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Mechanisms of Immune Tolerance in Liver Transplantation-Crosstalk Between Alloreactive T Cells and Liver Cells With Therapeutic Prospects.

ABSTRACT: Liver transplantation (LTx) is currently the most powerful treatment for end-stage liver disease. Although liver allograft is more tolerogenic compared to other solid organs, the majority of LTx recipients still require long-term immune suppression (IS) to control the undesired alloimmune responses, which can lead to severe side effects. Thus, understanding the mechanism of liver transplant tolerance and crosstalk between immune cells, especially alloreactive T cells and liver cells, can shed light on more specific tolerance induction strategies for future clinical translation. In this review, we focus on alloreactive T cell mediated immune responses and their crosstalk with liver sinusoidal endothelial cells (LSECs), hepatocytes, hepatic stellate cells (HSCs), and cholangiocytes in transplant setting. Liver cells mainly serve as antigen presenting cells (APCs) to T cells, but with low expression of co-stimulatory molecules. Crosstalk between them largely depends on the different expression of adhesion molecules and chemokine receptors. Inflammatory cytokines secreted by immune cells further elaborate this crosstalk and regulate the fate of naïve T cells differentiation within the liver graft. On the other hand, regulatory T cells (Tregs) play an essential role in inducing and keeping immune tolerance in LTx. Tregs based adoptive cell therapy provides an excellent therapeutic option for clinical transplant tolerance induction. However, many questions regarding cell therapy still need to be solved. Here we also address the current clinical trials of adoptive Tregs therapy and other tolerance induction strategies in LTx, together with future challenges for clinical translation from bench to bedside.

SUBMITTER: Lei H

PROVIDER: S-EPMC6877506 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Mechanisms of Immune Tolerance in Liver Transplantation-Crosstalk Between Alloreactive T Cells and Liver Cells With Therapeutic Prospects.

Lei Hong H Reinke Petra P Volk Hans-Dieter HD Lv Yi Y Wu Rongqian R

Frontiers in immunology 20191119

Liver transplantation (LTx) is currently the most powerful treatment for end-stage liver disease. Although liver allograft is more tolerogenic compared to other solid organs, the majority of LTx recipients still require long-term immune suppression (IS) to control the undesired alloimmune responses, which can lead to severe side effects. Thus, understanding the mechanism of liver transplant tolerance and crosstalk between immune cells, especially alloreactive T cells and liver cells, can shed li ...[more]

PMID: 31803188

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Project description:Liver transplantation is the ideal treatment approach for a variety of end-stage liver diseases. However, life-long, 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.

Dataset Information

Mechanisms of Immune Tolerance in Liver Transplantation-Crosstalk Between Alloreactive T Cells and Liver Cells With Therapeutic Prospects.

Publications

Mechanisms of Immune Tolerance in Liver Transplantation-Crosstalk Between Alloreactive T Cells and Liver Cells With Therapeutic Prospects.

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