Semin Liver Dis 2009; 29(1): 091-101
DOI: 10.1055/s-0029-1192058
© Thieme Medical Publishers

Unique Aspects of Rejection and Tolerance in Liver Transplantation

Stuart J. Knechtle1 , Jean Kwun1
  • 1Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia
Further Information

Publication History

Publication Date:
23 February 2009 (online)

ABSTRACT

Spontaneous acceptance of liver allografts occurs in several species. However, tolerance is rare in human transplant patients even though rejection is relatively easily reversed. Histological features of acute rejection in liver transplantation are similar to those in other organs. Nevertheless, mechanisms of rejection of liver transplants may differ in degrees and cellular involvement. Liver-specific cell populations, such as Kupffer cells (KCs), liver sinusoidal epithelial cells (LSECs), and hepatic stellate cells (HSCs), may contribute to liver tolerogenicity. Other mechanisms, such as microchimerism, soluble major histocompatibility complex (MHC molecules), donor human leukocyte antigen (HLA)-C genotype, and regulatory T cells, may participate in inducing tolerance. The low incidence of hyperacute or antibody-mediated rejection in liver might be linked to the infrequency of chronic rejection of liver transplants. Understanding the mechanisms of liver transplant rejection/tolerance and the availability of better immune monitoring could help develop strategies to recognize tolerance and reduce rejection.

REFERENCES

  • 1 Calne R. Immunological tolerance: the liver effect.  J Gastroenterol Hepatol. 2002;  17(Suppl) S488-S490
  • 2 Flye M W, Pennington L, Kirkman R, Weber B, Sindelar W, Sachs D H. Spontaneous acceptance or rejection of orthotopic liver transplants in outbred and partially inbred miniature swine.  Transplantation. 1999;  68 599-607
  • 3 Zimmermann F A, Butcher G W, Davies H S et al.. Techniques for orthotopic liver transplantation in the rat and some studies of the immunologic responses to fully allogeneic liver grafts.  Transplant Proc. 1979;  11 571-577
  • 4 Zimmermann F A, Davies H S, Knoll P P, Gokel J M, Schmidt T. Orthotopic liver allografts in the rat. The influence of strain combination on the fate of the graft.  Transplantation. 1984;  37 406-410
  • 5 Kamada N, Calne R Y. A surgical experience with five hundred thirty liver transplants in the rat.  Surgery. 1983;  93 64-69
  • 6 Kamada N, Davies H S, Wight D, Culank L, Roser B. Liver transplantation in the rat. Biochemical and histological evidence of complete tolerance induction in non-rejector strains.  Transplantation. 1983;  35 304-311
  • 7 Scientific Registry of Transplant Recipients. Available at: http://www.ustransplant.org/ Accessed September 11, 2008
  • 8 Knechtle S J, Kolbeck P, Tsuchimoto S, Sanfilippo F, Bollinger R R. Hyperacute rejection of liver transplants in rats.  Curr Surg. 1986;  43 303-305
  • 9 Knechtle S J, Kolbeck P C, Tsuchimoto S et al.. Hepatic transplantation into sensitized recipients. Demonstration of hyperacute rejection.  Transplantation. 1987;  43 8-12
  • 10 Palmer S M, Davis R D, Hadjiliadis D et al.. Development of an antibody specific to major histocompatibility antigens detectable by flow cytometry after lung transplant is associated with bronchiolitis obliterans syndrome.  Transplantation. 2002;  74 799-804
  • 11 Suciu-Foca N, Reed E, Marboe C et al.. The role of anti-HLA antibodies in heart transplantation.  Transplantation. 1991;  51 716-724
  • 12 Mannon R B, Griffiths R, Ruiz P, Platt J L, Coffman T M. Absence of donor MHC antigen expression ameliorates chronic kidney allograft rejection.  Kidney Int. 2002;  62 290-300
  • 13 Terasaki P I. Humoral theory of transplantation.  Am J Transplant. 2003;  3 665-673
  • 14 Starzl T E. Immunosuppressive therapy and tolerance of organ allografts.  N Engl J Med. 2008;  358 407-411
  • 15 Alexander S I, Smith N, Hu M et al.. Chimerism and tolerance in a recipient of a deceased-donor liver transplant.  N Engl J Med. 2008;  358 369-374
  • 16 Banff schema for grading liver allograft rejection: an international consensus document.  Hepatology. 1997;  25 658-663
  • 17 Adams D. Mechanisms of liver allograft rejection in man.  Clin Sci (Lond). 1990;  78 343-350
  • 18 Lanier L L. NK cell receptors.  Annu Rev Immunol. 1998;  16 359-393
  • 19 Parham P. MHC class I molecules and KIRs in human history, health and survival.  Nat Rev Immunol. 2005;  5 201-214
  • 20 Anfossi N, Doisne J M, Peyrat M A et al.. Coordinated expression of Ig-like inhibitory MHC class I receptors and acquisition of cytotoxic function in human CD8+ T cells.  J Immunol. 2004;  173 7223-7229
  • 21 Snyder M R, Muegge L O, Offord C et al.. Formation of the killer Ig-like receptor repertoire on CD4+CD28null T cells.  J Immunol. 2002;  168 3839-3846
  • 22 Mandelboim O, Reyburn H T, Sheu E G et al.. The binding site of NK receptors on HLA-C molecules.  Immunity. 1997;  6 341-350
  • 23 Tran T H, Mytilineos J, Scherer S et al.. Analysis of KIR ligand incompatibility in human renal transplantation.  Transplantation. 2005;  80 1121-1123
  • 24 Bishara A, Brautbar C, Zamir G, Eid A, Safadi R. Impact of HLA-C and Bw epitopes disparity on liver transplantation outcome.  Hum Immunol. 2005;  66 1099-1105
  • 25 Moya-Quiles M R, Alvarez R, Miras M et al.. Impact of recipient HLA-C in liver transplant: a protective effect of HLA-Cw*07 on acute rejection.  Hum Immunol. 2007;  68 51-58
  • 26 Hanvesakul R, Spencer N, Cook M et al.. Donor HLA-C genotype has a profound impact on the clinical outcome following liver transplantation.  Am J Transplant. 2008;  8(9) 1931-1941
  • 27 Doherty D G, Norris S, Madrigal-Estebas L et al.. The human liver contains multiple populations of NK cells, T cells, and CD3+CD56+ natural T cells with distinct cytotoxic activities and Th1, Th2, and Th0 cytokine secretion patterns.  J Immunol. 1999;  163 2314-2321
  • 28 Knolle P A, Schmitt E, Jin S et al.. Induction of cytokine production in naive CD4(+) T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells.  Gastroenterology. 1999;  116 1428-1440
  • 29 Limmer A, Ohl J, Kurts C et al.. Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance.  Nat Med. 2000;  6 1348-1354
  • 30 Smedsrød B. Clearance function of scavenger endothelial cells.  Comp Hepatol. 2004;  3(Suppl 1) S22
  • 31 Knolle P A, Limmer A. Neighborhood politics: the immunoregulatory function of organ-resident liver endothelial cells.  Trends Immunol. 2001;  22 432-437
  • 32 Sumitran-Holgersson S, Ge X, Karrar A et al.. A novel mechanism of liver allograft rejection facilitated by antibodies to liver sinusoidal endothelial cells.  Hepatology. 2004;  40 1211-1221
  • 33 Ge X, Nowak G, Ericzon B G, Sumitran-Holgersson S. Liver sinusoidal endothelial cell function in rejected and spontaneously accepted rat liver allografts.  Transpl Int. 2008;  21 49-56
  • 34 Chen Y, Liu Z, Liang S et al.. Role of Kupffer cells in the induction of tolerance of orthotopic liver transplantation in rats.  Liver Transpl. 2008;  14 823-836
  • 35 Tokita D, Mazariegos G V, Zahorchak A F et al.. High PD-L1/CD86 ratio on plasmacytoid dendritic cells correlates with elevated T-regulatory cells in liver transplant tolerance.  Transplantation. 2008;  85 369-377
  • 36 Sumpter T L, Abe M, Tokita D, Thomson A W. Dendritic cells, the liver, and transplantation.  Hepatology. 2007;  46 2021-2031
  • 37 Toyokawa H, Nakao A, Bailey R J et al.. Relative contribution of direct and indirect allorecognition in developing tolerance after liver transplantation.  Liver Transpl. 2008;  14 346-357
  • 38 Senoo H. Structure and function of hepatic stellate cells.  Med Electron Microsc. 2004;  37 3-15
  • 39 Bilezikci B, Demirhan B, Sar A et al.. Hepatic stellate cells in biopsies from liver allografts with acute rejection.  Transplant Proc. 2006;  38 589-593
  • 40 Yu M C, Chen C H, Liang X et al.. Inhibition of T-cell responses by hepatic stellate cells via B7–H1-mediated T-cell apoptosis in mice.  Hepatology. 2004;  40 1312-1321
  • 41 Chen C H, Kuo L M, Chang Y et al.. In vivo immune modulatory activity of hepatic stellate cells in mice.  Hepatology. 2006;  44 1171-1181
  • 42 Liu C, Gaca M D, Swenson E S et al.. Smads 2 and 3 are differentially activated by transforming growth factor-beta (TGF-beta) in quiescent and activated hepatic stellate cells. Constitutive nuclear localization of Smads in activated cells is TGF-beta-independent.  J Biol Chem. 2003;  278 11721-11728
  • 43 Steger U, Denecke C, Sawitzki B et al.. Exhaustive differentiation of alloreactive CD8+ T cells: critical for determination of graft acceptance or rejection.  Transplantation. 2008;  85 1339-1347
  • 44 Bishop G A, Wang C, Sharland A F, McCaughan G. Spontaneous acceptance of liver transplants in rodents: evidence that liver leucocytes induce recipient T-cell death by neglect.  Immunol Cell Biol. 2002;  80 93-100
  • 45 Wight D GD. The morphology of rejection of liver transplants. In: Calne RY Transplantation Immunology: Clinical and Experimental. Oxford, UK; Oxford University Press 1984: 53-77
  • 46 Ratner L E, Phelan D, Brunt E M, Mohanakumar T, Hanto D W. Probable antibody-mediated failure of two sequential ABO-compatible hepatic allografts in a single recipient.  Transplantation. 1993;  55 814-819
  • 47 Olausson M, Mjornstedt L, Norden G et al.. Successful combined partial auxiliary liver and kidney transplantation in highly sensitized cross-match positive recipients.  Am J Transplant. 2007;  7 130-136
  • 48 Kamada N, Sumimoto R, Baguerizo A et al.. Mechanisms of transplantation tolerance induced by liver grafting in rats: involvement of serum factors in clonal deletion.  Immunology. 1988;  64 315-317
  • 49 Kamada N, Goto S, Kobayashi E et al.. Release of soluble MHC class I antigens before and after orthotopic liver retransplantation in the rat.  Transplant Proc. 1993;  25 2857
  • 50 Brouard S, Ashton-Chess J, Soulillou J P. Surrogate markers for the prediction of long-term outcome in transplantation: Nantes Actualité Transplantation (NAT) 2007 meeting report.  Hum Immunol. 2008;  69 2-8
  • 51 Schmeding M, Dankof A, Krenn V et al.. C4d in acute rejection after liver transplantation–a valuable tool in differential diagnosis to hepatitis C recurrence.  Am J Transplant. 2006;  6 523-530
  • 52 Andreoni K A, Lin J I, Groben P A. Liver transplantation 27 years after bone marrow transplantation from the same living donor.  N Engl J Med. 2004;  350 2624-2625
  • 53 Wekerle T, Sykes M. Mixed chimerism as an approach for the induction of transplantation tolerance.  Transplantation. 1999;  68 459-467
  • 54 Domiati-Saad R, Klintmalm G B, Netto G et al.. Acute graft versus host disease after liver transplantation: patterns of lymphocyte chimerism.  Am J Transplant. 2005;  5 2968-2973
  • 55 Schlitt H J. Is microchimerism needed for allograft tolerance?.  Transplant Proc. 1997;  29 82-84
  • 56 Sivasai K S, Alevy Y G, Duffy B F et al.. Peripheral blood microchimerism in human liver and renal transplant recipients: rejection despite donor-specific chimerism.  Transplantation. 1997;  64 427-432
  • 57 Schlitt H J, Hundrieser J, Ringe B, Pichlmayr R. Donor-type microchimerism associated with graft rejection eight years after liver transplantation.  N Engl J Med. 1994;  330 646-647
  • 58 Berquist R K, Berquist W E, Esquivel C O et al.. Non-adherence to post-transplant care: prevalence, risk factors and outcomes in adolescent liver transplant recipients.  Pediatr Transplant. 2008;  12 194-200
  • 59 Assy N, Adams P C, Myers P et al.. Randomized controlled trial of total immunosuppression withdrawal in liver transplant recipients: role of ursodeoxycholic acid.  Transplantation. 2007;  83 1571-1576
  • 60 Mazariegos G V, Sindhi R, Thomson A W, Marcos A. Clinical tolerance following liver transplantation: long term results and future prospects.  Transpl Immunol. 2007;  17 114-119
  • 61 Manez R, Kusne S, Linden P et al.. Temporary withdrawal of immunosuppression for life-threatening infections after liver transplantation.  Transplantation. 1994;  57 149-151
  • 62 Reyes J, Zeevi A, Ramos H et al.. Frequent achievement of a drug-free state after orthotopic liver transplantation.  Transplant Proc. 1993;  25 3315-3319
  • 63 Starzl T E, Demetris A J, Trucco M et al.. Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance.  Hepatology. 1993;  17 1127-1152
  • 64 Mazariegos G V, Reyes J, Marino I R et al.. Weaning of immunosuppression in liver transplant recipients.  Transplantation. 1997;  63 243-249
  • 65 Ramos H C, Reyes J, Abu-Elmagd K et al.. Weaning of immunosuppression in long-term liver transplant recipients.  Transplantation. 1995;  59 212-217
  • 66 Takatsuki M, Uemoto S, Inomata Y et al.. Weaning of immunosuppression in living donor liver transplant recipients.  Transplantation. 2001;  72 449-454
  • 67 Hurwitz M, Desai D M, Cox K L et al.. Complete immunosuppressive withdrawal as a uniform approach to post-transplant lymphoproliferative disease in pediatric liver transplantation.  Pediatr Transplant. 2004;  8 267-272
  • 68 Kawasaki M, Iwasaki M, Koshiba T et al.. Gene expression profile analysis of the peripheral blood mononuclear cells from tolerant living-donor liver transplant recipients.  Int Surg. 2007;  92 276-286
  • 69 Li Y, Koshiba T, Yoshizawa A et al.. Analyses of peripheral blood mononuclear cells in operational tolerance after pediatric living donor liver transplantation.  Am J Transplant. 2004;  4 2118-2125
  • 70 Lake J R, David K M, Steffen B J et al.. Addition of MMF to dual immunosuppression does not increase the risk of malignant short-term death after liver transplantation.  Am J Transplant. 2005;  5 2961-2967
  • 71 Brennan D C, Daller J A, Lake K D, Cibrik D, Del Castillo D. Rabbit antithymocyte globulin versus basiliximab in renal transplantation.  N Engl J Med. 2006;  355 1967-1977
  • 72 Kirk A D, Cherikh W S, Ring M et al.. Dissociation of depletional induction and posttransplant lymphoproliferative disease in kidney recipients treated with alemtuzumab.  Am J Transplant. 2007;  7 2619-2625
  • 73 Yoshizawa A, Ito A, Li Y et al.. The roles of CD25+CD4+ regulatory T cells in operational tolerance after living donor liver transplantation.  Transplant Proc. 2005;  37 37-39
  • 74 Morelli A E, Thomson A W. Dendritic cells: regulators of alloimmunity and opportunities for tolerance induction.  Immunol Rev. 2003;  196 125-146
  • 75 Mazariegos G V, Zahorchak A F, Reyes J et al.. Dendritic cell subset ratio in tolerant, weaning and non-tolerant liver recipients is not affected by extent of immunosuppression.  Am J Transplant. 2005;  5 314-322
  • 76 Mazariegos G V, Reyes J, Webber S A et al.. Cytokine gene polymorphisms in children successfully withdrawn from immunosuppression after liver transplantation.  Transplantation. 2002;  73 1342-1345
  • 77 Kwun J, Knechtle S J, Hu H. Determination of the functional status of alloreactive T cells by interferon-gamma kinetics.  Transplantation. 2006;  81 590-598
  • 78 Kalb B, Votaw J R, Salman K, Sharma P, Martin D R. Magnetic resonance nephrourography: current and developing techniques.  Radiol Clin North Am. 2008;  46 11-24
  • 79 Semelka R C, Martin D R, Balci N C. Magnetic resonance imaging of the liver: how I do it.  J Gastroenterol Hepatol. 2006;  21 632-637

Stuart J KnechtleM.D. 

101 Woodruff Circle, 5115 WMB

Atlanta, GA 30033

Email: stuart.knechtle@emoryhealthcare.org

    >