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  • Review Article
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Understanding, predicting and achieving liver transplant tolerance: from bench to bedside

Nature Reviews Gastroenterology & Hepatology volume 17, pages 719–739 (2020)Cite this article

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Abstract

In the past 40 years, liver transplantation has evolved from a high-risk procedure to one that offers high success rates for reversal of liver dysfunction and excellent patient and graft survival. The liver is the most tolerogenic of transplanted organs; indeed, immunosuppressive therapy can be completely withdrawn without rejection of the graft in carefully selected, stable long-term liver recipients. However, in other recipients, chronic allograft injury, late graft failure and the adverse effects of anti-rejection therapy remain important obstacles to improved success. The liver has a unique composition of parenchymal and immune cells that regulate innate and adaptive immunity and that can promote antigen-specific tolerance. Although the mechanisms underlying liver transplant tolerance are not well understood, important insights have been gained into how the local microenvironment, hepatic immune cells and specific molecular pathways can promote donor-specific tolerance. These insights provide a basis for the identification of potential clinical biomarkers that might correlate with tolerance or rejection and for the development of novel therapeutic targets. Innovative approaches aimed at promoting immunosuppressive drug minimization or withdrawal include the adoptive transfer of donor-derived or recipient-derived regulatory immune cells to promote liver transplant tolerance. In this Review, we summarize and discuss these developments and their implications for liver transplantation.

Key points

  • Liver transplant tolerance occurs in animals without immunosuppressive therapy. In humans, donor–recipient histocompatibility is not considered important for graft survival; in carefully selected patients, complete immunosuppression withdrawal is currently possible.

  • Parenchymal and non-parenchymal cells, particularly those of the innate and adaptive immune system, seem to have key roles in promoting a tolerogenic environment within the liver via various mechanisms.

  • Donor-derived haematopoietic cells trafficking to the host, exhaustion or death of graft-infiltrating donor-reactive T cells, and regulatory dendritic cell and regulatory T cell responses have been implicated in experimental liver transplant tolerance.

  • Early (<3 months) acute cellular rejection might not harm the graft in the long term; patients might, however, harbour latent T cell-mediated rejection and/or fibrosis. The pathogenicity of donor-specific antibodies remains uncertain.

  • Graft biopsy assessment and intra-graft gene expression profiling (identification of potential ‘tolerance biomarker’ genes) might aid patient selection for early immunosuppressive drug withdrawal. Identification of non-invasive biomarkers is a priority.

  • Early-phase clinical trials of adoptive regulatory immune cell therapy in liver transplantation are underway. In combination with biomarkers, this approach might enable minimization or complete withdrawal of immunosuppression.

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Fig. 1: Mechanisms that subvert liver conventional mDC activation and enhance their tolerogenic properties to promote liver allograft tolerance.
Fig. 2: Cellular and molecular mechanisms implicated in regulating the balance between liver transplant tolerance and rejection.
Fig. 3: Modern immunosuppression withdrawal trials in liver transplantation and classic inclusion criteria.

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Acknowledgements

The authors’ work is supported by National Institutes of Health grants R01 AI 118777, U19 AI 131453 and U01 AI 136779 (A.W.T), the Medical Research Council Centre for Transplantation and the National Institute for Health Research Biomedical Research Centre based at Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College London (A.S.-F.) and the Swiss National Science Foundation grant P2LAP3_181318 (J.V.). The authors thank M. Freeman for skilful administrative support.

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  1. Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Angus W. Thomson

  2. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Angus W. Thomson

  3. Institute of Liver Studies, Medical Research Council (MRC) Centre for Transplantation, School of Immunology and Infectious Diseases, King’s College London University, King’s College Hospital, London, UK

    Julien Vionnet & Alberto Sanchez-Fueyo

  4. Transplantation Center, University Hospital of Lausanne, Lausanne, Switzerland

    Julien Vionnet

  5. Service of Gastroenterology and Hepatology, University Hospital of Lausanne, Lausanne, Switzerland

    Julien Vionnet

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Thomson, A.W., Vionnet, J. & Sanchez-Fueyo, A. Understanding, predicting and achieving liver transplant tolerance: from bench to bedside. Nat Rev Gastroenterol Hepatol 17, 719–739 (2020). https://doi.org/10.1038/s41575-020-0334-4

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