Immunosuppressive Drugs in Liver Transplant: An Insight
2022; Elsevier BV; Volume: 12; Issue: 6 Linguagem: Inglês
10.1016/j.jceh.2022.06.007
ISSN2213-3453
AutoresCharles Panackel, Joe F. Mathew, Mohamed Fawas N, Mathew Jacob,
Tópico(s)Liver Disease and Transplantation
ResumoLiver 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. 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. Liver transplantation (LT) is the standard of care for end-stage liver failure and hepatocellular carcinoma (HCC).1Van Thiel D.H. Schade R.R. Starzl T.E. et al.Liver transplantation in adults.Hepatology. 1982 Sep-Oct; 2: 637-640Crossref PubMed Scopus (101) Google Scholar Post-liver transplant patient and graft survival has improved in the last 50 years due to improved surgical techniques, better perioperative care and increased efficacy of immunosuppressive drugs.1Van Thiel D.H. Schade R.R. Starzl T.E. et al.Liver transplantation in adults.Hepatology. 1982 Sep-Oct; 2: 637-640Crossref PubMed Scopus (101) Google Scholar Data from United Network for Organ Sharing (UNOS) database and liver registry with Organ Procurement and Transplantation Network (OPTN) showed that 1-year survival post-liver transplant improved from 66% in 1986 to 92% in 2015.2Rana A. Ackah R.L. Webb G.J. et al.No gains in long-term survival after liver transplantation over the past three decades.Ann Surg. 2019 Jan; 269: 20-27Crossref PubMed Scopus (48) Google Scholar At the same time, post-LT long-term survival has not improved mainly due to increased incidence of immunosuppression-related metabolic side effects, opportunistic infections, and malignancies.2Rana A. Ackah R.L. Webb G.J. et al.No gains in long-term survival after liver transplantation over the past three decades.Ann Surg. 2019 Jan; 269: 20-27Crossref PubMed Scopus (48) Google Scholar In the 1960s, corticosteroids and azathioprine (AZA) were the only immunosuppressive agents available for use in LT.3Tasdogan B.E. Ma M. Simsek C. Saberi B. Gurakar A. Update on immunosuppression in liver transplantation.Euroasian J Hepato-Gastroenterol. 2019 Jul-Dec; 9: 96-101Crossref PubMed Google Scholar This was followed by the introduction of cyclosporine (1983), tacrolimus (TAC) (1994), mycophenolate mofetil (MMF) (1995), anti-thymocyte globulin (ATG) (1998), basiliximab (1998), sirolimus (SRL) (1999), mycophenolate sodium (2004), and everolimus (EVR) (2010).3Tasdogan B.E. Ma M. Simsek C. Saberi B. Gurakar A. Update on immunosuppression in liver transplantation.Euroasian J Hepato-Gastroenterol. 2019 Jul-Dec; 9: 96-101Crossref PubMed Google Scholar The improved efficacy of immunosuppressive regimens came at the cost of long-term side effects. In long-term survivors of LT, mortality due to rejection was only 1.7%.2Rana A. Ackah R.L. Webb G.J. et al.No gains in long-term survival after liver transplantation over the past three decades.Ann Surg. 2019 Jan; 269: 20-27Crossref PubMed Scopus (48) Google Scholar Immunosuppression-related malignancy (16.4%) and opportunistic infections (10.5%) were the leading cause of death in long-term survivors.2Rana A. Ackah R.L. Webb G.J. et al.No gains in long-term survival after liver transplantation over the past three decades.Ann Surg. 2019 Jan; 269: 20-27Crossref PubMed Scopus (48) Google Scholar More potent immunosuppressive drugs also led to increased metabolic disorders, cardiovascular events, and renal dysfunction, with chronic kidney disease seen in 20% of patients surviving more than 5-years post-liver transplant.4Ojo A.O. Held P.J. Port F.K. et al.Chronic renal failure after transplantation of a nonrenal organ.N Engl J Med. 2003 Sep 4; 349: 931-940Crossref PubMed Scopus (1750) Google Scholar The aim of immunosuppression in LT is to prevent the host immune system from rejecting the allograft, at the same time, preserve the immune control over neoplasia and infections. Current immunosuppressive regimens in liver transplants use various combinations of calcineurin inhibitors (CNIs), corticosteroids, molecular target of rapamycin (mTOR) inhibitors, antimetabolites, and biological agents. The combination protocols permit the use of drugs at lower doses without increasing the risk for allograft rejection and concurrently reducing the toxicity of individual agents. These regimens allow a delicate balance between optimal immunosuppression and minimal toxicity. Each regimen is individualized, taking into account the patient's preoperative and perioperative risk profile and changed according to its efficacy, toxicity, and time from transplant.5Charlton M. Levitsky J. Aqel B. et al.International liver transplantation society consensus statement on immunosuppression in liver transplant recipients.Transplantation. 2018 May; 102: 727-743Crossref PubMed Scopus (101) Google Scholar The liver is an immune-privileged organ with less rejection rates than other solid organs.5Charlton M. Levitsky J. Aqel B. et al.International liver transplantation society consensus statement on immunosuppression in liver transplant recipients.Transplantation. 2018 May; 102: 727-743Crossref PubMed Scopus (101) Google Scholar Unlike other organs, human leukocyte antigen (HLA) typing is not done in LT as matching does not affect post-LT outcomes.6Navarro V. Herrine S. Katopes C. Colombe B. Spain C.V. The effect of HLA class I (A and B) and class II (DR) compatibility on liver transplantation outcomes: an analysis of the OPTN database.Liver Transplant. 2006 Apr; 12: 652-658Crossref PubMed Scopus (0) Google Scholar The possible explanations for the immune privilege are (1) transfer of passenger donor immune cells to the recipient, establishing a form of microchimerism, (2) production of soluble donor MHC class I molecules by the liver that block preformed antibodies in LT recipients and inhibit T-cell activation, and (3) resistance of liver to damage by rejection by its sheer size and regenerative capacity.7Geissler E.K. Schlitt H.J. Immunosuppression for liver transplantation.Gut. 2009 Mar; 58: 452-463Crossref PubMed Scopus (92) Google Scholar However, LT recipients experience immunological rejection and requires long-term immunosuppressive medication, but at a much lower dose. With time, alloreactivity in LT recipients declines, and patients acquire “tolerance,” defined as the successful cessation of immunosuppression while maintaining graft function and avoiding rejection.8Knechtle S.J. Kwun J. Unique aspects of rejection and tolerance in liver transplantation.Semin Liver Dis. 2009 Feb; 29: 91-101Crossref PubMed Scopus (0) Google Scholar Here, immune responses to the allograft occur but are kept in check by suppressive mechanisms, hence the term “operational tolerance.”8Knechtle S.J. Kwun J. Unique aspects of rejection and tolerance in liver transplantation.Semin Liver Dis. 2009 Feb; 29: 91-101Crossref PubMed Scopus (0) Google Scholar Hepatic allograft rejection is due to an adaptive immune response triggered by the mismatch of a major histocompatibility complex (MHC) between the donor and the recipient and innate responses initiated by surgical trauma and organ reperfusion injury.9Choudhuri K. Wiseman D. Brown M.H. Gould K. van der Merwe P.A. T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand.Nature. 2005 Jul 28; 436: 578-582Crossref PubMed Scopus (251) Google Scholar Interactions with foreign antigens activate antigen-presenting cells (APCs) from both the donor and the recipient present in the hepatic allograft.10Martinez O.M. Rosen H.R. Basic concepts in transplant immunology.Liver Transplant. 2005 Apr; 11: 370-381Crossref PubMed Scopus (0) Google Scholar These activated antigen-bearing cells move to secondary lymphoid organs where they engage with T-cell receptors (TCRs; CD3 complex) on alloantigen reactive naive T-cells and memory cells to activate lymphocytes (Figure-1). This interaction between donor peptides presented by MHC molecules on the APCs and TCRs (CD3 complex) on alloantigen reactive naive T-cells is called signal-1.10Martinez O.M. Rosen H.R. Basic concepts in transplant immunology.Liver Transplant. 2005 Apr; 11: 370-381Crossref PubMed Scopus (0) Google Scholar When CD80 and CD86 receptors on the APCs interact with CD28 receptors on T lymphocytes, co-stimulation or signal-2 for T-cell activation occurs.11Wang D. Matsumoto R. You Y. et al.CD3/CD28 costimulation-induced NF-kappaB activation is mediated by recruitment of protein kinase C-theta, Bcl10, and IkappaB kinase beta to the immunological synapse through CARMA1.Mol Cell Biol. 2004 Jan; 24: 164-171Crossref PubMed Scopus (0) Google Scholar The signal-1 and signal-2 activate the transcription factors nuclear factor of activated T-cells, activating protein 1 (AP-1), and nuclear factor-kB (NF-kB) via three signaling pathways: calcium–calcineurin, mitogen-activated protein kinase, and protein kinase C–nuclear factor-kB (NF-kB), which in turn promotes transcription of CD154 (which further activates APCs), interleukin-2 receptor alpha chain (CD25), and interleukin-2. Interleukin-2 (IL-2) along with interleukin-15 (IL-15) initiate the cell replication cycle via growth signals (signal-3) through the phosphoinositide-3-kinase (PI-3K) pathway and the mTOR pathway. Lymphocytes require the synthesis of purine and pyrimidine nucleotides for replication. It is regulated by inosine monophosphate dehydrogenase (IMPDH) and dihydroorotate dehydrogenase, respectively. Lymphocyte proliferation generations large numbers of effector T- and B-cells in lymphoid organs, which migrate to the hepatic allograft and initiate an inflammatory response leading to allograft destruction.12Wiesner R.H. Ludwig J. van Hoek B. Krom R.A. Current concepts in cell-mediated hepatic allograft rejection leading to ductopenia and liver failure.Hepatology. 1991 Oct; 14: 721-729Crossref PubMed Scopus (128) Google Scholar The understanding of these pathways helped develop newer drugs used in current immunosuppression regimens. The various immunosuppressive drugs act by inhibiting small molecules downstream of signals 1, 2, and 3 (Table 1). CNIs bind to intracellular small molecules, “cyclophilin” for cyclosporine A (CsA) and “FK506-binding protein (FKBP12)” for TAC and inhibit calcium/calmodulin-dependent phosphatase, “calcineurin.”40Pillai A.A. Levitsky J. Overview of immunosuppression in liver transplantation.World J Gastroenterol. 2009 Sep 14; 15: 4225-4233Crossref PubMed Scopus (54) Google Scholar The calcineurin inhibition prevents IL-2 gene transcription, which inturn inhibits T-cell activation and proliferation. mTOR inhibitors bind intracellularly to FK506-binding protein (FKBP12) but inhibit the mammalian target of rapamycin complex instead of calcineurin.57Halloran P.F. Immunosuppressive drugs for kidney transplantation.N Engl J Med. 2004 Dec 23; 351: 2715-2729Crossref PubMed Scopus (1155) Google Scholar,58Shihab F. Christians U. Smith L. Wellen J.R. Kaplan B. Focus on mTOR inhibitors and tacrolimus in renal transplantation: pharmacokinetics, exposure-response relationships, and clinical outcomes.Transpl Immunol. 2014 Jun; 31: 22-32Crossref PubMed Scopus (30) Google Scholar,59De Simone P. Fagiuoli S. Cescon M. et al.Consensus PanelUse of everolimus in liver transplantation: recommendations from a working group.Transplantation. 2017 Feb; 101: 239-251Crossref PubMed Scopus (0) Google Scholar It, thus, blocks signal-3 of T-cell activation, thereby inhibiting IL-2 and IL-15 induced T-cell proliferation. The antimetabolite group of drugs inhibit T-cell proliferation by reversible inhibition of purine synthesis. MMF and its active metabolite, mycophenolic acid (MPA), have additional immunomodulatory actions. Corticosteroids have anti-inflammatory and immunomodulatory action by interacting with antigen-presenting dendritic cells, modulating IL-1 transcription, decreasing the number of circulating CD4+ T-cells, and inhibiting IL-1-dependent lymphocyte activation. The various biological agents act by either depleting T-cells and B-cells or inhibiting their proliferation by binding to respective receptors.Table 1Classification and Action of Immunosuppressants.ImmunosuppressantActionT-cell activation inhibitors CyclosporineInhibits calcineurin via cyclophilin, blocking IL2 transcription TacrolimusInhibits calcineurin via FKBP12, blocking IL2 transcription BelataceptCTLA-4 homologue competing with CD28 for CD80/86 binding, inhibiting T-cell co-stimulationT-cell depletion Anti-thymocyte globulinAntibody preparation directed against lymphocytes AlemtuzumabAnti-CD52-specific antibody highly depletive of lymphocytes, as well as NK cells, monocytes and thymocytes Muromonab-CD3 (OKT3)Anti-CD3-specific antibody causing T-cell depletionT-cell proliferation inhibitors MPA prodrugsIMPDH inhibitor: enzyme required for de novo synthesis of guanosine nucleotides, required for lymphocyte proliferation mTOR inhibitorsmTOR blockade prevents IL2-induced T-cell proliferation AzathioprineInhibits purine synthesis, thereby blocking immune cell proliferation IL2 receptor antibodiesBlocks IL2 engagement and resultant lymphocyte proliferationAPC, antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte antigen 4; FKBP12, FK-binding protein-12; IL2, interleukin 2; IMPDH, inosine-59-monophosphate dehydrogenase; LFA-1, leukocyte function-associated antigen-1; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin; NK, natural killer. Open table in a new tab APC, antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte antigen 4; FKBP12, FK-binding protein-12; IL2, interleukin 2; IMPDH, inosine-59-monophosphate dehydrogenase; LFA-1, leukocyte function-associated antigen-1; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin; NK, natural killer. There are two types of immunosuppressive drugs: (1) pharmacological agents or small molecule agents and (2) biological agents (i.e., polyclonal and monoclonal anti-lymphocyte antibodies) (Figure 2).13Halloran P.F. Immunosuppressive drugs for kidney transplantation.N Engl J Med. 2004 Dec 23; 351: 2715-2729Crossref PubMed Scopus (1155) Google Scholar,14Bush W.W. Overview of transplantation immunology and the pharmacotherapy of adult solid organ transplant recipients: focus on immunosuppression.AACN Clin Issues. 1999 May; 10: 253-269Crossref PubMed Google Scholar,15Wiesner R.H. Fung J.J. Present state of immunosuppressive therapy in liver transplant recipients.Liver Transplant. 2011 Nov; 17: S1-S9Crossref PubMed Scopus (74) Google Scholar The pharmacological immunosuppressive agents act by inhibiting cytokine release (CNIs, corticosteroids) or inhibiting the cell cycle (anti-metabolites and mTOR inhibitors.14Bush W.W. Overview of transplantation immunology and the pharmacotherapy of adult solid organ transplant recipients: focus on immunosuppression.AACN Clin Issues. 1999 May; 10: 253-269Crossref PubMed Google Scholar,15Wiesner R.H. Fung J.J. Present state of immunosuppressive therapy in liver transplant recipients.Liver Transplant. 2011 Nov; 17: S1-S9Crossref PubMed Scopus (74) Google Scholar Biological immunosuppressive are classified into lymphocyte-depleting immunosuppressive agents that deplete T-cells (ATG), B-cells (rituximab), or plasma cells (bortezomib) and non–lymphocyte-depleting agents (basiliximab) that inhibit T-cell proliferation without affecting lymphocyte populations.16Turner A.P. Knechtle S.J. Induction immunosuppression in liver transplantation: a review.Transpl Int. 2013 Jul; 26: 673-683Crossref PubMed Scopus (0) Google Scholar,17Penninga L. Wettergren A. Wilson C.H. Chan A.W. Steinbrüchel D.A. Gluud C. Antibody induction versus placebo, no induction, or another type of antibody induction for liver transplant recipients.Cochrane Database Syst Rev. 2014 Jun 5; : CD010253PubMed Google Scholar,18Yadav D.K. Hua Y.F. Bai X. et al.ABO-incompatible adult living donor liver transplantation in the era of rituximab: a systematic review and meta-analysis.Gastroenterol Res Pract. 2019; 20198589402Crossref Scopus (9) Google Scholar,19Lee C.F. Eldeen F.Z. Chan K.M. et al.Bortezomib is effective to treat acute humoral rejection after liver transplantation.Transplant Proc. 2012 Mar; 44: 529-531Crossref PubMed Scopus (25) Google Scholar In LT, biological agents are used as antibody induction agents, in treating steroid-refractory rejection, in ABO-incompatible LT and management of antibody-mediated rejection (AMR).16Turner A.P. Knechtle S.J. Induction immunosuppression in liver transplantation: a review.Transpl Int. 2013 Jul; 26: 673-683Crossref PubMed Scopus (0) Google Scholar,17Penninga L. Wettergren A. Wilson C.H. Chan A.W. Steinbrüchel D.A. Gluud C. Antibody induction versus placebo, no induction, or another type of antibody induction for liver transplant recipients.Cochrane Database Syst Rev. 2014 Jun 5; : CD010253PubMed Google Scholar,18Yadav D.K. Hua Y.F. Bai X. et al.ABO-incompatible adult living donor liver transplantation in the era of rituximab: a systematic review and meta-analysis.Gastroenterol Res Pract. 2019; 20198589402Crossref Scopus (9) Google Scholar,19Lee C.F. Eldeen F.Z. Chan K.M. et al.Bortezomib is effective to treat acute humoral rejection after liver transplantation.Transplant Proc. 2012 Mar; 44: 529-531Crossref PubMed Scopus (25) Google Scholar Immunosuppressive agents can also be classified based on their mechanism of action (Table 1). Antibodies that inhibit or deplete T-cells are used as induction agents or to treat steroid-refractory rejection in LT (Table 2).16Turner A.P. Knechtle S.J. Induction immunosuppression in liver transplantation: a review.Transpl Int. 2013 Jul; 26: 673-683Crossref PubMed Scopus (0) Google Scholar,20Lee J.G. Lee J. Lee J.J. Efficacy of rabbit anti-thymocyte globulin for steroid-resistant acute rejection after liver transplantation.Medicine (Baltim). 2016; 95e3711Google Scholar, 21Fernandes M.L. Lee Y.M. Sutedja D. Treatment of steroid-resistant acute liver transplant rejection with basiliximab.Transplant Proc. 2005; 37: 2179Crossref PubMed Scopus (0) Google Scholar, 22Choudhary N.S. Saigal S. Bansal R.K. Saraf N. Gautam D. Soin A.S. Acute and chronic rejection after liver transplantation: what A clinician needs to know.J Clin Exp Hepatol. 2017; 7: 358-366Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Antibody induction is commonly used in "steroid-free" protocols and as CNI sparing agents in LT.5Charlton M. Levitsky J. Aqel B. et al.International liver transplantation society consensus statement on immunosuppression in liver transplant recipients.Transplantation. 2018 May; 102: 727-743Crossref PubMed Scopus (101) Google Scholar,16Turner A.P. Knechtle S.J. Induction immunosuppression in liver transplantation: a review.Transpl Int. 2013 Jul; 26: 673-683Crossref PubMed Scopus (0) Google Scholar,17Penninga L. Wettergren A. Wilson C.H. Chan A.W. Steinbrüchel D.A. Gluud C. Antibody induction versus placebo, no induction, or another type of antibody induction for liver transplant recipients.Cochrane Database Syst Rev. 2014 Jun 5; : CD010253PubMed Google Scholar This "steroid-free" regime is beneficial in hepatitis C and non-alcoholic steatohepatitis (NASH)-related cirrhosis.5Charlton M. Levitsky J. Aqel B. et al.International liver transplantation society consensus statement on immunosuppression in liver transplant recipients.Transplantation. 2018 May; 102: 727-743Crossref PubMed Scopus (101) Google Scholar,16Turner A.P. Knechtle S.J. Induction immunosuppression in liver transplantation: a review.Transpl Int. 2013 Jul; 26: 673-683Crossref PubMed Scopus (0) Google Scholar,17Penninga L. Wettergren A. Wilson C.H. Chan A.W. Steinbrüchel D.A. Gluud C. Antibody induction versus placebo, no induction, or another type of antibody induction for liver transplant recipients.Cochrane Database Syst Rev. 2014 Jun 5; : CD010253PubMed Google Scholar Antibody induction permits delayed CNI introduction, thus protecting renal function in LT recipients.23Ramirez C.B. Doria C. Frank A.M. et al.Completely steroid-free immunosuppression in liver transplantation: a randomized study.Clin Transplant. 2013; 27: 463-471Crossref PubMed Scopus (0) Google Scholar,24Neuberger J.M. Mamelok R.D. Neuhaus P. et al.Delayed introduction of reduced-dose tacrolimus, and renal function in liver transplantation: the 'ReSpECT' study.Am J Transplant. 2009; 9: 327-336Crossref PubMed Scopus (140) Google Scholar,25Soliman T. Hetz H. Burghuber C. et al.Short-term induction therapy with anti-thymocyte globulin and delayed use of calcineurin inhibitors in orthotopic liver transplantation.Liver Transplant. 2007; 13: 1039-1044Crossref PubMed Scopus (0) Google Scholar Overall, there is decreased acute rejection episodes and no increase in adverse side effects with antibody induction.16Turner A.P. Knechtle S.J. Induction immunosuppression in liver transplantation: a review.Transpl Int. 2013 Jul; 26: 673-683Crossref PubMed Scopus (0) Google Scholar However, they are costly. Biological agents used in induction therapy are classified into, T-cell-depleting agents [polyclonal – ATGs, monoclonal – alemtuzumab (Campath – 1H), muromonab-CD3 (OKT3)], and non-depleting agents [interleukin 2 receptor antagonists (IL- 2Ra), anti-CD28 inhibitor (belatacept)].16Turner A.P. Knechtle S.J. Induction immunosuppression in liver transplantation: a review.Transpl Int. 2013 Jul; 26: 673-683Crossref PubMed Scopus (0) Google Scholar,26Dhesi S. Boland B. Colquhoun S. Alemtuzumab and liver transplantation: a review.Curr Opin Organ Transplant. 2009 Jun; 14: 245-249Crossref PubMed Scopus (0) Google Scholar,27Perez C.P. Patel N. Mardis C.R. Meadows H.B. Taber D.J. Pilch N.A. Belatacept in solid organ transplant: review of current literature across transplant types.Transplantation. 2018 Sep; 102: 1440-1452Crossref PubMed Scopus (27) Google ScholarTable -2Biological Agents in Liver Transplantation.DrugMechanism of actionUseCommentsMuromonab-CD3 (OKT3)T-cell-depleting monoclonal antibodyInduction of immunosuppression, treatment of steroid resistant rejectionWithdrawn from the market.Alemtuzumab (campath-1H)T-cell-depleting monoclonal antibodyInduction of immunosuppressionVariable between centers, a single dose of 30 mg may be used in operating room.ATG (thymoglobulin, ATGAM)T-cell-depleting polyclonal antibodyInduction of immunosuppression, treatment of steroid resistant rejectionVariable between centers, for induction 1.5 mg/kg per day iv for 3 d and for treatment of rejection 1.5 mg/kg per day iv for 5–7 d of thymoglobulin may be used. For ATGAM a higher dose of 15 mg/kg per day is usually used.Daclizumab (Zenapax)IL-2Ra, monoclonal antibodyInduction of immunosuppression, treatment of steroid-resistant rejectionWithdrawn from the market.Basiliximab (Simulect)IL-2Ra, monoclonal antibodyInduction of immunosuppression, treatment of steroid resistant rejectionFor induction a 20 mg iv dose is administered within 6 h of reperfusion and another 20 mg on days 4 post Tx.BelataceptAnti-CD28 monoclonal antibodyCNI sparing agentNot recommended in LT.ATG: Anti-thymocyte globulin, IL-2Ra Interleukin-2 receptor. Open table in a new tab ATG: Anti-thymocyte globulin, IL-2Ra Interleukin-2 receptor. ATGs are polyclonal antibodies used to deplete circulating lymphocytes.28Schmitt T.M. Phillips M. Sawyer R.G. et al.Anti-thymocyte globulin for the treatment of acute cellular rejection following liver transplantation.Dig Dis Sci. 2010; 55: 3224-3234Crossref PubMed Scopus (19) Google Scholar,29Langrehr J.M. Nüssler N.C. Neumann U. et al.A prospective randomized trial comparing interleukin-2 receptor antibody versus antithymocyte globulin as part of a quadruple immunosuppressive induction therapy following orthotopic liver transplantation.Transplantation. 1997; 63: 1772-1781Crossref PubMed Scopus (0) Google Scholar ATG is mostly used to treat steroid resistance rejection and rarely as an induction agent in LT. Of the two preparations of ATG, ATGAM is from the horse, and Thymoglobulin is of rabbit origin.30Brennan D.C. Flavin K. Lowell J.A. et al.A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients.Transplantation. 1999; 67: 1011-1018Crossref PubMed Scopus (275) Google Scholar Thymoglobulin is superior to the ATGAM with fewer opportunistic infections, less serious adverse side effects and better efficacy.29Langrehr J.M. Nüssler N.C. Neumann U. et al.A prospective randomized trial comparing interleukin-2 receptor antibody versus antithymocyte globulin as part of a quadruple immunosuppressive induction therapy following orthotopic liver transplantation.Transplantation. 1997; 63: 1772-1781Crossref PubMed Scopus (0) Google Scholar,30Brennan D.C. Flavin K. Lowell J.A. et al.A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients.Transplantation. 1999; 67: 1011-1018Crossref PubMed Scopus (275) Google Scholar But More profound leucopenia is observed with thymoglobulin than ATGAM.28Schmitt T.M. Phillips M. Sawyer R.G. et al.Anti-thymocyte globulin for the treatment of acute cellular rejection following liver transplantation.Dig Dis Sci. 2010; 55: 3224-3234Crossref PubMed Scopus (19) Google Scholar,29Langrehr J.M. Nüssler N.C. Neumann U. et al.A prospective randomized trial comparing interleukin-2 receptor antibody versus antithymocyte globulin as part of a quadruple immunosuppressive induction therapy following orthotopic liver transplantation.Transplantation. 1997; 63: 1772-1781Crossref PubMed Scopus (0) Google Scholar,30Brennan D.C. Flavin K. Lowell J.A. et al.A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients.Transplantation. 1999; 67: 1011-1018Crossref PubMed Scopus (275) Google Scholar A daily infusion of 2.5 mg/kg/d of Thymoglobulin for ten days is the standard procedure for ATG induction therapy. Shorter three-day courses have shown similar efficacy in LT with fewer adverse effects.28Schmitt T.M. Phillips M. Sawyer R.G. et al.Anti-thymocyte globulin for the treatment of acute cellular rejection following liver transplantation.Dig Dis Sci. 2010; 55: 3224-3234Crossref PubMed Scopus (19) Google Scholar,31Soliman T. Hetz H. Burghuber C. et al.Short-term versus long-term induction therapy with antithymocyte globulin in orthotopic liver transplantation.Transpl Int. 2007; 20: 447-452Crossref PubMed Scopus (0) Google Scholar Intermittent dosing of ATGAM, where subsequent doses of ATG are given only if CD3 count is above 20 cells/mm3 is also effective and has cost benefit.31Soliman T. Hetz H. Burghuber C. et al.Short-term versus long-term induction therapy with antithymocyte globulin in orthotopic liver transplantation.Transpl Int. 2007; 20: 447-452Crossref PubMed Scopus (0) Google Scholar Infusion reactions, serum sickness, severe cytokine release sy
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