Abstract
The constant exposure of the liver to gut derived foreign antigens has resulted in this organ attaining unique immunological characteristics, however it remains susceptible to immune mediated injury. Our understanding of this type of injury, in both the native and transplanted liver, has improved significantly in recent decades. This includes a greater awareness of the tolerance inducing CD4+ CD25+ CD127low T-cell lineage with the transcription factor FoxP3, known as regulatory T-Cells (Tregs). These cells comprise 5-10% of CD4+ T cells and are known to function as an immunological “braking” mechanism, thereby preventing immune mediated tissue damage. Therapies that aim to increase Treg frequency and function have proved beneficial in the setting of both autoimmune diseases and solid organ transplantations. The safety and efficacy of Treg therapy in liver disease is an area of intense research at present and has huge potential. Due to these cells possessing significant plasticity, and the potential for conversion towards a T-helper 1 (Th1) and 17 (Th17) subsets in the hepatic microenvironment, it is pre-requisite to modify the microenvironment to a Treg favourable atmosphere to maintain these cells’ function. In addition, implementation of therapies that effectively increase Treg functional activity in the liver may result in the suppression of immune responses and will hinder those that destroy tumour cells. Thus, fine adjustment is crucial to achieve this immunological balance. This review will describe the hepatic microenvironment with relevance to Treg function, and the role these cells have in both native diseased and transplanted livers.
Highlights
The tissue damage that occurs in many liver diseases results from immunologically mediated mechanisms [1]
This trial was terminated early due to rejection occurring in three subjects that were transplanted for autoimmune liver diseases, the high rate of operational tolerance achieved at such a short time interval from transplant was viewed as a step forward
The prospect of manipulating Tregs to protect the liver from immunologically mediated damage in chronic liver disease or transplant setting is being met with excitement in the scientific community
Summary
The tissue damage that occurs in many liver diseases results from immunologically mediated mechanisms [1]. In liver transplant recipients on calcineurin inhibitor (Tacrolimus) therapy, the frequency of CD45RA+FoxP3lo and CD45RA−FoxP3hi was decreased in comparison to healthy controls, but CD45-FoxP3lo were similar [34] These authors concluded that a limited availability of IL-2 was responsible for Treg cell death. Mechanisms include CTLA-4 on Treg leading to trans-endocytosis of CD80/ 86 molecules on antigen presenting cells, depriving effector T-cells of IL-2 by competitive consumption, depletion of extracellular ATP via the release of adenosine through the CD39 molecule on Tregs, secretion of immunosuppressive cytokines (IL-10, IL-35 and TGFb) and cytotoxic enzymes Granzyme and Perforin to kill T effector cells [25, 37] These functional mechanisms of Tregs can vary depending on given immune scenario, the stimulus and corresponding microenvironment [25, 38, 39]. In a murine model of acute liver injury an alleviation of inflammation occurred with adoptive transfer of Tregs and this was associated with increased IL-10 levels within the liver [40, 41]
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