The Liver: A Special Case in Transplantation Tolerance

Abstract

Liver transplants are not often rejected in patients weaned from immunosuppression and are spontaneously accepted in some animal models. We review past and recent findings of liver transplantation and propose a unified model in which several mechanisms act in concert to induce and maintain tolerance in both naïve and effector T cell compartments. First, passenger leukocytes migrate to lymphoid tissues and induce apoptosis of alloreactive naïve T cells. Second, antigen-specific activation and subsequent deletion of naïve and effector cells within the liver itself purge the repertoire of alloreactive T cells. Other mechanisms such as microchimerism and migration of donor dendritic cells to the thymus may play a predominant role in maintaining tolerance, and soluble major histocompatibility complex molecules, donor peptides, and regulatory T cells may participate in the induction and maintenance phases. Thus, the major challenge in liver transplantation will be to favor these tolerogenic processes while developing strategies that specifically inhibit alloreactive memory T cells.

Emodin inhibits the differentiation and maturation of dendritic cells and increases the production of regulatory T cells

“…It is well known that dendritic cells (DCs) and regulatory T cells (Tregs) play a pivotal role in inhibiting the rejection of transplantation (11)(12)(13)(14)(15). DCs are professional antigen-presenting cells (APCs) that are specialized for the initiation and regulation of T cell immunity.…”

“…The function of DCs in organ transplantation has been defined, they can capture allogenic antigen and present it to specific T cells to induce an immune response against donors (11,12). Decreasing the antigen-presenting function of DCs is able to inhibit the rejection of transplantation by DC-induced tolerance (13).…”

Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses

“…This tolerogenic capability of the liver is demonstrated in animal models of liver transplantation, in which liver allografts are accepted across complete MHC mismatch barriers and are able to protect other donor tissues from rejection (reviewed in ref. 3). In humans, the tolerogenic hepatic environment is likely to contribute to impaired immune clearance of the hepatitis B virus (HBV) and hepatitis C virus (HCV), which result in persistent infection in a significant proportion of exposed individuals and are associated with major morbidity and mortality.…”

Apoptotic cells attenuate fulminant hepatitis by priming Kupffer cells to produce interleukin-10 through membrane-bound TGF-β

“…1 Hepatic tolerance is also reflected in immune tolerance toward oral antigens and liver grafts. 2 Nonparenchymal liver cells, including liver sinusoidal endothelial cells, dendritic cells (DCs) and Kupffer cells (KCs), have been shown to be responsible for the creation of a local immunosuppressive microenvironment, permitting immune effector cells, such as T cells, to deliver tolerogenic signals, which contributes to the tolerogenic properties of the liver. [3][4][5][6] However, the exact mechanisms for the hepatic immunosuppressive microenvironment remain to be fully understood.…”