Skip to main content
SpringerLink
Log in

Tolerance in Liver Transplantation

Just a Promise or an Evolving Reality?

  • Chapter
  • First Online:
Liver Transplantation

Part of the book series: Clinical Gastroenterology ((CG))

  • 1165 Accesses

Abstract

In recent years, a variety of immunosuppressive (IS) agents has emerged. The best application and combination of these new agents along with traditional immunosuppressive agents present challenges and opportunities to transplant physicians. Two anti-IL2 receptor monoclonal antibodies are currently available for clinical use: daclizumab (Zenapax, Roche) and basiliximab (Simulect, Novartis). Both bind to the alpha subunit of the IL-2 receptor (CD-25), which is expressed on activated, but not resting, lymphocytes. These drugs are the most commonly used induction agents in the United States. Campath-1H (C-1H) or alemtuzumab (Ilex Pharmacenticals) has been used in a limited fashion in liver transplantation recipients with mixed results. The role of sirolimus in liver transplantation remains controversial. However, this agent may offer specific advantages in patients with hepatocellular carcinoma or renal dysfunction. Because hepatitis C is the most common indication for liver transplantation, the application of immunosuppression in these patients is important. However, the best regimen for these patients remains controversial. The role of new immunosuppressive drugs including FTY720, FK778, and LEA29Y offers the promise for better immunosuppression for future liver transplantation recipients.

In recent years, a variety of immunosuppressive (IS) agents has emerged. The best application and combination of these new agents along with traditional immunosuppressive agents present challenges and opportunities to transplant physicians. Two anti-IL2 receptor monoclonal antibodies are currently available for clinical use: daclizumab (Zenapax, Roche) and basiliximab (Simulect, Novartis). Both bind to the alpha subunit of the IL-2 receptor (CD-25), which is expressed on activated, but not resting, lymphocytes. These drugs are the most commonly used induction agents in the United States. Campath-1H (C-1H) or alemtuzumab (Ilex Pharmacenticals) has been used in a limited fashion in liver transplantation recipients, with mixed results. The role of sirolimus in liver transplantation remains controversial. However, this agent may offer specific advantages in patients with hepatocellular carcinoma or renal dysfunction. Because hepatitis C is the most common indication for liver transplantation, the application of immunosuppression in these patients is important. However, the best regimen for these patients remains controversial. The role of new immunosuppressive drugs including FTY720, FK778, and LEA29Y offers the promise for better immunosuppression for future liver transplantation recipients.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Calne RY, Sells RA, Pena JR, Ashby BS, Herbertson BM, Millard PR, et al. Toleragenic effects of porcine liver allografts. Br J Surg 1969; 56(9):692–3.

    Article  PubMed  CAS  Google Scholar 

  2. Kamada N, Davies HS, Roser B. Reversal of transplantation immunity by liver grafting. Nature 1981; 292(5826):840–2.

    Article  PubMed  CAS  Google Scholar 

  3. Kamada N, Davies HS, 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(4):304–11.

    Article  PubMed  CAS  Google Scholar 

  4. Starzl TE, Demetris AJ, Murase N, Ildstad S, Ricordi C, Trucco M. Cell migration, chimerism, and graft acceptance. Lancet 1992; 339(8809):1579–82.

    Article  PubMed  CAS  Google Scholar 

  5. Shapiro R, Young JB, Milford EL, Trotter JF, Bustami RT, Leichtman AB. Immunosuppression: Evolution in practice and trends, 1993–2003. Am J Transpl 2005; 5(4 Pt 2):874–86.

    Article  Google Scholar 

  6. Tisone G, Orlando G, Cardillo A, Palmieri G, Manzia TM, Baiocchi L, et al. Complete weaning off immunosuppression in HCV liver transplant recipients is feasible and favourably impacts on the progression of disease recurrence. J Hepatol 2006; 44(4): 702–9.

    Google Scholar 

  7. Takatsuki M, Uemoto S, Inomata Y, Egawa H, Kiuchi T, Fujita S, et al. Weaning of immunosuppression in living donor liver transplant recipients. Transplantation 2001; 72(3):449–54.

    Article  PubMed  CAS  Google Scholar 

  8. Mazariegos GV, Reyes J, Marino IR, Demetris AJ, Flynn B, Irish W, et al. Weaning of immunosuppression in liver transplant recipients. Transplantation 1997; 63(2):243–9.

    Article  PubMed  CAS  Google Scholar 

  9. Ramos HC, Reyes J, Abu-Elmagd K, Zeevi A, Reinsmoen N, Tzakis A, et al. Weaning of immunosuppression in long-term liver transplant recipients. Transplantation 1995; 59(2):212–7.

    PubMed  CAS  Google Scholar 

  10. Flye MW, Pennington L, Kirkman R, Weber B, Sindelar W, Sachs DH. Spontaneous acceptance or rejection of orthotopic liver transplants in outbred and partially inbred miniature swine. Transplantation 1999; 68(5):599–607.

    Article  PubMed  CAS  Google Scholar 

  11. Chase MW. Inhibition of experimental drug allergy by prior feeding of the sensitizing agent. Proc Soc Exp Biol Med 1946; 61:2579.

    Google Scholar 

  12. Sulzberger MB. Hypersensitiveness to neoarsphenamine in guinea-pigs: Experiments in prevention and in desensitization. Arch Derm Syph 1929; 20:669–81.

    Article  Google Scholar 

  13. Ilan Y, Gotsman I, Pines M, Beinart R, Zeira M, Ohana M, et al. Induction of oral tolerance in splenocyte recipients toward pretransplant antigens ameliorates chronic graft versus host disease in a murine model. Blood 2000; 95(11):3613–9.

    PubMed  CAS  Google Scholar 

  14. Nagler A, Pines M, Abadi U, Pappo O, Zeira M, Rabbani E, et al. Oral tolerization ameliorates liver disorders associated with chronic graft versus host disease in mice. Hepatology 2000; 31(3):641–8.

    Article  PubMed  CAS  Google Scholar 

  15. Ilan Y, Prakash R, Davidson A, Jona V, Droguett G, Horwitz MS, et al. Oral tolerization to adenoviral antigens permits long-term gene expression using recombinant adenoviral vectors. J Clin Invest 1997; 99(5):1098–106.

    Google Scholar 

  16. Morita H, Sugiura K, Inaba M, Jin T, Ishikawa J, Lian Z, et al. A strategy for organ allografts without using immunosuppressants or irradiation. Proc Natl Acad Sci USA 1998; 95(12):6947–52.

    Article  PubMed  CAS  Google Scholar 

  17. Opelz G, Margreiter R, Dohler B. Prolongation of long-term kidney graft survival by a simultaneous liver transplant: The liver does it, and the heart does it too. Transplantation 2002; 74(10):1390–4.

    Article  PubMed  Google Scholar 

  18. Starzl TE, Murase N, Demetris A, Trucco M, Fung J. The mystique of hepatic tolerogenicity. Semin Liver Dis 2000; 20(4):497–510.

    Article  PubMed  CAS  Google Scholar 

  19. Meyer D, Otto C, Rummel C, Gassel HJ, Timmermann W, Ulrichs K, et al. “Tolerogenic effect” of the liver for a small bowel allograft. Transpl Int 2000; 13(Suppl 1):S123–S126.

    PubMed  Google Scholar 

  20. Sarnacki S, Revillon Y, Cerf-Bensussan N, Calise D, Goulet O, Brousse N. Long-term small-bowel graft survival induced by a spontaneously tolerated liver allograft in inbred rat strains. Transplantation 1992; 54(2):383–5.

    Article  PubMed  CAS  Google Scholar 

  21. Kamada N, Wight DG. Antigen-specific immunosuppression induced by liver transplantation in the rat. Transplantation 1984; 38(3):217–21.

    Article  PubMed  CAS  Google Scholar 

  22. Eason JD, Cohen AJ, Nair S, Alcantera T, Loss GE. Tolerance: Is it worth the risk? Transplantation 2005; 79(9):1157–9.

    Article  PubMed  Google Scholar 

  23. Adams AB, Williams MA, Jones TR, Shirasugi N, Durham MM, Kaech SM, et al. Heterologous immunity provides a potent barrier to transplantation tolerance. J Clin Invest 2003; 111(12):1887–95.

    PubMed  CAS  Google Scholar 

  24. Lorenz EN. Deterministic nonperiodic flow. J Atm Sci 1963; 20:130–41.

    Article  Google Scholar 

  25. Li TY, Yorke JA. Period three implies chaos. Am Math Monthly 1975; 82:985.

    Article  Google Scholar 

  26. Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology 2006; 43(2 Suppl 1):S54–S62.

    Article  PubMed  CAS  Google Scholar 

  27. Lau AH, Thomson AW. Dendritic cells and immune regulation in the liver. Gut 2003; 52(2):307–14.

    Article  PubMed  CAS  Google Scholar 

  28. Sanchez-Fueyo A, Strom TB. Immunological tolerance and liver transplantation. J Hepatol 2004; 41(5):698–705.

    Article  PubMed  CAS  Google Scholar 

  29. Pahlavan PS, Feldmann RE, Jr., Zavos C, Kountouras J. Prometheus' challenge: Molecular, cellular and systemic aspects of liver regeneration. J Surg Res 2006; 134(2): 238–51.

    Google Scholar 

  30. Wisse E, Gregoriadis G, Daems WT. Electron microscopic cytochemical localization of intravenously injected liposome-encapsulated horseradish peroxidase in rat liver cells. Adv Exp Med Biol 1976; 73(Pt A):237–45.

    PubMed  Google Scholar 

  31. Wisse E. Ultrastructure and function of Kupffer cells and other sinusoidal cells in the liver. Med Chir Dig 1977; 6(7):409–18.

    PubMed  CAS  Google Scholar 

  32. Wisse E, De Zanger RB, Charels K, Van Der SP, McCuskey RS. The liver sieve: Considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. Hepatology 1985; 5(4):683–92.

    Article  PubMed  CAS  Google Scholar 

  33. Onoe T, Ohdan H, Tokita D, Shishida M, Tanaka Y, Hara H, et al. Liver sinusoidal endothelial cells tolerize T cells across MHC barriers in mice. J Immunol 2005; 175(1):139–46.

    PubMed  CAS  Google Scholar 

  34. Onoe T, Ohdan H, Tokita D, Hara H, Tanaka Y, Ishiyama K, et al. Liver sinusoidal endothelial cells have a capacity for inducing nonresponsiveness of T cells across major histocompatibility complex barriers. Transpl Int 2005; 18(2):206–14.

    Article  PubMed  Google Scholar 

  35. Bowen DG, Zen M, Holz L, Davis T, McCaughan GW, Bertolino P. The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. J Clin Invest 2004; 114(5):701–12.

    PubMed  CAS  Google Scholar 

  36. Wick MJ, Leithauser F, Reimann J. The hepatic immune system. Crit Rev Immunol 2002; 22(1):47–103.

    PubMed  CAS  Google Scholar 

  37. Dini L, Lentini A, Diez GD, Rocha M, Falasca L, Serafino L, et al. Phagocytosis of apoptotic bodies by liver endothelial cells. J Cell Sci 1995; 108(Pt 3):967–73.

    PubMed  CAS  Google Scholar 

  38. Steffan AM, Gendrault JL, McCuskey RS, McCuskey PA, Kirn A. Phagocytosis, an unrecognized property of murine endothelial liver cells. Hepatology 1986; 6(5):830–6.

    Article  PubMed  CAS  Google Scholar 

  39. Limmer A, Ohl J, Kurts C, Ljunggren HG, Reiss Y, Groettrup M, 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(12):1348–54.

    Article  PubMed  CAS  Google Scholar 

  40. Knolle PA, Gerken G, Loser E, Dienes HP, Gantner F, Tiegs G, et al. Role of sinusoidal endothelial cells of the liver in concanavalin A-induced hepatic injury in mice. Hepatology 1996; 24(4):824–9.

    Article  PubMed  CAS  Google Scholar 

  41. Knolle P, Schlaak J, Uhrig A, Kempf P, Meyer zum Buschenfelde KH, Gerken G. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J Hepatol 1995; 22(2):226–9.

    Article  PubMed  CAS  Google Scholar 

  42. Groux H, Bigler M, de Vries JE, Roncarolo MG. Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J Exp Med 1996; 184(1):19–29.

    Article  PubMed  CAS  Google Scholar 

  43. Bertolino P, McCaughan GW, Bowen DG. Role of primary intrahepatic T-cell activation in the “liver tolerance effect.” Immunol Cell Biol 2002; 80(1):84–92.

    Article  PubMed  Google Scholar 

  44. Crispe IN, Dao T, Klugewitz K, Mehal WZ, Metz DP. The liver as a site of T-cell apoptosis: Graveyard, or killing field? Immunol Rev 2000; 174:47–62.

    Article  PubMed  CAS  Google Scholar 

  45. Scherer MN, Graeb C, Tange S, Dyson C, Jauch KW, Geissler EK. Immunologic considerations for therapeutic strategies utilizing allogeneic hepatocytes: Hepatocyte-expressed membrane-bound major histocompatibility complex class I antigen sensitizes while soluble antigen suppresses the immune response in rats. Hepatology 2000; 32(5):999–1007.

    Article  PubMed  CAS  Google Scholar 

  46. Behrens D, Lange K, Fried A, Yoo-Ott KA, Richter K, Fandrich F, et al. Donor-derived soluble MHC antigens plus low-dose cyclosporine induce transplantation unresponsiveness independent of the thymus by down-regulating T cell-mediated alloresponses in a rat transplantation model. Transplantation 2001; 72(12): 1974–82.

    Article  PubMed  CAS  Google Scholar 

  47. Tang H, McLachlan A. Transcriptional regulation of hepatitis B virus by nuclear hormone receptors is a critical determinant of viral tropism. Proc Natl Acad Sci USA 2001; 98(4):1841–6.

    Article  PubMed  CAS  Google Scholar 

  48. Ishikawa T, Ganem D. The pre-S domain of the large viral envelope protein determines host range in avian hepatitis B viruses. Proc Natl Acad Sci USA 1995; 92(14):6259–63.

    Article  PubMed  CAS  Google Scholar 

  49. Yamaguchi Y, Tsumura H, Miwa M, Inaba K. Contrasting effects of TGF-beta 1 and TNF-alpha on the development of dendritic cells from progenitors in mouse bone marrow. Stem Cells 1997; 15(2):144–53.

    Article  PubMed  CAS  Google Scholar 

  50. Steinbrink K, Wolfl M, Jonuleit H, Knop J, Enk AH. Induction of tolerance by IL-10-treated dendritic cells. J Immunol 1997; 159(10):4772–80.

    PubMed  CAS  Google Scholar 

  51. Thomson AW, Lu L, Murase N, Demetris AJ, Rao AS, Starzl TE. Microchimerism, dendritic cell progenitors and transplantation tolerance. Stem Cells 1995; 13(6):622–39.

    Article  PubMed  CAS  Google Scholar 

  52. Starzl TE, Demetris AJ, Rao AS, Thomson AW, Trucco M, Murase N. Migratory nonparenchymal cells after organ allotransplantation: With particular reference to chimerism and the liver. Prog Liver Dis 1994; 12:191–213.

    PubMed  CAS  Google Scholar 

  53. Starzl TE, Demetris AJ, Trucco M, Murase N, Ricordi C, Ildstad S, et al. Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance. Hepatology 1993; 17(6):1127–52.

    Article  PubMed  CAS  Google Scholar 

  54. Exley MA, Koziel MJ. To be or not to be NKT: Natural killer T cells in the liver. Hepatology 2004; 40(5):1033–40.

    Article  PubMed  Google Scholar 

  55. de Creus A, Abe M, Lau AH, Hackstein H, Raimondi G, Thomson AW. Low TLR4 expression by liver dendritic cells correlates with reduced capacity to activate allogeneic T cells in response to endotoxin. J Immunol 2005; 174(4): 2037–45.

    PubMed  Google Scholar 

  56. Limmer A, Knolle PA. Liver sinusoidal endothelial cells: A new type of organ-resident antigen-presenting cell. Arch Immunol Ther Exp (Warsz ) 2001; 49(Suppl 1):S7–S11.

    Google Scholar 

  57. Xu H, Zhang X, Mannon RB, Kirk AD. Platelet-derived or soluble CD154 induces vascularized allograft rejection independent of cell-bound CD154. J Clin Invest 2006; 116(3):769–74.

    Article  PubMed  CAS  Google Scholar 

  58. Billingham RE, Brent L, Medawar PB. Activity acquired tolerance of foreign cells. Nature 1953; 172(4379):603–6.

    Article  PubMed  CAS  Google Scholar 

  59. Mazariegos GV, Ramos H, Shapiro R, Zeevi A, Fung JJ, Starzl TE. Weaning of immunosuppression in long-term recipients of living related renal transplants: A preliminary study. Transpl Proc 1995; 27(1):207–9.

    CAS  Google Scholar 

  60. Devlin J, Doherty D, Thomson L, Wong T, Donaldson P, Portmann B, et al. Defining the outcome of immunosuppression withdrawal after liver transplantation. Hepatology 1998; 27(4):926–33.

    Article  PubMed  CAS  Google Scholar 

  61. Girlanda R, Rela M, Williams R, O'Grady JG, Heaton ND. Long-term outcome of immunosuppression withdrawal after liver transplantation. Transpl Proc 2005; 37(4):1708–9.

    Article  CAS  Google Scholar 

  62. Inomata Y, Hamamoto R, Yoshimoto K, Zeledon M. [Current status and perspective of pediatric liver transplantation in Japan.] Nippon Rinsho 2005; 63(11):1986–92.

    PubMed  Google Scholar 

  63. Ueda M, Koshiba T, Li Y, Pirenne J, Inazawa Y, Egawa H, et al. Requirement of protocol biopsy before and after complete cessation of immunosuppression following living-donor liver transplantation. Am J Transpl 2005; 5(11):374.

    Google Scholar 

  64. Pons JA, Yelamos J, Ramirez P, Oliver-Bonet M, Sanchez A, Rodriguez-Gago M, et al. Endothelial cell chimerism does not influence allograft tolerance in liver transplant patients after withdrawal of immunosuppression. Transplantation 2003; 75(7):1045–7.

    Article  PubMed  Google Scholar 

  65. Calne R. WOFIE hypothesis: Some thoughts on an approach toward allograft tolerance. Transpl Proc 1996; 28(3):1152.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Health and Human Services, National Institutes of Health, Transplantation Branch, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, MD

    David A. Bruno (MD)

Authors
  1. David A. Bruno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Allan D. Kirk
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2009 Humana Press, a part of Springer Science+Business Media, LLC

    About this chapter

    Cite this chapter

    Bruno, D.A., Kirk, A.D. (2009). Tolerance in Liver Transplantation. In: Trotter, J., Everson, G. (eds) Liver Transplantation. Clinical Gastroenterology. Humana Press. https://doi.org/10.1007/978-1-60327-028-1_1

    Download citation

    • DOI: https://doi.org/10.1007/978-1-60327-028-1_1

    • Published:

    • Publisher Name: Humana Press

    • Print ISBN: 978-1-58829-793-8

    • Online ISBN: 978-1-60327-028-1

    • eBook Packages: MedicineMedicine (R0)

    Publish with us

    Policies and ethics

    Search

    Navigation