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Mechanisms of Disease: the evolving understanding of liver allograft rejection

Nature Clinical Practice Gastroenterology & Hepatology volume 5, pages 209–219 (2008)Cite this article

Abstract

Liver transplantation is a successful treatment for select forms of liver disease and is unrivalled amongst other forms of solid organ transplantation in the ability of the recipient to develop long-term tolerance to the allograft. Much of this success can be attributed to the inherently tolerogenic manner in which antigens are presented in the liver and the presence of specialized regulatory lymphocyte populations. These observations are not universal, however, and a proportion of recipients develop problematic allograft rejection. Anti-allograft responses lead to an influx of effector cells that target hepatic parenchymal cells and induce apoptosis through members of the tumor necrosis factor superfamily. Anti-rejection therapies have traditionally targeted the entire lymphocyte response against the allograft and, whilst these therapies have been efficacious at limiting effector cell responses, they have also had deleterious effects on the regulatory cell populations that are required to promote long-term tolerance. The emergence of newer anti-rejection drugs that have the potential to target the effector response selectively, whilst preserving the much needed tolerogenic responses, has afforded us the opportunity to refine our future immunosuppressant strategies.

Key Points

  • Liver transplantation is an effective treatment for select patients with liver disease, but its success is still hampered by allograft rejection

  • Antigen presentation in the liver is skewed towards tolerance and encourages allograft acceptance

  • Loss of tolerance and a shift towards an anti-allograft effector response leads to sustained targeting and apoptosis of cholangiocytes and hepatocytes through members of the tumor necrosis factor superfamily

  • Regulatory T cells have an important role in allograft tolerance

  • Modern anti-rejection therapies should be tailored to preserve regulatory T-cell function whilst targeting the effector responses

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Figure 1: Intracellular and cell-surface markers expressed by regulatory T cells.

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Acknowledgements

The help and constructive criticism of Professor Kathryn Wood in the preparation of the manuscript is gratefully acknowledged. We are also indebted to Professor David Adams and Dr Simon Afford at the University of Birmingham whose work in this field has formed the basis of many of the concepts discussed in this article.

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Authors and Affiliations

  1. B Eksteen is a MRC Clinician Scientist and JM Neuberger is a Consultant Physician at the Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.,

    Bertus Eksteen & James M Neuberger

  2. JM Neuberger is also an Honorary Professor in Medicine at the University of Birmingham, Birmingham, UK.,

    James M Neuberger

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  1. Bertus Eksteen
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Correspondence to James M Neuberger.

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Competing interests

James M Neuberger has received speaker support from Hoffmann-La Roche, Novartis and Astellas, and is a consultant for Bristol-Myers. Bertus Eksteen declared no competing interests.

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Eksteen, B., Neuberger, J. Mechanisms of Disease: the evolving understanding of liver allograft rejection. Nat Rev Gastroenterol Hepatol 5, 209–219 (2008). https://doi.org/10.1038/ncpgasthep1070

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