclosporine) and Tacrolimus, on the immune system are multifaceted and can be understood through their mechanisms of action and the outcomes of various studies.

• CN inhibitors work by preventing the rejection of transplanted organs by inhibiting the expression of interleukin-2 in T cells and inhibiting T-cell growth and proliferation 3.
• They are potent inhibitors of calcineurin, which is crucial for the activation of T cells, a key component of the immune response 4, 5, 6.

Side Effects of CN Inhibitors

The use of CN inhibitors is associated with several side effects, including:

• Nephrotoxicity, which can contribute to allograft deterioration in the long term 4, 3, 7.
• Metabolic disorders, such as new onset of diabetes and dyslipidemia 4, 5.
• Neurotoxicity 4, 3.
• Promotion of de novo cancers 4.
• Hypertension, hyperlipidaemia, and cosmetic changes like gum hypertrophy and hirsutism, which seem to be less frequent with tacrolimus than with cyclosporine 5.

Comparison of Cyclosporine and Tacrolimus

Studies have compared the efficacy and side effects of cyclosporine and tacrolimus in immunosuppressive regimens:

• Both drugs have similar short-term patient and graft survival rates 5.
• Tacrolimus may have a lower incidence of acute rejection, especially when used with azathioprine 5.
• The choice between cyclosporine and tacrolimus may depend on individual patient risk factors, such as risk of rejection, hypertension, and hyperlipidaemia 5, 7.

Nephrotoxicity Profiles

Recent research has shown that cyclosporine and tacrolimus have distinctive nephrotoxicity profiles within renal compartments:

• Tacrolimus affects the glomerular filtration barrier more severely, with deteriorations in endothelium and podocytes 7.
• Cyclosporine affects proximal tubule epithelia more severely, with lysosomal dysfunction, enhanced apoptosis, and impaired proteostasis 7.