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Abstract

  1. Top of page
  2. Abstract
  3. IMMUNOLOGICAL MECHANISMS OF THE REJECTION RESPONSE: THE 3-SIGNAL PATHWAY OF LYMPHOCYTE ACTIVATION
  4. CONCEPTS IN IMMUNOSUPPRESSION
  5. PHASES OF IMMUNOSUPPRESSION
  6. CLASSIFICATION OF IMMUNOSUPPRESSIVE DRUGS
  7. PRACTICE OF LT IMMUNOSUPPRESSION IN THE UNITED STATES
  8. CONCLUSIONS
  9. REFERENCES

Key Points

1. Our increasing understanding of the signaling pathways and cellular interactions in transplant immunobiology has facilitated targeted strategies using novel immunosuppressive agents.

2. The pattern of immunosuppressive drug use in the United States continues to change, and the changes include the use of antibody induction therapy and the agents used in maintenance therapy.

3. The driving forces behind the development of new immunosuppressive regimens are the long-term complications of current immunosuppressive regimens (particularly renal dysfunction and metabolic disturbances). Liver Transpl, 2011. © 2011 AASLD.

Recent advances in molecular and cellular immunology have further unraveled the interactions between antigen-presenting cells (APCs), T cells, and B cells. These advances include the elucidation of pathways involved in T cell activation and apoptosis, the identification of novel regulatory cells (including T regulatory cells and suppressive APCs), and a greater appreciation of the complex interactions between innate and adaptive immunity. Furthermore, the elucidation of the triggers of B cell activation and antibody synthesis has allowed the development of B cell–specific immunosuppression, although the impact of donor-specific antibodies and B cells on liver transplantation (LT) is still being assessed. Nevertheless, the focus of immunosuppressive drug development has continued to be the T cell. Thus, we briefly review our current understanding of T cell activation and proliferation as well as the mechanisms of action of immunosuppressive agents.

IMMUNOLOGICAL MECHANISMS OF THE REJECTION RESPONSE: THE 3-SIGNAL PATHWAY OF LYMPHOCYTE ACTIVATION

  1. Top of page
  2. Abstract
  3. IMMUNOLOGICAL MECHANISMS OF THE REJECTION RESPONSE: THE 3-SIGNAL PATHWAY OF LYMPHOCYTE ACTIVATION
  4. CONCEPTS IN IMMUNOSUPPRESSION
  5. PHASES OF IMMUNOSUPPRESSION
  6. CLASSIFICATION OF IMMUNOSUPPRESSIVE DRUGS
  7. PRACTICE OF LT IMMUNOSUPPRESSION IN THE UNITED STATES
  8. CONCLUSIONS
  9. REFERENCES

Hepatic allograft rejection is related to the recipient's immunological response, which is precipitated by donor-recipient mismatching of a major histocompatibility complex (MHC); this leads to what is called an alloimmune response. In the hepatic allograft and its surrounding tissue, dendritic cells or APCs from the donor and the recipient become activated by their interactions with foreign antigens, and they subsequently migrate to the T cell areas of secondary lymphoid organs (Fig. 1).

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Figure 1. Alloreactivity versus the time after LT. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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There, the antigen-bearing cells engage alloantigen, reactive naive T cells, and memory cells and trigger lymphocyte activation, which is transduced through the T cell receptor (TCR; CD3 complex); this is often called signal 1.2, 3 Dendritic cells provide costimulation (or signal 2) when CD80 and CD86 markers on the surface of dendritic cells engage CD28 receptors on T lymphocytes.4, 5 Signals 1 and 2 activate signal transduction pathways, which include (1) the calcium/calcineurin pathway and (2) the RAS mitogen-activated protein (MAP) kinase and nuclear factor kappa B (NF-κB) pathways. These pathways activate transcription factors that trigger the expression of many new molecules, including interleukin-2 (IL-2) and other cytokines, which are able to activate the pathway (target of rapamycin) providing signal 3 or the trigger for cell proliferation.5 Lymphocyte proliferation also requires nucleotide synthesis. This proliferation of T cells leads to differentiation and the production of large numbers of effector T and B cells. Effector cells emerging from lymphoid organs infiltrate the hepatic allograft and orchestrate an inflammatory response.6 In T lymphocyte–mediated rejection, the graft is infiltrated by effector T cells, activated macrophages, secretory B cells, and plasma cells, and this ultimately leads to organ damage (Fig. 1). T cell–mediated damage results from the secretion of numerous factors, such as tumor necrosis factor α and tumor necrosis factor β, the expression of Fas ligand, and the secretion of cytotoxins such as perforin and granzyme F. The diagnostic pathology of lymphocyte-mediated rejection is the invasion of the liver by mononuclear cells, which target small arteries, veins, and bile duct epithelium.3, 7, 8 In addition, antibodies against donor antigens are produced through these mechanisms. However, antibody-mediated rejection in LT patients appears to be a rare phenomenon and is rarely thought to be clinically significant.

The elucidation of these pathways has aided in the development of novel agents that have been used (or will be tested clinically) either alone or in combination with more conventional immunosuppressive drugs (Fig. 2). The vast array of immunosuppressive combinations has dramatically lowered the incidence of acute liver allograft rejection; nevertheless, much remains to be done to reduce the impact of chronic immunosuppressive drug toxicity on the longer term survival of LT recipients. In this review, we describe the current state of immunosuppression in the United States.

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Figure 2. Pathway of immune activation of the host by migration of donor antigens processed through host APC (indirect antigen presentation) and/or donor antigens present on donor APC (direct antigen presentation) migrates to a lymphoid organ (spleen or lymph node), whereby recipient T cells are activated and 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.

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CONCEPTS IN IMMUNOSUPPRESSION

  1. Top of page
  2. Abstract
  3. IMMUNOLOGICAL MECHANISMS OF THE REJECTION RESPONSE: THE 3-SIGNAL PATHWAY OF LYMPHOCYTE ACTIVATION
  4. CONCEPTS IN IMMUNOSUPPRESSION
  5. PHASES OF IMMUNOSUPPRESSION
  6. CLASSIFICATION OF IMMUNOSUPPRESSIVE DRUGS
  7. PRACTICE OF LT IMMUNOSUPPRESSION IN THE UNITED STATES
  8. CONCLUSIONS
  9. REFERENCES

Today, the administration of immunosuppression remains more of an art than a science. Indeed, there are few markers of overall immunosuppression, rejection, or tolerance. In addition, there is generally a poor correlation between rejection and the degree of liver test abnormalities or immunosuppression levels. Liver biopsy remains the gold standard for the diagnosis of acute hepatic allograft rejection.

Optimal transplant immunosuppression is defined as the level of drug therapy that achieves stable allograft function with the least suppression of systemic immunity. In this way, the amount of systemic toxicity (ie, metabolic alterations, infections, and malignancies) and the number of drug-specific side effects are minimized, although they are not entirely eliminated. Therapeutic drug monitoring is limited to only a few immunosuppressive agents, and in practice, overimmunosuppression or underimmunosuppression almost invariably becomes apparent only in retrospect, especially with the increasing use of combinations of induction antibodies, calcineurin inhibitors (CNIs), and antimetabolite agents.9 Recently, the monitoring of CD4+ lymphocyte adenosine triphosphate levels has been suggested as an alternative means of assessing the net state of immunosuppression,10 although others have suggested that the utility of this assay is its ability to better identify recipients who are more susceptible to infection-related complications.11 Clearly, specific and meaningful biomarkers are needed to assess individual risks for immunological complications.12, 13 Although immunosuppression minimization has been shown to reduce the complications of chronic immunosuppression,14, 15 only a minority of LT recipients are able to achieve complete withdrawal,16 and this means that the majority of patients likely will remain on chronic immunosuppression for their entire lives.

The timing, dosing, and selection of immunosuppressive agents differ widely between centers. Most current protocols use multiple agents, which are directed at various phases of the activation cascade of cells participating in the immune response (Fig. 2). The agents in a given protocol generally have different modes of action and different toxicities, and this allows lower doses of any specific drug. In addition, the profiles and proportions of the immunosuppressive agents generally change with time after transplantation, and individualized decisions based on the initial disease process, the status of immune sensitization before transplantation, and the behavior after transplantation are required. The intensity of immunosuppression is usually directed in the early post-LT phase when the risk of acute rejection is highest, but this must be balanced by the longer term effects of these agents, including infectious, metabolic, and renal complications. Fortunately, the impact of an acute rejection episode is less significant in LT versus kidney and heart transplantation and has minimal impact on graft survival.7

PHASES OF IMMUNOSUPPRESSION

  1. Top of page
  2. Abstract
  3. IMMUNOLOGICAL MECHANISMS OF THE REJECTION RESPONSE: THE 3-SIGNAL PATHWAY OF LYMPHOCYTE ACTIVATION
  4. CONCEPTS IN IMMUNOSUPPRESSION
  5. PHASES OF IMMUNOSUPPRESSION
  6. CLASSIFICATION OF IMMUNOSUPPRESSIVE DRUGS
  7. PRACTICE OF LT IMMUNOSUPPRESSION IN THE UNITED STATES
  8. CONCLUSIONS
  9. REFERENCES

The phases of immunosuppression are classified as follows: (1) induction, (2) maintenance, and (3) the treatment of acute cellular rejection (Fig. 3). Induction immunosuppression is often defined as the initial immunosuppressive regimen used in the first 30 days after transplantation when alloreactivity is at its peak. In the past, induction immunosuppression referred to the use of anti-lymphocyte antibody preparations, which were often used to spare patients from the nephrotoxicity associated with CNIs. However, antibody induction therapy is used in a minority of LT recipients, and the most common induction regimen includes a triple-drug therapy with a CNI, corticosteroids, and an antimetabolite [most often mycophenolic acid (MPA)].

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Figure 3. Model of T cell activation and sites of action for immunosuppressive agents. See text for detailed explanation.

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Maintenance immunosuppression refers to an immunosuppressive regimen begun after 30 days and used indefinitely thereafter. During maintenance therapy, there is usually an attempt to reduce the number and doses of agents. After the first year, many patients are receiving monotherapy with just a CNI. In general, the minimization of immunosuppression rarely causes acute rejection (except in cases of complete withdrawal or noncompliance).

The treatment of acute rejection refers to the addition of immunosuppressive therapy when a histological diagnosis of acute rejection is made. In general, high-dose, intravenous-bolus corticosteroid therapy is administered, and if a response is not obtained (steroid-resistant rejection), the patient receives an anti-lymphocyte antibody. Hepatitis C virus (HCV) is a special case: increases in CNI and antimetabolite doses might be tried before bolus steroids, which can enhance HCV.

Today, chronic rejection is rare, and at this time, no proven strategies for treating the condition are known.

CLASSIFICATION OF IMMUNOSUPPRESSIVE DRUGS

  1. Top of page
  2. Abstract
  3. IMMUNOLOGICAL MECHANISMS OF THE REJECTION RESPONSE: THE 3-SIGNAL PATHWAY OF LYMPHOCYTE ACTIVATION
  4. CONCEPTS IN IMMUNOSUPPRESSION
  5. PHASES OF IMMUNOSUPPRESSION
  6. CLASSIFICATION OF IMMUNOSUPPRESSIVE DRUGS
  7. PRACTICE OF LT IMMUNOSUPPRESSION IN THE UNITED STATES
  8. CONCLUSIONS
  9. REFERENCES

Immunosuppressive drugs can be broadly divided into 2 categories: (1) pharmacological or small-molecule drugs and (2) biological agents (ie, polyclonal and monoclonal anti-lymphocyte antibodies, which can be further classified as lymphocyte-depleting or non–lymphocyte-depleting agents).

Most small-molecule immunosuppressive agents are derived from microbial products and target proteins that are important to the alloimmune response. These agents include corticosteroids, cyclosporine A (CSA), tacrolimus (TAC), MPA, azathioprine, and rapamycin (Table 1).

Table 1. Classification of Pharmacological (Small-Molecule) and Biological Immunosuppressive Agents
Pharmacological Immunosuppressive Agents
 CorticosteroidsInhibition of cytokine transcription by APCs
 CNIsInhibition of signal 2 transduction
  CSA 
  TAC 
 AzathioprineInhibition of purine and DNA synthesis and prevention of T cell proliferation
 MPAInhibition of purine and DNA synthesis and prevention of T cell proliferation
  CellCept 
  Myfortic 
 Rapamycin (mTOR inhibitors)Inhibition of signal 3 transduction and prevention of T cell proliferation
  Sirolimus 
  Everolimus 
Biological Immunosuppressive Agents
 T cell–depleting agents 
  Anti-CD3 (monoclonal): OKT3Interference with signal 1
  ATG: horse and rabbit ATG and ALGInterference with signals 1 to 3
  Anti-CD52 (monoclonal): Campath 1H (alemtuzumab)Depletion, thymocytes T cell, B cell—monocytes
 Non–T cell–depleting agents 
  Anti–IL-2 receptorsInhibition of T cell proliferation and signal 3
   Basiliximab 
   Daclilumumab 
  BelataceptInhibition of signal 2
  DaclizumabCompetition with CD28 for CD80/CD86 binding

Biological immunosuppressive drugs include lymphocyte-depleting immunosuppressive agents, which are antibodies that destroy T cells, B cells, or both. T cell depletion is often accompanied by a release of cytokines, which produce severe systemic symptoms, especially after the first dose (Table 1). The use of depleting antibodies reduces the risk of early rejection but increases the risk of infection by cytomegalovirus and fungi and the development of posttransplant lymphoproliferative disease. Recovery from immune-depleting lymphocyte antibodies takes months to years and may never be complete in older individuals. The depletion of antibody-producing cells is better tolerated than T cell depletion because it is not usually accompanied by a release of cytokines, and immunoglobulin levels are usually maintained. However, the depletion of antibody-producing cells is incomplete because many plasma cells are resistant to available antibodies that target B cells, such as anti-CD20 antibody (rituximab).

Non–lymphocyte-depleting immunosuppressive agents are monoclonal antibodies or fusion proteins that reduce responsiveness without compromising lymphocyte populations (Table 1). These drugs have low nonimmune toxicity because they target proteins that are expressed only on immune cells and trigger little release of cytokines. They typically target mechanisms such as IL-2 receptors, and this explains their limited efficacy and the absence of immunodeficiency complications. They are generally used in combination with corticosteroids, CNIs, and antimetabolites.

PRACTICE OF LT IMMUNOSUPPRESSION IN THE UNITED STATES

  1. Top of page
  2. Abstract
  3. IMMUNOLOGICAL MECHANISMS OF THE REJECTION RESPONSE: THE 3-SIGNAL PATHWAY OF LYMPHOCYTE ACTIVATION
  4. CONCEPTS IN IMMUNOSUPPRESSION
  5. PHASES OF IMMUNOSUPPRESSION
  6. CLASSIFICATION OF IMMUNOSUPPRESSIVE DRUGS
  7. PRACTICE OF LT IMMUNOSUPPRESSION IN THE UNITED STATES
  8. CONCLUSIONS
  9. REFERENCES

Induction Immunosuppression

In the United States, induction immunosuppression is usually achieved with a CNI and corticosteroids with or without the use of an antimetabolite such as MPA. In contrast to other solid organ transplants, the use of induction antibody preparations in LT remains relatively uncommon.9 As shown in Table 2, the overall use of induction immunosuppression for LT recipients in 2008 was only 26.7%; however, this rate reflects a steady increase since 1999 (when the rate was 13.3%). This rise in induction has been ascribed to (1) attempts to avoid CNIs in the early posttransplant period to prevent the aggravation of renal dysfunction (this recognizes the increasing prevalence of patients with higher Model for End-Stage Liver Disease scores and renal dysfunction) and (2) attempts to reduce or prevent the need for early corticosteroid use (the use of antibody induction immunosuppression was associated with a reduction of steroid use from 84.5% to 49.6% in 2008).

Table 2. Use of Induction Agents in LT
 1999200020012002200320042005200620072008
Polyclonal agents (%)1.201.902.804.707.007.807.509.2010.7011.40
OKT3 (%)1.400.800.700.300.300.200.802.702.902.50
IL-2RA (%)11.0013.2012.0012.4012.8011.1011.1012.3013.7014.60
Campath (%)0.000.000.000.000.701.601.601.401.401.00
No induction drugs recorded (%)86.7084.5084.6082.7079.5079.5079.9077.2074.4073.40

The trend of antibody induction selection in LT continues to favor the class of anti–IL-2 receptors [interleukin-2 receptor alpha chain (IL-2RA) monoclonal antibody receptors]; the overall rate of use in primary LT is 15% (Table 2). The ability of anti–IL-2RA to provide sufficient coverage for the delayed introduction (posttransplant day 5) of CNIs was demonstrated in a multicenter, prospective, randomized trial in LT recipients.17 Adult primary LT patients were randomized to (1) standard-dose TAC and corticosteroids, (2) mycophenolate mofetil (MMF), reduced-dose TAC, and corticosteroids, or (3) anti–IL-2RA induction, MMF, reduced-dose TAC, and corticosteroids. The primary endpoint was the change in the estimated glomerular filtration rate (GFR), and the investigators found that the decline in the estimated GFR after LT was significantly lower in the induction group versus the standard group, and so was the need for post-LT hemodialysis. The rates of biopsy-proven acute rejection and patient and graft survival were reportedly similar. These conclusions were supported by a recent meta-analysis18; however, at least 1 study has reported no benefit to renal function from an anti–IL-2RA induction regimen.19

Although the US Food and Drug Administration has not approved the use of polyclonal anti-lymphocyte globulins (ALGs) as induction therapy in LT, rabbit anti-thymocyte globulin (RATG) has experienced the greatest increase in use (from 2% to 11% of all primary LT recipients over the past 10 years). The potency of polyclonal preparations has been felt to be appropriate in the setting of corticosteroid-free immunosuppressive protocols.20 However, a more important aspect of RATG may be its ability to delay CNI exposure in order to minimize early compromising of kidney function after LT, as described in a pilot phase 2 study of Thymoglobulin in de novo LT.21 In a 3-arm study, 2 dosing schedules for RATG (2 or 3 doses at 1.5 mg/kg) along with the delayed introduction of TAC (posttransplant day 10) were compared to a standard TAC regimen with a rapid steroid-tapering protocol; MMF was given to all patients in the standard fashion. Although there were more biopsy-proven rejections in the low-dose RATG group in the first 30 days, there were no significant differences at the end of 6 months. However, the GFRs were higher in the 2 RATG groups versus the TAC control group at 6 months, and they further diverged at 12 months. This lends support to a future phase 3 study of RATG induction with an extended delay of CNI therapy in LT.

Although alemtuzumab, a humanized recombinant anti-CD52 monoclonal antibody, has been used in LT, the overall experience has been mixed,22, 23 and its use is currently limited to 1% of LT recipients. Patients undergoing LT for HCV have experienced severe recurrence, so alemtuzumab is not recommended for HCV patients. Finally, the recent discontinuation of OKT3 (anti-CD3) and daclizumab (anti–IL-2RA) by their manufacturers will likely shift LT patients to other induction agents.

Maintenance Immunosuppression

The profile of maintenance immunosuppression in LT continues to favor CNI-based therapy. With the decreasing length of hospital stays after LT and the adoption of induction antibody use with the delayed initiation of CNIs, the correlation of maintenance immunosuppressive therapy at the time of discharge with long-term outcomes has become increasingly difficult to determine. Nevertheless, the use of CNIs was reported in 97% of patients discharged from the hospital after LT in 2008 (Table 3), and TAC continued to the most used CNI (90% of LT recipients). This pattern of CNI use has persisted despite the retrospective observation that HCV-positive LT patients who were treated with anti-HCV therapy were more likely to achieve viral clearance if they were on CSA versus TAC.24 This overall benefit of CSA for LT recipients with HCV was not sustained in a recent meta-analysis of the impact of CNIs on HCV recurrence after LT. Similar rates of fibrosis and patient and graft survival were noted 1 year after transplantation.25 In a retrospective analysis of the Scientific Registry of Transplant Recipients (SRTR) database, CSA-treated LT patients with HCV had significantly higher odds of death and graft failure.26 The results of a multicenter, randomized, open-label phase 4 study comparing the development of liver fibrosis 12 months after transplantation in HCV patients receiving either a CSA microemulsion or TAC27 have not yet been published.

The rate of use of antimetabolite agents (particularly MMF and MPA) at the time of discharge has increased to 77% in all LT recipients (Table 3), and they are most commonly used in combination with TAC and corticosteroids (Table 4). A recent prospective, randomized study of de novo LT patients has suggested that a combination of MMF and lower dose TAC is associated with equal outcomes but has metabolic and renal benefits in comparison with just a standard-dose TAC regimen,15 and this confirms the findings of a previous single-center study.28 Azathioprine is used rarely in the United States, but European studies have suggested benefits for HCV recipients.

Table 3. Maintenance Immunosuppression at LT Discharge
 1999200020012002200320042005200620072008
Corticosteroids (%)9391.990.290.482.480.678.978.476.180
CSA (%)25.918.511.910.28.78.176.77.17
TAC (%)71.676.683.186.888.888.790.891.390.890.4
Mycophenolate (%)36.743.347.748.154.156.260.668.772.276.8
mTOR inhibitors (%)0.69.49.96.64.45.04.03.72.52.2
Table 4. Most Frequent Immunosuppression Combinations at LT Discharge
 1999200020012002200320042005200620072008
TAC and corticosteroids (%)38.832.132.335.429.426.224.021.519.216.0
TAC (%)2.31.43.44.87.69.810.05.54.63.7
TAC and MMF/MPA (%)1.62.52.62.86.56.38.412.815.613.8
TAC, MMF/MPA, and corticosteroids (%)24.130.535.136.639.541.444.848.148.954.7
CSA and corticosteroids (%)9.76.12.62.11.41.01.10.50.70.5

The use of mammalian target of rapamycin (mTOR) inhibitors (either sirolimus or everolimus) has remained at low levels; only 2.2% of LT recipients were receiving an mTOR inhibitor at the time of discharge in 2008. However, the proportions of patients on mTOR inhibitors increased to 5.5% 1 year after LT and to 8.3% 2 years after LT. We can only speculate about the reasons for the increasing use of mTOR inhibitors after LT: some have suggested that one benefit of mTOR use is a reduction of the risk of hepatocellular carcinoma (HCC) recurrence.29 In a retrospective analysis of the SRTR database, which included 2491 adult LT recipients with HCC between 2002 and 2009, anti-CD25 antibody induction (hazard ratio = 0.64, P < 0.01) and sirolimus-based maintenance therapy were associated with improved patient survival (hazard ratio = 0.53, P ≤ 0.05), although the impact on HCC could not be assessed with the SRTR database.

The timing of mTOR use after LT, particularly in light of the black-box warning for sirolimus use in de novo LT recipients,30 is also uncertain. A prospective, multicenter, randomized controlled study comparing sirolimus-containing immunosuppression and mTOR inhibitor–free immunosuppression in patients undergoing LT for HCC is being conducted. Patients with a histologically confirmed HCC diagnosis will be randomized into 2 groups within 4 to 6 weeks after LT; the control group will be maintained on a center-specific mTOR inhibitor–free immunosuppressive protocol, and the sirolimus treatment group will be converted 4 to 6 weeks after LT. The follow-up period will be 5 years, and HCC-free survival will be the primary endpoint.31

Another reason for the use of mTOR inhibitors in LT is the preservation of renal function,32 although some have questioned this.33 In a prospective phase 2 study, adult LT patients with renal impairment (estimated GFR < 50 mL/minute and/or serum creatinine level > 1.5 mg/dL) will receive CNI-free combination therapy (anti–IL-2RA, MMF, steroids, and delayed sirolimus), and the primary endpoint will be the incidence of steroid-resistant acute rejection within the first 30 days after LT.23 A similar study using MPA and everolimus after LT has been proposed.34

Corticosteroid avoidance was relatively uncommon (5%-8%) until 1999, with the rates gradually increasing to 20% for all primary LT procedures by 2008 (Table 3). It has been postulated that corticosteroid avoidance may be beneficial for reducing the impact of HCV recurrence after LT.35 However, the early results of a prospective, randomized study of steroid avoidance have not shown any modulations in HCV replication, histological recurrence, or survival in HCV-positive LT recipients.36 In a prospective, multicenter, randomized study (the HCV-3 study), 312 HCV LT patients were randomized to 1 of 3 arms: TAC and prednisolone; TAC, prednisolone, and MMF; or TAC, MMF, and anti–IL-2RA. There were no differences in the rates of acute cellular rejection, patient survival, or graft survival between the 3 arms. More importantly, there were no differences in HCV RNA levels and no differences in the overall incidence of severe HCV recurrence at 2 years. Similar findings were noted in a Spanish prospective, randomized trial: LT patients were randomized to receive immunosuppression with anti–IL-2RA and CSA either with or without steroids. An examination of the 2-year post-LT protocol biopsy results showed that the proportions of biopsy samples with grade 3 or 4 fibrosis at 6 months, 1 year, and 2 years were 0%, 8%, and 22%, respectively, in the no-steroid group and 8%, 19%, and 31%, respectively, in the steroid group; however, these differences were not statistically significant.37

The withdrawal or elimination of corticosteroids early in the posttransplant period has been suggested as a way of avoiding adverse effects related to corticosteroid use. Thus, long-term steroid-free regimens have been widely touted; SRTR data reveal that corticosteroid administration has indeed decreased over time (Tables 5 and 6). Approximately 80% of LT recipients are using corticosteroids at the time of discharge, but only 33% are still using corticosteroids by the end of the first year after LT, and this percentage falls to 23% within 2 years after LT. In the case of HCV patients, some have advocated that low doses of corticosteroids may be beneficial for LT recipients with HCV. A group from the University of Bologna conducted a small single-center study to examine the effects of long-term maintenance with low-dose steroids versus steroid withdrawal at 90 days on HCV recurrence.38 Although the rates of histological recurrence were similar in the 2 groups, only 7.6% of the patients in the low-dose corticosteroid group developed advanced fibrosis 1 year after LT, whereas 42.1% of the patients in the rapid-taper group did (P = 0.03); this difference remained significant at the 2-year mark.

Table 5. Most Frequent Immunosuppression Combinations 1 Year After LT
 1998199920002001200220032004200520062007
TAC and corticosteroids (%)32.930.526.722.822.320.918.115.715.112.5
TAC (%)19.420.523.628.931.330.128.328.626.528.5
TAC and MMF/MPA (%)4.85.57.17.310.113.715.218.122.125.0
TAC, MMF/MPA, and corticosteroids (%)8.810.410.813.212.614.115.516.817.415.2
CSA and corticosteroids (%)11.110.35.82.92.32.01.71.21.21.0
Table 6. Most Frequent Immunosuppression Combinations 2 Years After LT
 199819992000200120022003200420052006
TAC and corticosteroids (%)23.820.917.915.815.413.812.19.79.1
TAC (%)29.234.338.240.239.937.936.035.935.6
TAC and MMF/MPA (%)4.86.27.59.812.216.017.521.024.5
TAC, MMF/MPA, and corticosteroids (%)6.26.97.08.28.89.410.010.910.1
CSA and corticosteroids (%)10.26.93.62.21.61.41.00.80.7

Treatment of Acute Rejection

The incidence of acute rejection in LT patients has fallen from 60% to 70% in the CSA era to 30% in recent studies using triple-drug regimens.15, 39 The incidence of acute rejection varies by the liver disease etiology: young patients with autoimmune disease have the highest incidence of acute rejection, and older patients with alcoholic liver disease have the lowest incidence. No difference has been found between living donor LT and deceased donor LT with respect to rejection. However, the cold ischemia time has been correlated closely with the incidence of acute rejection.39

Most LT recipients who experience rejection do so within the first 42 days after LT; the median time to rejection is 12 days. The majority of acute rejection episodes are mild, and 83% will respond to additional immunosuppression (most commonly intravenous-bolus corticosteroids). Usually, Solu-Medrol (500-1000 mg) is administered every other day for a total of 3 doses.40, 41 However, 17% of acute rejection episodes are steroid-resistant, and anti–lymphocyte-depleting preparations are often required for a reversal. Recent studies have found that less than 7% of late graft losses (after 1 year) are related to acute or chronic rejection. Thus, the prevention and treatment of rejection have been highly successful in the LT population.

Minimization of Immunosuppression (1-Drug Regimen) in LT

As time passes after LT, many patients can maintain graft function with smaller doses and less toxic immunosuppressive agents. Some patients can tolerate the complete withdrawal of therapy without exhibiting rejection6; however, this is best done as a protocol-based strategy with patients under strict supervision. The current general approach is to minimize immunosuppression over the long term. Various minimization protocols target individual components of the immunosuppressive regimen, such as corticosteroids or CNIs, in an attempt to decrease the long-term complications of immunosuppression.

Monotherapy immunosuppression was noted in only 6% of patients at the time of hospital discharge in 2008. SRTR data show that 1 year after LT, the proportion of recipients on monotherapy increased to 34%, with 84% of these patients on TAC, 6% on CSA, 5% on sirolimus, and <1% on MMF/MPA. Two years after LT, monotherapy was being used for 42% of recipients, with 85% on TAC alone, 6% on CSA, 8% on sirolimus, and 1% on an MMF/MPA treatment. The major advantages of monotherapy are reduced costs and decreases in gastrointestinal side effects with MMF.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. IMMUNOLOGICAL MECHANISMS OF THE REJECTION RESPONSE: THE 3-SIGNAL PATHWAY OF LYMPHOCYTE ACTIVATION
  4. CONCEPTS IN IMMUNOSUPPRESSION
  5. PHASES OF IMMUNOSUPPRESSION
  6. CLASSIFICATION OF IMMUNOSUPPRESSIVE DRUGS
  7. PRACTICE OF LT IMMUNOSUPPRESSION IN THE UNITED STATES
  8. CONCLUSIONS
  9. REFERENCES

During the past decade, the rates of rejection and rejection-related graft loss have decreased dramatically. Today, the long-term complications of immunosuppression have replaced rejection as the major therapeutic challenge. Indeed, 80% of liver recipients experience renal dysfunction, 75% have hypertension, 50% have hyperlipidemia, and 20% to 25% develop new-onset diabetes mellitus. In addition, the incidence of skin cancer approaches 40% in LT recipients.

With low rates of rejection and high rates of immunosuppression-related complications, the data suggest that LT patients are being overimmunosuppressed. Although there have been many trials assessing the ability of new immunosuppressive drugs to reduce the incidence of rejection, we have few clinical trials to address ways of minimizing our use of these potent immunosuppressive agents. Today, the goals of immunosuppression are (1) to minimize the number of immunosuppressive agents that are used, (2) to minimize the dose of each of these immunosuppressive agents, (3) to minimize the side effects related to these medications, and (4) to tailor the regimen to the individual patient according to his or her age, sex, liver function, and liver disease etiology. In essence, we are in a balancing act in which we are attempting to reduce immunosuppressive therapy in order to reduce side effects and complications, reduce maintenance drug costs, improve the convenience for patients, improve the quality of life for patients, and finally prolong patient and graft survival. Although studies continue in areas of tolerance (including examinations of biomarkers that will allow more reliable dosing of immunosuppressive agents), the importance of immunosuppressive drug therapy based on clinical judgment remains as important as ever today.

REFERENCES

  1. Top of page
  2. Abstract
  3. IMMUNOLOGICAL MECHANISMS OF THE REJECTION RESPONSE: THE 3-SIGNAL PATHWAY OF LYMPHOCYTE ACTIVATION
  4. CONCEPTS IN IMMUNOSUPPRESSION
  5. PHASES OF IMMUNOSUPPRESSION
  6. CLASSIFICATION OF IMMUNOSUPPRESSIVE DRUGS
  7. PRACTICE OF LT IMMUNOSUPPRESSION IN THE UNITED STATES
  8. CONCLUSIONS
  9. REFERENCES