Transplantation: Mechanisms of Tacrolimus PHM142 Fall 2017 Instructor: Dr. Jeffrey Henderson Transplantation: Mechanisms of Tacrolimus Gabrielle Busque, Shreeya Thakrar, Jacqueline Chan, Charlotte Boone

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  

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 http://ib.bioninja.com.au

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

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

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

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 http://www.istockphoto.com/

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

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.

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

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