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Immunology of Liver Transplantation

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Book cover Contemporary Liver Transplantation

Part of the book series: Organ and Tissue Transplantation ((OTT))

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Abstract

Immunosuppression has allowed the liver transplant recipient to have prolonged graft survival in the modern era. Graft loss from acute and chronic rejection has greatly declined, allowing clinicians to focus more on disease recurrence rather than rejection. The use of induction regimens in liver transplant has increased over the last decade to approximately 30 % of liver transplant recipients, and their main role is to decrease the short- and long-term renal effects of calcineurin inhibitors. Today, the mainstay of maintenance immunosuppression includes a calcineurin inhibitor, an antimetabolite agent, and in certain circumstances the addition of low-dose corticosteroids. Newer agents such as the mammalian target of rapamycin inhibitors may be viable options to diminish the renal effects of calcineurin inhibitors and may have a role in preventing hepatocellular carcinoma recurrence. Given the potent systemic effects of all immunosuppressive medications, they have long-term complications that need to be managed, as well as high potential for drug-drug interactions. The incidence of acute cellular rejection has decreased in the modern era. A single episode of rejection does not portend worse survival, with the exception of patients with hepatitis C virus. Lastly, the incidence of chronic rejection is extremely low, and early recognition and treatment may improve overall graft survival.

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References

  • Abdelmalek MF, Humar A, Stickel F et al (2012) Sirolimus conversion regimen versus continued calcineurin inhibitors in liver allograft recipients: a randomized trial. Am J Transplant 12:694–705

    Article  CAS  PubMed  Google Scholar 

  • Asrani SK, Leise MD, West CP et al (2010) Use of sirolimus in liver transplant recipients with renal insufficiency: a systematic review and meta-analysis. Hepatology 52:1360–1370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Asrani SK, Wiesner RH, Trotter JF et al (2014) De novo sirolimus and reduced-dose tacrolimus versus standard-dose tacrolimus after liver transplantation: the 2000–2003 phase II prospective randomized trial. Am J Transplant 14:356–366

    Article  CAS  PubMed  Google Scholar 

  • Bogetti D, Sankary HN, Jarzembowski TM et al (2005) Thymoglobulin induction protects liver allografts from ischemia/reperfusion injury. Clin Transplant 19:507–511

    Article  PubMed  Google Scholar 

  • Boillot O, Seket B, Dumortier J et al (2009) Thymoglobulin induction in liver transplant recipients with a tacrolimus, mycophenolate mofetil, and steroid immunosuppressive regimen: a five-year randomized prospective study. Liver Transpl 15:1426–1434

    Article  PubMed  Google Scholar 

  • Burton JR, Rosen HR (2006) Acute rejection in HCV-infected liver transplant recipients: the great conundrum. Liver Transpl 12:2–3

    Article  Google Scholar 

  • Cantarovich M, Barkun JS, Tchervenkov JI et al (1998) Comparison of neoral dose monitoring with cyclosporine through levels versus 2-hr postdose levels in stable liver transplant patients. Transplantation 66:1621–1627

    Article  CAS  PubMed  Google Scholar 

  • Cantisani GPC, Zanotelli ML, Gleisner AL et al (2006) Enteric-coated mycophenolate sodium experience in liver transplant patients. Transplant Proc 38:932–933

    Article  CAS  PubMed  Google Scholar 

  • Charlton MR (2013) How important is acute cellular rejection? Liver Transpl 19(Suppl 2):S9–S13

    Article  PubMed  Google Scholar 

  • Colonna JO, Goldstein LI, Brems JJ et al (1987) A prospective study on the use of monoclonal anti-T3-cell antibody (OKT3) to treat steroid-resistant liver transplant rejection. Arch Surg 122:1120–1123

    Article  PubMed  Google Scholar 

  • De Simone P, Nevens F, De Carlis L et al (2012) Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant 12:3008–3020

    Article  PubMed  PubMed Central  Google Scholar 

  • Demetris AJ, Batts KP, Dhillon AP et al (1997) Banff schema for grading liver allograft rejection: an international consensus document. Hepatology 25:658–663

    Article  Google Scholar 

  • Demetris A, Adams D, Bellamy C et al (2000) Update of the International Banff Schema for Liver Allograft Rejection: working recommendations for the histopathologic staging and reporting of chronic rejection. An International Panel. Hepatology 31:792–799

    Article  CAS  PubMed  Google Scholar 

  • Dumortier J, Gagnieu MC, Salandre J et al (2006) Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in liver transplant patients presenting gastrointestinal disorders: a pilot study. Liver Transpl 12:1342–1346

    Article  PubMed  Google Scholar 

  • Eason JD, Blazek J, Mason A et al (2001) Liver transplantation. Clin Transplant 1471:1470–1471

    Google Scholar 

  • European FK506 Multicentre Liver Study Group (1994) Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. European FK506 Multicentre Liver Study Group. Lancet 344:423–428

    Article  Google Scholar 

  • Fernandes ML, Lee YM, Sutedja D et al (2005) Treatment of steroid-resistant acute liver transplant rejection with Basiliximab. Transplant Proc 37:2179–2180

    Article  CAS  PubMed  Google Scholar 

  • Fischer L, Sterneck M, Gahlemann CG et al (2000) A prospective study comparing safety and efficacy of mycophenolate mofetil versus azathioprine in primary liver transplant recipients. Transplant Proc 32:2125–2127

    Article  CAS  PubMed  Google Scholar 

  • Fischer L, Klempnauer J, Beckebaum S et al (2012) A randomized, controlled study to assess the conversion from calcineurin-inhibitors to everolimus after liver transplantation – PROTECT. Am J Transplant 12:1855–1865

    Article  CAS  PubMed  Google Scholar 

  • Game DS, Lechler RI (2002) Pathways of allorecognition: implications for transplantation tolerance. Transpl Immunol 10:101–108

    Article  CAS  PubMed  Google Scholar 

  • Gane EJ, Naoumov NV, Qian KP et al (1996) A longitudinal analysis of hepatitis C virus replication following liver transplantation. Eur J Gastroenterol Hepatol 8:295

    Article  Google Scholar 

  • Germani G, Pleguezuelo M, Villamil F et al (2009) Azathioprine in liver transplantation: a reevaluation of its use and a comparison with mycophenolate mofetil. Am J Transplant 9:1725–1731

    Article  CAS  PubMed  Google Scholar 

  • Gonwa TA, Mai ML, Melton LB et al (2001) End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: risk of development and treatment. Transplantation 72:1934–1939

    Article  CAS  PubMed  Google Scholar 

  • Goralczyk AD, Hauke N, Bari N et al (2011) Interleukin 2 receptor antagonists for liver transplant recipients: a systematic review and meta-analysis of controlled studies. Hepatology 54:541–554

    Article  CAS  PubMed  Google Scholar 

  • Haddad EM, McAlister VC, Renouf E et al (2006) Cyclosporin versus tacrolimus for liver transplanted patients. Cochrane Database Syst Rev CD005161

    Google Scholar 

  • Heeger PS, Dinavahi R (2012) Transplant immunology for non-immunologist. Mt Sinai J Med 79:376–387

    Article  PubMed  Google Scholar 

  • Humar A, Crotteau S, Gruessner A et al (2007) Steroid minimization in liver transplant recipients: impact on hepatitis C recurrence and post-transplant diabetes. Clin Transplant 21:526–531

    Article  PubMed  Google Scholar 

  • Kahan B, Napoli K, Kelly P et al (2000) Therapeutic drug monitoring of sirolimus: correlations with efficacy and toxicity. Clin Transplant 14:97–109

    Article  CAS  PubMed  Google Scholar 

  • Keown P, Landsberg D, Halloran P et al (1996) A randomized, prospective multicenter pharmacoepidemiologic study of cyclosporine microemulsion in stable renal graft recipients. Report of the Canadian Neoral Renal Transplantation Study Group. Transplantation 62:1744–1752

    Article  CAS  PubMed  Google Scholar 

  • Kim WR, Lake JR, Smith JM et al (2015) OPTN/SRTR 2013 annual data report: liver. Am J Transplant 15(Suppl 2):1–28

    Article  PubMed  Google Scholar 

  • Kirk AD (2006) Induction immunosuppression. Transplantation 82:593–602

    Article  PubMed  Google Scholar 

  • Klintmalm GB, Davis GL, Teperman L et al (2011) A randomized, multicenter study comparing steroid-free immunosuppression and standard immunosuppression for liver transplant recipients with chronic hepatitis C. Liver Transpl 17:1394–1403

    Article  PubMed  Google Scholar 

  • Klintmalm GB, Feng S, Lake JR et al (2014) Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II randomized study. Am J Transplant 14:1817–1827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levitsky J, Thudi K, Ison MG et al (2011) Alemtuzumab induction in non-hepatitis C positive liver transplant recipients. Liver Transpl 17:32–37

    Article  PubMed  Google Scholar 

  • Liang W, Wang D, Ling X et al (2012) Sirolimus-based immunosuppression in liver transplantation for hepatocellular carcinoma: a meta-analysis. Liver Transpl 18:62–69

    Article  PubMed  Google Scholar 

  • Lladó L, Fabregat J, Castellote J et al (2008) Impact of immunosuppression without steroids on rejection and hepatitis C virus evolution after liver transplantation: results of a prospective randomized study. Liver Transpl 14:1752–1760

    Article  PubMed  Google Scholar 

  • Magy N, Cribier B, Schmitt C et al (1999) Effects of corticosteroids on HCV infection. Int J Immunopharmacol 21:253–261

    Article  CAS  PubMed  Google Scholar 

  • Marcos A, Eghtesad B, Fung JJ et al (2004) Use of alemtuzumab and tacrolimus monotherapy for cadaveric liver transplantation: with particular reference to hepatitis C virus. Transplantation 78:966–971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mardigyan V, Tchervenkov J, Metrakos P et al (2005) Best single time points as surrogates to the tacrolimus and mycophenolic acid area under the curve in adult liver transplant patients beyond 12 months of transplantation. Clin Ther 27:463–469

    Article  CAS  PubMed  Google Scholar 

  • Martinez OM, Rosen HR (2005) Basic concepts in transplant immunology. Liver Transpl 11:370–381

    Article  PubMed  Google Scholar 

  • McKenna GJ, Trotter JF, Klintmalm E et al (2013) Sirolimus and cardiovascular disease risk in liver transplantation. Transplantation 95:215–221

    Article  CAS  PubMed  Google Scholar 

  • Naesens M, Kuypers DRJ, Sarwal M (2009) Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 4:481–508

    CAS  PubMed  Google Scholar 

  • Nankivell BJ, Borrows RJ, Fung CL-S et al (2003) The natural history of chronic allograft nephropathy. N Engl J Med 349:2326–2333

    Article  CAS  PubMed  Google Scholar 

  • Neuberger JM, Mamelok RD, Neuhaus P et al (2009) Delayed introduction of reduced-dose tacrolimus, and renal function in liver transplantation: the “ReSpECT” study. Am J Transplant 9:327–336

    Article  CAS  PubMed  Google Scholar 

  • O’Grady JG, Burroughs A, Hardy P et al (2002) Tacrolimus versus microemulsified ciclosporin in liver transplantation: the TMC randomised controlled trial. Lancet 360:1119–1125

    Article  PubMed  Google Scholar 

  • O’Grady JG, Hardy P, Burroughs AK, Elbourne D (2007) Randomized controlled trial of tacrolimus versus microemulsified cyclosporin (TMC) in liver transplantation: poststudy surveillance to 3 years. Am J Transplant 7:137–141

    Article  PubMed  Google Scholar 

  • Orr DW, Portmann BC, Knisely AS et al (2005) Anti-interleukin 2 receptor antibodies and mycophenolate mofetil for treatment of steroid-resistant rejection in adult liver transplantation. Transplant Proc 37:4373–4379

    Article  CAS  PubMed  Google Scholar 

  • Penninga L, Wettergren A, Wilson Colin H et al (2012) Antibody induction versus placebo, no induction, or another type of antibody induction for liver transplant recipients. Cochrane Database Syst Rev. doi:10.1002/14651858.CD010253

    Google Scholar 

  • Petrovic LM (2006) Early recurrence of hepatitis C virus infection after liver transplantation. Liver Transpl 12:S32–S37

    Article  PubMed  Google Scholar 

  • Rostaing L, Christiaans MHL, Kovarik JM, Pascual J (2014) The pharmacokinetics of everolimus in de novo kidney transplant patients receiving tacrolimus: an analysis from the randomized ASSET study. Ann Transplant 19:337–345

    Article  PubMed  Google Scholar 

  • Samonakis DN, Germani G, Burroughs AK (2012) Immunosuppression and HCV recurrence after liver transplantation. J Hepatol 56:973–983

    Article  CAS  PubMed  Google Scholar 

  • Schiff J, Cole E, Cantarovich M (2007) Therapeutic monitoring of calcineurin inhibitors for the nephrologist. Clin J Am Soc Nephrol 2:374–384

    Article  CAS  PubMed  Google Scholar 

  • Sgourakis G, Radtke A, Fouzas I et al (2009) Corticosteroid-free immunosuppression in liver transplantation: a meta-analysis and meta-regression of outcomes. Transpl Int 22:892–905

    Article  CAS  PubMed  Google Scholar 

  • Sharma P, Welch K, Eikstadt R et al (2009) Renal outcomes after liver transplantation in the model for end-stage liver disease era. Liver Transpl 15:1142–1148

    Article  PubMed  Google Scholar 

  • Soliman T, Hetz H, Burghuber C et al (2007) Short-term induction therapy with anti-thymocyte globulin and delayed use of calcineurin inhibitors in orthotopic liver transplantation. Liver Transpl 13:1039–1044

    Article  PubMed  Google Scholar 

  • Solomon H, Gonwa TA, Mor E et al (1993) OKT3 rescue for steroid-resistant rejection in adult liver transplantation. Transplantation 55:87–91

    Article  CAS  PubMed  Google Scholar 

  • Starzl TE, Ishikawa M, Putnam CW et al (1974) Progress in and deterrents to orthotopic liver transplantation, with special reference to survival, resistance to hyperacute rejection, and biliary duct reconstruction. Transplant Proc 6:129–139

    CAS  PubMed  PubMed Central  Google Scholar 

  • Starzl TE, Klintmalm GB, Porter KA et al (1981) Liver transplantation with use of cyclosporin a and prednisone. N Engl J Med 305:266–269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sterneck M, Fischer L, Gahlemann C et al (2000) Mycophenolate mofetil for prevention of liver allograft rejection: initial results of a controlled clinical trial. Ann Transplant 5:43–46

    CAS  PubMed  Google Scholar 

  • Tchervenkov JI, Tzimas GN, Cantarovich M et al (2004) The impact of thymoglobulin on renal function and calcineurin inhibitor initiation in recipients of orthotopic liver transplant: a retrospective analysis of 298 consecutive patients. Transplant Proc 36:1747–1752

    CAS  PubMed  Google Scholar 

  • Thurairajah PH, Carbone M, Bridgestock H et al (2013) Late acute liver allograft rejection; a study of its natural history and graft survival in the current era. Transplantation 95:955–959

    Article  PubMed  Google Scholar 

  • Tryphonopoulos P, Madariaga JR, Kato T et al (2005) The impact of Campath 1H induction in adult liver allotransplantation. Transplant Proc 37:1203–1204

    Article  CAS  PubMed  Google Scholar 

  • Turner AP, Knechtle SJ (2013) Induction immunosuppression in liver transplantation: a review. Transpl Int 26:673–683

    Article  CAS  PubMed  Google Scholar 

  • Tzakis AG, Tryphonopoulos P, Kato T et al (2004) Preliminary experience with alemtuzumab (Campath-1H) and low-dose tacrolimus immunosuppression in adult liver transplantation. Transplantation 77:1209–1214

    Article  CAS  PubMed  Google Scholar 

  • U.S. Multicenter FK506 Liver Study Group (1994) A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. The U.S. Multicenter FK506 Liver Study Group. N Engl J Med 331:1110–1115

    Article  Google Scholar 

  • Valujskikh A, Hartig C, Heeger PS (2001) Indirectly primed CD8+ T cells are a prominent component of the allogeneic T-cell repertoire after skin graft rejection in mice. Transplantation 71:418–421

    Article  CAS  PubMed  Google Scholar 

  • Van Gelder T, Hilbrands LB, Vanrenterghem Y et al (1999) A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation. Transplantation 68:261–266

    Article  PubMed  Google Scholar 

  • Van Gelder T, Le Meur Y, Shaw LM et al (2006) Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 28:145–154

    Article  PubMed  Google Scholar 

  • Vivarelli M, Burra P, La Barba G et al (2007) Influence of steroids on HCV recurrence after liver transplantation: a prospective study. J Hepatol 47:793–798

    Article  CAS  PubMed  Google Scholar 

  • Volpin R, Angeli P, Galioto A et al (2002) Comparison between two high-dose methylprednisolone schedules in the treatment of acute hepatic cellular rejection in liver transplant recipients: a controlled clinical trial. Liver Transpl 8:527–534

    Article  PubMed  Google Scholar 

  • Wang XF, Li JD, Peng Y et al (2010) Interleukin-2 receptor antagonists in liver transplantation: a meta-analysis of randomized trials. Transplant Proc 42:4567–4572

    Article  CAS  PubMed  Google Scholar 

  • Wang YC, Wu TJ, Wu TH et al (2012) The risk factors to predict acute rejection in liver transplantation. Transplant Proc 44:526–528

    Article  PubMed  Google Scholar 

  • Wiesner RH, Fung JJ (2011) Present state of immunosuppressive therapy in liver transplant recipients. Liver Transpl 17(Suppl 3):S1–S9

    Article  PubMed  Google Scholar 

  • Wiesner RH, Demetris AJ, Belle SH et al (1998) Acute hepatic allograft rejection: incidence, risk factors, and impact on outcome. Hepatology 28:638–645

    Article  CAS  PubMed  Google Scholar 

  • Wiesner RH, Batts KP, Krom RA (1999) Evolving concepts in the diagnosis, pathogenesis, and treatment of chronic hepatic allograft rejection. Liver Transpl Surg 5:388–400

    Article  CAS  PubMed  Google Scholar 

  • Wiesner R, Rabkin J, Klintmalm G et al (2001) A randomized double-blind comparative study of mycophenolate mofetil and azathioprine in combination with cyclosporine and corticosteroids in primary liver transplant recipients. Liver Transpl 7:442–450

    Article  CAS  PubMed  Google Scholar 

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  1. Einstein Medical Center, Philadelphia, PA, USA

    Richard DePalma, John Knorr & Victor Navarro

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  1. Richard DePalma
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  2. John Knorr
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  3. Victor Navarro
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Correspondence to Richard DePalma .

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Editors and Affiliations

  1. Nicoletti Family Professor of Transplant Surgery, Director, Jefferson Transplant Institute, Director, Division of Transplantation, Surgical Director, Kimmel Cancer Center – Jefferson Liver Tumor Center, Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA

    Cataldo Doria

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DePalma, R., Knorr, J., Navarro, V. (2017). Immunology of Liver Transplantation. In: Doria, C. (eds) Contemporary Liver Transplantation. Organ and Tissue Transplantation. Springer, Cham. https://doi.org/10.1007/978-3-319-07209-8_20

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  • DOI: https://doi.org/10.1007/978-3-319-07209-8_20

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