From the Guidelines
Tacrolimus works by inhibiting calcineurin, a phosphatase enzyme that plays a crucial role in T-cell activation, thereby reducing the immune response responsible for organ transplant rejection and autoimmune conditions. This mechanism is supported by the study published in the Journal of Hepatology in 2016 1, which highlights the importance of calcineurin inhibition in preventing IL-2 gene transcription and T cell IL production.
Key Points
- Tacrolimus binds to FK-binding proteins (FKBPs), particularly FKBP-12, forming a complex that inhibits calcineurin 1.
- This inhibition prevents the dephosphorylation and nuclear translocation of nuclear factor of activated T-cells (NFAT), a transcription factor necessary for the production of interleukin-2 (IL-2) and other cytokines essential for T-cell proliferation and immune response.
- By blocking this pathway, tacrolimus effectively suppresses T-cell activation and proliferation, making it particularly useful in preventing cell-mediated rejection.
- The study published in the American Journal of Transplantation in 2009 1 also supports the use of tacrolimus as an immunosuppressant, highlighting its effectiveness in preventing organ transplant rejection.
Mechanism of Action
The mechanism of action of tacrolimus involves the inhibition of calcineurin, which is a pivotal enzyme in T cell receptor signalling 1. This inhibition prevents the production of IL-2 and other cytokines, thereby reducing the immune response responsible for organ transplant rejection and autoimmune conditions.
Clinical Implications
The clinical implications of tacrolimus's mechanism of action are significant, as it allows for the prevention of organ transplant rejection and the treatment of autoimmune conditions such as atopic dermatitis. The study published in the Journal of Hepatology in 2016 1 highlights the importance of tacrolimus in preventing acute rejection and reducing the incidence of post-transplant diabetes mellitus.
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 mechanism of action of tacrolimus is through the inhibition of calcineurin, which prevents the activation of T-lymphocytes and B-cells, resulting in immunosuppression. The key steps in this process are:
- Binding to FKBP-12
- Inhibition of calcineurin phosphatase activity
- Prevention of NF-AT and NF-κB translocation
- Inhibition of cytokine expression and production
- Inhibition of IL-2 receptor expression and nitric oxide release
- Induction of apoptosis and production of transforming growth factor beta 2
From the Research
Mechanism of Action of Tacrolimus
The mechanism of action of tacrolimus involves the inhibition of the expression of interleukin-2 in T cells, which in turn inhibits T-cell growth and proliferation 3, 4. This is similar to the mechanism of action of cyclosporine, but tacrolimus has been shown to be a more potent immunosuppressant 4.
Key Features of Tacrolimus
- Tacrolimus is a macrolide antibiotic with potent immunosuppressive properties 4
- It is metabolized solely in the liver and the metabolites are primarily excreted in the bile 4
- The elimination half-life of tacrolimus is approximately 8.5 hours, and is prolonged in hepatic dysfunction 4
- Tacrolimus has shown efficacy in the prophylaxis of allograft rejection in both animals and human clinical trials 3, 4
Effects on T Cells
- Tacrolimus inhibits the expression of interleukin-2 in T cells, which inhibits T-cell growth and proliferation 3, 4
- It also decreases T-cell proliferation, activation marker expression, and IL-2 protein expression in vitro 5
- The sensitivity of whole-blood T lymphocytes to tacrolimus can vary between individuals, with some individuals showing marked suppression of IL-2 mRNA expression and others showing variable tacrolimus sensitivity 5