Immunosuppressive Drugs in Liver Transplant: An Insight

Abstract

Liver transplantation (LT) is the standard of care for end-stage liver failure and hepatocellular carcinoma. Over the years, immunosuppression regimens have improved, resulting in enhanced graft and patient survival. At present, the side effects of immunosuppressive agents are a significant threat to post-LT quality of life and long-term outcome. The role of personalized immunosuppression is to reach a delicate balance between optimal immunosuppression and minimal side effects. Today, immunosuppression in LT is more of an art than a science. There are no validated markers for overimmunosuppression and underimmunosuppression, only a few drugs have therapeutic drug monitoring and immunosuppression regimens vary from center to center. The immunosuppressive agents are broadly classified into biological agents and pharmacological agents. Most regimens use multiple agents with different modes of action to reduce the dosage and minimize the toxicities. The calcineurin inhibitor (CNI)-related toxicities are reduced by antibody induction or using mTOR inhibitor/antimetabolites as CNI sparing or CNI minimization strategies. Post-liver transplant immunosuppression has an intensive phase in the first three months when alloreactivity is high, followed by a maintenance phase when immunosuppression minimization protocols are implemented. Over time some patients achieve "tolerance," defined as the successful stopping of immunosuppression with good graft function and no indication of rejection. Cell-based therapy using immune cells with tolerogenic potential is the future and may permit complete withdrawal of immunosuppressive agents.

Keywords: AMR, Antibody-mediated rejection; APCs, Antigen-presenting cells; ATG, Anti-thymocyte globulin; CNI, Calcineurin inhibitors; CsA, Cyclosporine A; EVR, Everolimus; IL-2R, Interleukin 2 Receptor; LT, Liver transplantation; MMF, Mycophenolate mofetil; MPA, Mycophenolic acid; SRL, Sirolimus; TAC, Tacrolimus; TCMR, T-cell-mediated rejection; antimetabolites; basiliximab; calcineurin inhibitors; cyclosporine; everolimus; immunosuppression; liver transplantation; mTORi, mammalian targets of rapamycin inhibitor; mycophenolate mofetil; tacrolimus.

Figure-1

A- Pathway of immune activation of the host by donor antigens processed through host antigen-presenting cell (APC) (indirect antigen presentation) and/or donor antigens present on donor APC (direct antigen presentation). Host and donor APCs migrates to a lymphoid organ (spleen or lymph node), whereby recipient T-cells are activated and they traffic back to the allograft. Cell adhesion receptors signal circulating alloreactive T-cells to bind and infiltrate the graft where targets of alloimmunity include the biliary epithelium and endothelial cells, causing bile duct injury and endothelitis, hallmarks of acute rejection. B- Model of three signal T-cell activation (adapted with permission from Halloran et al and Wiesner RH et al¹⁵).

Figure 2

Individual immunosuppressive drugs and sites of action in the Three-Signal Model (adapted with permission from Halloran et al¹³).

Figure-3

Newer immunosuppressant drugs: Mechanism of action (adapted with permission from Wong TC et al⁸⁹).