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Immune Tolerance After Liver Transplantation

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Pediatric Hepatology and Liver Transplantation

Abstract

The liver has long been viewed as the most “tolerogenic” of all solid organs transplanted. This was initially based on observations made more than half a century ago that liver allografts, unlike other organs, are spontaneously accepted across certain strains of pigs without the need for any immunosuppression. Since these seminal observations, much has been discovered about the liver’s anatomy and biology that evidences its tolerogenic nature and elucidates the underlying mechanisms. Clinicians have assimilated these lessons, and, as a result, there have been attempts to minimize and even completely discontinue immunosuppression. Multiple single center reports and a few prospective, multicenter clinical trials of immunosuppression withdrawal have been published, clearly demonstrating proof-of-principle: among highly selected adult and pediatric liver transplant recipients, spontaneous tolerance does exist. Liver allografts can continue to function, in the short- and mid-term, well with stable biochemical and, very importantly, histological profiles in the complete absence of immunosuppression. The availability of patients with clinically defined phenotypes of tolerance and non-tolerance has supported considerable efforts to identify a biomarker reliably predictive of tolerance. Although several have been suggested, only one—a tissue-based biomarker—has shown sufficient promise to merit prospective testing for utility to increase the safety and success of attempted withdrawal. The existence of spontaneous tolerance has also motivated trials to induce tolerance in both pre-existing and de novo adult liver transplant recipients. Current approaches center on administration of manufactured cellular products, most often various preparations of autologous regulatory T cells that offer the prospect of donor-specific immunomodulation. In the upcoming decade, the liver transplant community can look forward to learning much more about both spontaneous and induced tolerance as well as biomarkers and underlying mechanisms of tolerance.

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Abbreviations

CNI:

Calcineurin inhibitor

DC:

Dendritic cell

DSA:

Donor-specific antibody

HCV:

Hepatitis C virus

HLA:

Human leukocyte antigen

IFN-γ :

Interferon gamma

iNKTs:

Invariant natural killer T cells

IS:

Immunosuppression

LPS:

Lipopolysaccharide

LSEC:

Liver sinusoidal endothelial cell

MHC:

Major histocompatibility complex

MLR:

Mixed lymphocyte reaction

NK:

Natural killer

PBMC:

Peripheral blood mononuclear cell

PD-1:

Programmed cell death protein 1

pDC:

Plasmacytoid dendritic cell

PD-L1:

Programmed death-ligand 1

TLR:

Toll-like receptor

Tregs:

Regulatory T cells

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Authors and Affiliations

  1. Division of Transplantation, Department of Surgery, University of California San Francisco, San Francisco, CA, USA

    Sandy Feng

  2. Institute of Liver Studies, King’s College, London, London, UK

    Alberto Sanchez-Fueyo

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  1. Sandy Feng
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  2. Alberto Sanchez-Fueyo
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Correspondence to Sandy Feng .

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Editors and Affiliations

  1. Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII Bergamo, Bergamo, Italy

    Lorenzo D'Antiga

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Feng, S., Sanchez-Fueyo, A. (2019). Immune Tolerance After Liver Transplantation. In: D'Antiga, L. (eds) Pediatric Hepatology and Liver Transplantation. Springer, Cham. https://doi.org/10.1007/978-3-319-96400-3_36

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