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.
Highlights
The location and anatomy of the liver, positioned between the gastrointestinal tract and the systemic circulation, allows it to conduct its functions of digestion, synthesis of plasma proteins and detoxification [1]
The non-parenchymal cell populations including dendritic cells (DC), Kupffer cells (KC), and Liver sinusoidal endothelial cells (LSEC) constitute the hepatic reticulo-endothelial system, which is responsible for clearing Ags and degradation of toxins from sinusoidal blood by uptake through endocytic receptors [1]
Immunosuppression, including high-dose antithymocyte globulin (ATG) induction followed by short-term rapamycin withdrawal at an early timepoint (4 month post-transplant) failed to induce operational liver transplant tolerance, which was associated with CD8+ memory T cell expansion and elevated IL-17+ cell infiltration in liver grafts [142]
Summary
The location and anatomy of the liver, positioned between the gastrointestinal tract and the systemic circulation, allows it to conduct its functions of digestion, synthesis of plasma proteins and detoxification [1]. In the first report showing spontaneous tolerance induction by liver transplantation, pig hepatic allografts demonstrated longterm survival without immunosuppression, protecting other donor-specific tissue but not third-party organs from rejection [37].
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