Most immunosuppressive medications have been incriminated in renal, cardiovascular, and neurological complications, relapse of viral hepatitis, and recurrence of HCC and other cancers. Efforts to minimize immunosuppression are directed toward decreasing medication side effects, increasing cost effectiveness, and decreasing economic burden without increasing the risk of rejection.
Liver transplantation (LT) is an expensive procedure, with the greatest cost in the first year and a considerable economic burden in the following years. A study from the USA for the estimation of the economic burden of LTs from 2008 to 2013 estimated that Medicare coverage reimbursed USD 185 thousand per recipient in the first year post-LT. The average cost after the first year was USD 154 thousand per recipient. The cost of re-transplantation was USD 388 thousand per-patient, and the costs in the second year post-LT were USD 28 thousand . In a study by Serper and colleagues, nearly one-fifth of the recipients made tradeoffs for the medications post-LT that led to decreased compliance and increased hospital admissions. Insurance type, presence of co-morbid conditions, health literacy, and number of medications were associated with increased medication tradeoffs, decreased frequency of administration, or delayed purchase of the medications .
In addition to an increased economic burden, chronic use of immunosuppressive drugs leads to significant morbidities and metabolic side effects. While calcineurin inhibitors (CNIs) exhibit considerable nephrotoxicity and neurotoxicity, steroids are diabetogenic, and mycophenolic acid derivatives (MMFs) have adverse hematologic effects. Mammalian target of rapamycin inhibitors (MTORis) have been implicated in the development of interstitial lung disease. Different classes of immunosuppressive medications are associated with an increased infection rate. Immunosuppressive drugs used for rejection pose a high risk of demyelination and tuberculosis reactivation . The long-term side effects of these drugs, including malignancies, opportunistic infections, metabolic disorders, and organ toxicities, represent the main clinical concern in formulating an immunosuppression protocol .
The 1-year survival post-LT improved to 85% after the introduction of CNIs in addition to the improvement of the recipients’ selection and surgical techniques . The overall survival is still multifactorial; medications’ side effects, the rate of original disease recurrence, and the presence of comorbidities all play an important role when choosing the optimal immunosuppression protocol. Minimization of the side effects of the drugs without exposing patients to an increased risk of rejection is the ultimate goal for successful immunosuppressive protocols .
2. Immunosuppression Protocols: The Past and the Present
The evolution of immune suppression started in the 1950s, when irradiation was the only treatment option available. Then, the discovery of CNIs, azathioprine (AZA), steroids, and anti-thymocyte globulin (ATG) increased the one-year survival rate. CNIs claimed the highest potency of all immunosuppressive drugs, but nearly 20% of patients on CNIs experienced chronic renal failure at 5 years post-LT 
. Early exposure to a high dose of CNIs is a driving force for renal damage 
Newer generations of immunosuppressive drugs are being tested in human and animal trials. Alemtuzumab is an anti-CD52 that depletes T cells, monocytes, and natural killer cells, and it can be used to reset the immune system. It showed promising results in chronic rejection. Belatacept interferes with T cell co-stimulation and can be used for the induction or maintenance of immunosuppression in LT. Efalizumab blocks T cells’ responses to antigen-presenting cells (APCs), but it is not yet approved for LT. Eculizumab prevents the formation of complement complexes 
. More recently, the use of cellular immunosuppression has addressed different interphases in immune response to grafts. Multiple trials have tested its ability to replace standard immunosuppression protocols 
: list of immunosuppressive medications, modes of action, and common side effects).
Table 1. List of immunosuppressive medications’ modes of action, indications, and common side effects.
|Year of Discovery/FDA Approval
||Mode of Action
||Main Adverse Effect
TAC in 1994
||Blocks protein transcription in response to Il-2 and
prevents cellular proliferation
||Interferes with DNA synthesis
||Reactivation of TB
||Inhibits cytokine receptor signal transduction
||IL2 receptor blocker
||Induction or maintenance
||Blocks CD80 co-stimulation ligand
||Post-TX lymphoproliferative disorder
||Induction, Maintenance, and Rejection
||Affects the production of several inflammatory mediators and multiple cytokines, including IL-1, IL-2, IL-3, IL-6, TNF-a, IFN-Y, leukotrienes, and prostaglandins
||Alemtuzumab (Campath 1H)
||Anti-CD52 on nucleated cells of BM
Post-TX Lymphoproliferative disorder
||Induction or rejection
||Anti-CD3 on lymphocytes
||Anaphylaxis, post-TX lymphoproliferative disorders
An approach to an immunosuppressive protocol can be patient-centered, where the immunosuppressive drugs are to be chosen according to pre-LT conditions and intraoperative risk factors. The other approach consists of the standard strategy, in which a general protocol is administered and titration is performed according to the toxicity and efficacy 
. When formulating an immune suppression protocol, clinicians should elaborate on the presence of comorbidities, drug toxicities, long-term exposure, and the potential recurrence of the original disease or malignancy. Newer protocols propose combinations of drugs with different mechanisms of action and toxicity profiles, thus targeting different pathways in the immune system to allow for dose minimization 
3. Strategies for Immune Suppression Withdrawal/Minimization
Post-transplant survival requires comprehensive care. Routine medical care post-LT should include the early detection of possible adverse events of immunosuppressive drugs. Patients should be monitored for the development of cardiovascular diseases, renal impairments, diabetes mellitus, malignancies, and osteoporosis for the best outcomes. Monitoring of dental health, mental health, sexual function, and immunization should also be provided 
Dose minimization/withdrawal of immunosuppression is associated with better outcomes in terms of decreased morbidity and mortality. A study of 275 liver transplant recipients with HCV or nonimmune and non-viral liver disease was conducted to test the effects of early immunosuppression withdrawal on liver transplant recipients. The study concluded that the complete withdrawal of immunosuppressive drugs was successful only in a few patients. The result of this trial highlighted the importance of the presence of specific criteria for recipients who can benefit from immunosuppression withdrawal. In this study, graft health was monitored by using a liver biopsy, which is invasive and requires trained physicians. The lack of specific predictors for possible rejections represents an enigma, as the elimination and modification of doses would be matters of trial and error 
Multiple studies tested the safety of immunosuppression withdrawal with respect to long-term graft survival. However, the ability to reverse graft injury after withdrawal is still debatable. This is why most studies tested gradual withdrawal in patients with stable graft function in order to avoid unpredicted rejection episodes  Table 2
Table 2. Trials for immunosuppression withdrawal.
||Duration of Withdrawal
||Successful Withdrawal Arm
|Feng/iWITH Study 
||37.5%% of 88 subjects
||1, 2, 3, 4 years
||>3 years post-LTWithdrawal over 6 months
||>50% of 15 subjects
||>3 years post-LTWithdrawal over 6–9 months
||40% of 98 subjects
||Up to 3 years
||>2 years post-LT
||42% of 12 subjects
In efforts to eliminate CNIs, MTOR inhibitors were tested—as a monotherapy or in combination with a reduced dose of CNIs—for their ability to maintain graft function and prevent graft loss. A consensus for when to start MTORis has still not been reached, as early introduction within one month post-LT is associated with hepatic artery (HA) thrombosis. Starting MTORis within one month post-LT was shown to result in the fewest incidences of HA thrombosis. Another clinical dilemma is that of target trough levels. In the H2304 study, everolimus (MTORi) was initiated at 1 month after transplantation. The target trough level was 3–8 ng/mL, which resulted in fewer adverse events as compared to the results of other studies that used higher levels of everolimus 
. Minimization of the dose of CNIs improved renal function, decreased post-transplant diabetes, and reduced viral hepatitis and HCC recurrence. However, everolimus has considerable side effects, and the reno-protective effect of everolimus was more prominent in candidates with GFR 70 > 55 mL/min 
A recent consensus by an Italian working group using the Delphi methodology tested the use of everolimus in LT. Everolimus facilitated a reduction in CNI doses as early as 10 days post-transplant, and conversion to CNI-free protocols could be achieved by 12 months post-LT 
. On the other hand, the results of a recently published Cochrane meta-analysis of 26 trials for the maintenance of immunosuppression in adults after liver transplantation were discouraging. The authors concluded that, at a maximal follow-up horizon, the combination of CNIs and MTORis was associated with increased mortality and graft loss. They attributed the result to the low quality of evidence in the published data and selection bias. The follow-ups ranged from 3 to 144 months post-transplant. However, in attempts to prevent graft loss, most of the available trials have had high rates of patient dropout and/or cross-over 
4. Deliberation on Strategies to Improve Immune Suppression Practice
There are multiple potential aspects in assessing the efficacy of cellular immune suppression for the induction of immune tolerance. The prediction of the sustainability of the response is the next challenge in achieving a consensus and improving patient selection criteria. Another challenge is the development of surrogates for liver biopsies for monitoring, as the role of the protocol biopsy is declining in liver transplantation in order to improve patients’ adherence to surveillance protocols. The third challenge is the optimal timing for immunosuppression withdrawal and how early it can be achieved 
Figure 1. Formulation of an immune suppression protocol for liver transplant recipients.