Liver transplant (LT) has become the standard treatment for advanced liver failure and hepatocellular carcinoma. The survival rates for both patients and grafts post-transplantation have seen significant improvements over the past five decades, attributed to advancements in surgical methods, enhanced perioperative care, and the heightened effectiveness of immunosuppressive medications. Despite these advancements, the long-term survival post-LT remains hindered, primarily due to a rise in metabolic side effects associated with immunosuppression, as well as an increase in opportunistic infections and cancers [1]. The gains in immunosuppressive regimen efficiency have unfortunately been accompanied by serious long-term adverse effects. Among those who have survived for extended periods, the death rate attributed to rejection stands at a mere 1.7% [2]. In these long-term survivors, the predominant causes of mortality were cancers and infections linked to immunosuppression.

The purpose of administering immunosuppressants during LT is two-fold: to avert the body’s immune system from rejecting the transplanted organ while maintaining sufficient immune response to counter infections and neoplastic growths. The immunosuppressive strategies in LT typically involve a blend of medications, including calcineurin inhibitors (CNIs), corticosteroids, inhibitors of the molecular target of rapamycin (mTOR), anti-metabolites, and biologic agents. The use of these drugs in combination allows for lower dosages of each, reducing the potential for graft rejection and simultaneously diminishing the toxicity associated with each drug. This approach is crafted to strike a balance between effective immunosuppression and minimizing adverse effects [3]. This review was focused on the biologic agents employed in the treatment of LT recipients.

Immunosuppressive medications used in transplantation are broadly categorized into two groups: pharmacologic or small molecule agents, and biological agents, which include both polyclonal and monoclonal anti-lymphocyte antibodies [4-6]. The pharmacologic agents function primarily by either suppressing the release of cytokines (CNIs and corticosteroids) or by impeding the cell cycle (anti-metabolites and mTOR inhibitors) [5,6]. Biological immunosuppressives are further divided into lymphocyte-depleting agents, which eliminate T-cells (anti-thymocyte globulin [ATG]), B-cells (rituximab), or plasma cells (bortezomib), and non-lymphocyte-depleting agents (basiliximab), which hinder T-cell proliferation without impacting overall lymphocyte counts [7-10]. In the context of LT, biological agents are utilized for various purposes, including as induction agents for antibodies, in managing steroid-resistant rejection, in ABO-incompatible LT scenarios, and in the treatment of antibody-mediated rejection [7-10].

Antibodies that act to either suppress or eliminate T-cells are employed in LT both as initial induction agents and for addressing steroid-resistant rejections [7,11-13]. Induction therapy with these antibodies is particularly prevalent in LT protocols that avoid the use of steroids and as a means to reduce reliance on CNIs [3,7,8]. Such steroid-free approaches have shown effectiveness in cases of cirrhosis related to hepatitis C and non-alcoholic steatohepatitis [3,7,8]. The use of antibody induction facilitates the postponed introduction of CNIs, which in turn helps to safeguard the renal function of LT recipients [14-16]. This strategy has been linked with a reduction in acute rejection incidents without an uptick in adverse side effects [7].

While the advantages are notable, the expenses associated with these therapies are an important aspect to consider. In the realm of induction therapy for LT, biological agents are classified into two main types: T-cell-depleting and non-depleting agents (Table 1). The former includes both polyclonal options like ATGs and monoclonal varieties such as alemtuzumab (Campath-1H) and muromonab-CD3 (OKT3). On the other hand, non-depleting agents encompass interleukin-2 receptor antagonists (IL-2Ras) and inhibitors targeting the CD28 pathway (Belatacept) [7].

Table 1 . Biological agents used in liver transplantation [35].

Drug	Mechanism of action	Use	Comments
Muromonab-CD3 (OKT3)	T-cell-depleting monoclonal antibody	Induction of immunosuppression, treatment of steroid resistant rejection	Withdrawn from the market
Alemtuzumab (campath-1H)	T-cell-depleting monoclonal antibody	Induction of immunosuppression	Variable between centers, a single dose of 30 mg may be used in operating room
ATG (thymoglobulin, ATGAM)	T-cell-depleting polyclonal antibody	Induction of immunosuppression, treatment of steroid resistant rejection	Variable between centers, for induction 1.5 mg/kg per day IV for 3 days and for treatment of rejection 1.5 mg/kg per day IV for 5–7 days of thymoglobulin may be used. For ATGAM a higher dose of 15 mg/kg per day is usually used
Daclizumab (Zenapax)	IL-2Ra, monoclonal antibody	Induction of immunosuppression, treatment of steroid-resistant rejection	Withdrawn from the market
Basiliximab (Simulect)	IL-2Ra, monoclonal antibody	Induction of immunosuppression, treatment of steroid resistant rejection	For induction a 20 mg IV dose is administered within 6 hours of reperfusion and another 20 mg on day 4 post-LT
Belatacept	Anti-CD28 monoclonal antibody	CNI sparing agent	Not recommended in LT

ATG, anti-thymocyte globulin; IL-2Ra, interleukin-2 receptor; IV, intravenous administration; LT, liver transplantation..

Data from the article of Panackel et al. (J Clin Exp Hepatol 2022;12:1557-1571) [35]..

Polyclonal T-Cell-Depleting Antibodies

ATGs, or polyclonal antibodies, are utilized primarily for the depletion of circulating lymphocytes [17,18]. In LT, their use is predominantly for addressing steroid-resistant rejections, and occasionally as induction agents. There are two main forms of ATG available: ATGAM, which is derived from horses, and Thymoglobulin, which is sourced from rabbits [19]. Comparatively, Thymoglobulin is considered more effective than ATGAM, exhibiting fewer instances of opportunistic infections, less severe adverse side effects, and enhanced overall efficacy [18,19]. However, it is noted that Thymoglobulin tends to cause more pronounced leukopenia compared to ATGAM [17-19].

The standard approach for ATG induction therapy typically involves administering Thymoglobulin at a daily dose of 2.5 mg/kg for a duration of ten days. However, shorter regimens lasting only three days have demonstrated comparable effectiveness in LT, while also presenting fewer adverse effects [17,20]. An alternative strategy involves the intermittent dosing of ATGAM, where additional doses are administered only if the CD3 count remains above 20 cells/mm3. This method has proven effective and offers a cost advantage [20].

While rare, adverse effects of ATG infusion can include infusion reactions, serum sickness, and severe cytokine release syndrome. To mitigate the risk of infusion reactions, the pre-administration of antihistamines and acetaminophen is recommended. Importantly, the likelihood of opportunistic infections, recurrence of hepatitis C virus, and the development of post-transplantation lymphoproliferative disorders does not appear to increase with ATG induction when compared to scenarios with no induction [17,21].

Monoclonal T-Cell-Depleting Antibodies

Alemtuzumab (also known as Campath-1H) is a humanized monoclonal antibody designed to deplete T-cells by targeting CD52 receptors found on these cells [22,23]. This agent is recognized for its potency; however, it also carries a heightened risk for opportunistic infections following LT. Additionally, there have been instances of accelerated progression of recurrent hepatitis C virus in patients who were treated with alemtuzumab induction. At present, the use of Alemtuzumab in LT is somewhat restricted, as its associated risks are considered to outweigh the benefits [22,23].

Muromonab-CD3, known commercially as OKT3, is a monoclonal antibody that targets and depletes T-cells by binding to the CD3 receptors on peripheral T-cells. This drug was found to be beneficial in managing steroid-resistant T-cell-mediated rejection and was also used in induction therapy. Nevertheless, due to a rise in adverse effects associated with its use, its production was halted in 2010 [24].

Non-Depleting Antibodies

Interleukin-2 and its receptor, CD25, play a crucial role in the activation and proliferation of T lymphocytes, which are key components of cell-mediated immunity [25]. Daclizumab, a fully humanized monoclonal antibody, and basiliximab, a chimeric monoclonal antibody, both target CD25 [26,27]. By binding to the IL-2 receptor on activated T lymphocytes, these drugs effectively inhibit T-cell proliferation [25]. In the context of LT, IL-2Ras like these are commonly used in induction therapy, serving as alternatives to steroids or CNIs.

Daclizumab was withdrawn from the market in 2010 due to a rise in cases of inflammatory encephalitis [28]. Research in the field of LT indicates that induction with IL-2Ra is as effective as ATG induction, but with fewer side effects [27]. Additionally, IL-2Ra induction has been linked to improved renal function, a reduction in opportunistic infections, and fewer metabolic issues compared to treatments involving steroids [29]. Importantly, there hasn’t been an observed increase in complications such as cytomegalovirus infections, post-transplantation lymphoproliferative disorder, or recurrence of hepatitis C virus associated with IL-2Ra induction [26]. Furthermore, IL-2Ra induction has been associated with fewer instances of acute rejection and enhanced graft survival [26,27,29].

The CD28 receptor on T-cells plays a pivotal role in the second signal necessary for T-cell activation and proliferation. Belatacept, a potent monoclonal antibody that inhibits CD28, is primarily used in kidney transplantation as a non-T-cell-depleting agent. However, further investigation is needed to establish its efficacy and safety for use in LT [30].

Achieving a balance in medical therapy where allograft function is stable with minimal impact on systemic immunity is referred to as optimal transplant immunosuppression [6,31]. The administration of immunosuppression is often considered more an art than a strict science. Nowadays, most transplant centers are transitioning from standardized protocol-based immunosuppression to more individualized regimens. Contemporary immunosuppressive strategies employ a combination of agents, each with distinct mechanisms of action. This approach enables the use of lower drug doses, reducing toxicity and leading to improved outcomes for both patients and grafts [6,31]. The selection of immunosuppressive agents is tailored according to various factors, including the recipient profile, the time elapsed since transplantation, the underlying disease, and the behavior of the graft.

Immunosuppression in LT can be segmented into three distinct phases: the induction phase, the maintenance phase, and the phase for treating acute cellular or T-cell–mediated rejection [31,32]. The induction phase refers to the initial immunosuppression strategy implemented in the first 30 days post-LT, a period when alloreactivity is most intense [6,31]. Typically, a triple-drug therapy consisting of a CNI, a corticosteroid, and an antimetabolite is the standard induction regimen [6,31]. Additionally, antibody induction therapy, which may include agents like ATG or basiliximab, is sometimes employed as a means to reduce reliance on steroids or CNIs [32-34].

Maintenance immunosuppression is the term used for the ongoing immunosuppressive treatment that begins 30 days after transplantation and is maintained indefinitely thereafter [6]. The concept of personalizing immunosuppression involves adapting these protocols to fit individual recipient factors. This includes considerations like renal function, metabolic syndrome, the underlying cause of the liver disease, and the degree of alloimmune activation. This approach is focused on customizing treatment to better suit the unique needs and conditions of each transplant recipient [35].

The evolution of immunosuppressive therapies has successfully reduced the incidence of acute rejections and notably extended the lifespan of transplanted grafts. However, this achievement has been accompanied by an increase in morbidity and mortality related to the use of these drugs. The primary aim of optimal immunosuppression is to enhance the efficacy of these medications while minimizing their negative side effects, thereby improving both the long-term survival of the graft and the quality of life of the recipient. Tailoring the immunosuppression regimen is essential and should consider various individual factors such as age, co-existing health conditions, reasons for transplantation, allograft behavior, complications arising from immunosuppression, and the physiological conditions post-LT.

There was no funding related to this study.

All authors have no conflicts of interest to declare.

Conceptualization: All. Data curation: CSP. Investigation: CSP. Methodology: All. Validation: CSP. Writing – original draft: All. Writing – review & editing: All.