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

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 The liver is the most tolerogenic of transplanted organs; indeed, immunosuppressive therapy can be completely withdrawn without rejection of the graft in carefully selected, stable long-term liver recipients.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.

Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer

“…Transplant rejection is limited solely through immunosuppressive drugs that are taken for the duration of a patient's life, increasing risk of infection. In the liver, however, withdrawal of immunosuppression post-transplant is possible in some patients and must be managed carefully (70).…”

Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection

“…Mouse liver DC heterogeneity has also been described using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) (23). The phenotype and function of liver interstitial DCs is influenced by the hepatic microenvironment that promotes their inherent tolerogenicity in the healthy steady-state (24)(25)(26). Thus, via their production of macrophage colony-stimulating factor and other soluble and cell-cell contact factors, liver stromal cells induce regulatory cDCs that secrete high levels of IL-10 and nitric oxide (NO), but little IL-12 and inhibit T cell proliferative responses/induce activated T cell apoptosis (24,27,28).…”

“…Both liver cDCs and pDCs only weakly stimulate allogeneic T cell proliferation and can promote activated T cell hyporesponsiveness/apoptosis and Tregs (32,(78)(79)(80). Together with other liver NPCs, liver DCreg appear to play key roles in the induction of liver transplant tolerance (24); reviewed in (25,26,70,81). The properties of mouse and human hepatic DCs that may promote regulation of alloreactive T cell responses/tolerance induction are summarized in Table 2.…”

Donor plasmacytoid dendritic cells modulate effector and regulatory T cell responses in mouse spontaneous liver transplant tolerance

“…Moreover, only in liver transplantation can about 20%–40% of carefully selected stable graft recipients (up to as high as 79%, depending on patient age, number of years posttransplant and other factors) be withdrawn from all IS therapy without rejection 2,3 . Mechanisms that underlie the induction and maintenance of clinical operational liver transplant tolerance are not well understood, 4 and there are no validated biomarkers to reliably predict rejection or tolerance. Studies in rodents, however, in particular use of the mouse orthotopic liver transplant model, 5 in which MHC‐mismatched grafts are accepted without IS treatment, 6 have advanced understanding of cellular and molecular pathways that regulate liver ischemia‐reperfusion injury 7 and immune‐mediated rejection versus tolerance 8 .…”