A Comprehensive Review of Immunosuppression Used for Liver Transplantation

Abstract

Since liver transplantation was approved for the treatment of end stage liver disease, calcineurin inhibitors (CNI's) have played a critical role in the preservation of allograft function. Unfortunately, these medications cause a variety of Side effects such as diabetes, hypertension and nephrotoxicity which in turn result in significant morbidity and reduced quality of life. A variety of newer immunosuppressants have been evaluated over the last decade in an attempt to either substitute for CNI's or use with reduced dose CNI's while still preserving allograft function However, current data does not recommend complete cessation of CNI's due to unacceptably high rates of allograft rejection. As these medications have their own unique adverse effects, a careful assessment on their risks and benefits is essential, particularly when additive or synergistic effects with CNI's may occur. Furthermore, the impact of these newer medications on the risk of hepatitis C recurrence and progression remains to be elucidated. Controlled trials are urgently required to assist transplant physicians with choosing the optimum immunosuppressive regimen for their patients. This review will discuss commonly used immunosuppressants prescribed in liver transplantation, emerging therapties and where appropriate, the impact of these medications on the recurrence of hepatitis C after liver transplantation.

Review on immunosuppression in liver transplantation

“…Maintenance of immunosuppression Starting 10-15 mg/kg per day divided every 12 h and adjust to the desired (C2) level Mycophenolate mofetil (Cellcept ® , Myfortic ® ) [60] Anti-metabolite Maintenance of immunosuppression, treatment of rejection Variable doses may be desired in any individual case Azathioprine (Imuran ® ) [65] Anti-metabolite Maintenance of immunosuppression Variable, maintenance dose may be 1.5-2.5 mg/kg per day, needs to be adjusted for adverse side effects Sirolimus (Rapamune ® ) [48,68,71] [44][45][46] T cell depleting monoclonal antibody…”

“…These agents are less immunogenic than other antibodies such as OKT3 [48] . For LT, IL-2Ras have a role for patients who need to avoid or to decrease dosages of an accompanied immunosuppressant agent, such as corticosteroids or CNIs.…”

“…It acts through blocking signal 3 of cell activation from IL2 receptors in Tcells and Bcells. Interestingly, despite binding to the same cell receptor, sirolimus and tacrolimus do not compete with each other and act synergistically [48] . Sirolimus was approved for use in renal transplantation by the Food and Drug Administration (FDA) in 1999.…”

An Overview of Current Status, Recent Techniques and Challenges of Liver Transplantation

“…Most liver transplant recipients receive corticosteroids plus a calcineurin inhibitor such as TAC or CsA plus a purine antagonist such as MMF. Side effects of immunosuppressive drug induced nephrotoxicity, diabetes, hypertension, hyperlipidaemia, osteoporosis and neuropathy play an essential role in long term allograft and patient survival (Encke et al, 2004;Mukherjee & Mukherjee, 2009). The adverse side effects of CNIs, the main class of immunosuppressive agents used in LT, has led to consideration of the use of antibody induction therapies for patients at higher risk of developing adverse side effects (Moini et al, 2015).…”

Cardiovascular Risk Factors and Liver Transplantation

“…It causes a dephosphorilation of activated T cell which is important for the transcription of cytokines for the activation of T cells, while Tacrolimus, from the same group of immunosuppressive drugs and with a similar mechanism of action, inhibits calcineurin binding to another specific immunophilin, FK binding protein 12. (27,28,29) These drugs seem to have complex activities besides immunosuppression, causing endothelial dysfunction and more specifically a decrease in the production of the vasodilator nitric oxide (NO) by endothelial NO synthase (eNOS), affecting the vasodilator function by negatively altering endothelial intracellular Ca2+ and eNOS phosphorylation. Ca2+ concentration is altered by intracellular Ca2+ leak and decreased agonist-induced intracellular Ca2+ release which negatively affects eNOS phosphorylation, NO production, and endothelium-dependent dilatation.…”