Transplant Tolerance Induction: Insights From the Liver

Abstract

A comparison of pre-clinical transplant models and of solid organs transplanted in routine clinical practice demonstrates that the liver is most amenable to the development of immunological tolerance. This phenomenon arises in the absence of stringent conditioning regimens that accompany published tolerizing protocols for other organs, particularly the kidney. The unique immunologic properties of the liver have assisted our understanding of the alloimmune response and how it can be manipulated to improve graft function and survival. This review will address important findings following liver transplantation in both animals and humans, and how these have driven the understanding and development of therapeutic immunosuppressive options. We will discuss the liver's unique system of immune and non-immune cells that regulate immunity, yet maintain effective responses to pathogens, as well as mechanisms of liver transplant tolerance in pre-clinical models and humans, including current immunosuppressive drug withdrawal trials and biomarkers of tolerance. In addition, we will address innovative therapeutic strategies, including mesenchymal stem cell, regulatory T cell, and regulatory dendritic cell therapy to promote liver allograft tolerance or minimization of immunosuppression in the clinic.

Keywords: cell therapy; immune tolerance; immunosuppression withdrawal; liver transplantation; mechanisms.

Figure 1

Mechanisms underlying experimental liver transplant tolerance. Hepatic immune and parenchymal cells interact with each other to generate a tolerogenic microenvironment. Liver dendritic cells (DC) express low levels of Toll-like receptor 4 (TLR4) and co-stimulatory molecules, but high levels of PDL1, weakly stimulate T cell responses, and promote regulatory CD4⁺ T cells (CD4 Treg) induction through TGF-β. Liver DC release high levels of IL-10, but low bioactive IL-12. Liver DC prevent T cell priming of orally-administered Ag through anergy or deletion of circulating T cells. Graft-infiltrating, cross-dressed DC over-express PDL1 and subvert anti-donor T cell proliferation to promote liver graft tolerance. The DNAX-activating protein of 12 kDa (DAP12) negatively regulates liver DC IL-12 production, but positively regulates liver DC IL-10 production and T cell allostimulatory capability. Kupffer cells can release IFN-γ-stimulated nitric oxide (NO) to inhibit T cell proliferation and produce IL-10 and TGF-β to promote tolerance. Liver sinusoidal endothelial cells (LSEC) present circulating exogenous antigens to T cells, resulting in Ag-specific T cell tolerance. LSEC and hepatic stellate cells (HSC) induce T cell apoptosis through PDL1/PD1 pathway interactions. The mechanism of hepatocyte-induced T cell death occurs through a type of apoptosis known as passive cell death (PCD). Exosomes derived from hepatocytes may also be critical to a tolerogenic phenotype. Mesenchymal stromal cells (MSC) suppress T cell proliferation and differentiation through cell-cell contact that is mediated by PDL1.