1. Transplantation: Mechanisms of Tacrolimus
PHM Fall 2017
Instructor: Dr. Jeffrey Henderson
Transplantation: Mechanisms of Tacrolimus
Gabrielle Busque, Shreeya Thakrar, Jacqueline Chan, Charlotte Boone

2. Tacrolimus Immunosuppressant Calcineurin inhibitor
Clinically used primarily in transplants: liver and kidney
Gained FDA approval in 1994
Used specifically for the prophylaxis and treatment of allograft rejection
Tacrolimus > other immunosuppressants
Sigma-Aldrich, Tacrolimus, 2017  

3. What happens during a transplant?
Immune response and organ rejection
MHC Class I molecules = cell surface recognition
Highly polymorphic
Recognition of peptides by T cells
Multiple mechanisms of rejection

4. The Direct Pathway Acute graft rejection
Recognition of self vs non-self
T cells recognize alloantigens
T cells stimulated by APCs from donor
T cell activation and proliferation
Garcia et al. J Transplant, 2012

5. The Indirect Pathway T-cell recognize foreign antigens from donor
Recipient APCs present these antigens
Also leads to T-cell proliferation
Garcia et al. J Transplant, 2012

6. T Cell Activation Increase intracellular calcium
Calcineurin dephosphorylates NFAT
IL-2 is upregulated
Azzi et Al. J Immunol, 2013

7. Tacrolimus Mechanism Pentameric Complex Overall effect
FK506 Binding Protein
Ca2+
Calmodium
Cacineurin
Overall effect
Cytokine Signal Molecule inhibition
Proliferation of T cells
B cell stimulation
NK cell activity
*Exact Mechanism is not known

9. Side Effects Dose dependent CYP3A4 metabolism
Usually related to the brain and kidney due to higher concentrations of calcineurin
Nephrotoxicity
Neurotoxicity
Headache and tremor
Insomnia
Metabolic effects – diabetogenesis
Glucose intolerance
Diabetes mellitus

10. Summary
Tacrolimus is a calcineurin inhibitor immunosuppressant drug used in mainly liver and kidney transplants for prophylaxis and treatment of allograft rejection.
Mechanisms of rejection include:
The direct pathway, in which recipient T cells recognize allo-MHC antigen complexes on the surface of donor cells via their T cell receptors
The indirect pathway, in which T cells are activated through self-APCs, leading to chronic graft rejection
T-cell activation and subsequent calcineurin activation, which dephosphorylates NFAT and upregulates IL-2 transcription.
Tacrolimus functions by forming a pentameric complex including calcineurin, inhibiting its activity. The downstream effect is cytokine inhibition.
Main side effects include nephrotoxicity and neurotoxicity due to the larger concentrations of calcineurin in the kidney and brain. Metabolic effects are also possible.

11. Summary 2 Increase intracellular calcium
Calcineurin dephosphorylates NFAT
IL-2 is upregulated
Azzi et Al. J Immunol, 2013

12. Sources
National Center for Biotechnology Information. PubChem Compound Database; CID=445643, (accessed Oct. 1, 2017).
Arman, L., Vallet, M., Acharya, S., Paguaga, G., Marcotte, S., Perrier, H., & Rangwala, I. (2013). CPS. compendium of pharmaceuticals and specialties (2017 ed., Vol. 2). Ottawa, Ont.: Canadian Pharmacists Association.
Tacrolimus Monograph
Taylor, A., Watson, C., & Bradley, J. (2005). Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy. Critical Reviews In Oncology/Hematology, 56(1),
Bowman, L., & Brennan, D. (2008). The role of tacrolimus in renal transplantation. Expert Opinion On Pharmacotherapy, 9(4),
Crabtree, G. R. (2001). Calcium, calcineurin, and the control of transcription. J Biol Chem, 276(4), doi: /jbc.R
Ingulli, E. (2010). Mechanism of cellular rejection in transplantation. Pediatr Nephrol, 25(1), doi: /s x
Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; Responses to alloantigens and transplant rejection. Available from: