The Role of Diverse Liver Cells in Liver Transplantation Tolerance

Abstract

Liver transplantation is the ideal treatment approach for a variety of end-stage liver diseases. However, lifelong , systemic immunosuppressive treatment after transplantation is required to prevent rejection and graft loss, which is associated with severe side effects, although liver allograft is considered more tolerogenic. Therefore, understanding the mechanism underlying the unique immunologically privileged liver organ is valuable for transplantation management and autoimmune disease treatment. The unique hepatic acinus anatomy and a complex cellular network constitute the immunosuppressive hepatic microenvironment, which are responsible for the tolerogenic properties of the liver. The hepatic microenvironment contains a variety of hepatic-resident immobile non-professional antigen-presenting cells, including hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, that are insufficient to optimally prime T cells locally and lead to the removal of alloreactive T cells due to the low expression of major histocompatibility complex (MHC) molecules, costimulatory molecules and proinflammatory cytokines but a rather high expression of coinhibitory molecules and anti-inflammatory cytokines. Hepatic dendritic cells (DCs) are generally immature and less immunogenic than splenic DCs and are also ineffective in priming naïve allogeneic T cells via the direct recognition pathway in recipient secondary lymphoid organs. Although natural killer cells and natural killer T cells are reportedly associated with liver tolerance, their roles in liver transplantation are multifaceted and need to be further clarified. Under these circumstances, T cells are prone to clonal deletion, clonal anergy and exhaustion, eventually leading to tolerance. Other proposed liver tolerance mechanisms, such as soluble donor MHC class I molecules, passenger leukocytes theory and a high-load antigen effect, have also been addressed. We herein comprehensively review the current evidence implicating the tolerogenic properties of diverse liver cells in liver transplantation tolerance.

Regulatory T Cells in the Mosaic of Liver Transplantation Tolerance

“…Although being involved in metabolism, toxin neutralization and glycogen synthesis, they function also as immune cells by expressing immune-associated molecules like pattern recognition receptors (PRRs), adhesion and major histocompatibility complex (MHC) molecules [30,31]. The latter permit hepatocytes to act as antigen-presenting cells for CD8+ T cells and to trigger their activation and proliferation [32]. However, the particular hepatic environment does not ensure the required survival factors Regulatory T Cells in the Mosaic of Liver Transplantation Tolerance DOI: http://dx.doi.org/10.5772/intechopen.94362 for CD8+ cells and they rapidly undergo activation-induced apoptosis [33].…”

“…Hepatic Stellate cells (HSCs) are another subset with immune function. This relatively small population (5-10% of liver parenchymal cells) resides in the space of Disse and is primarily involved in the storage of retinoid droplets and vitamin A and regulation of blood flow in the sinusoids [32,46,47]. In the intact liver, they are quiescent cells.…”

Ribosylation of the CD8αβ heterodimer permits binding of the nonclassical major histocompatibility molecule, H2-Q10

“…It is possible that the binding of H2-Q10 serves to further dampen down the immune response of CD8αβ T cells in the liver, either by blocking binding of MHC-Ia or potentially through preventing efficient signaling. Indeed, the liver is well recognized as a site of immune tolerance, evidenced by the observation that liver allografts are often not rejected despite mismatched MHC-Ia ( 36 ). Notably, although CD8α enhances the response of CD8αβ T cells by lipid raft partitioning of the TCR, it is the beta chain of CD8 that leads to efficient and effective Lck activity and downstream signaling ( 1 , 37 ).…”

Indoleamine 2,3-dioxygenase 1 limits hepatic inflammatory cells recruitment and promotes bile duct ligation-induced liver fibrosis

“…Hepatic and splenic CD11c + DC populations were decreased in BDL-induced liver fibrosis It is known that hepatic DCs could induce either immunogenic responses or tolerance according to physiologic circumstances and affect disease course 26 . Hepatic non-parenchymal cells(HNPCs) isolated from bile duct ligation or sham-operated mice were analyzed for DCs frequencies by flow cytometry.…”