The hepatic microenvironment and regulatory T cells.

The human liver is regarded as a lymphoid organ that contributes to both local and systemic immune response. Intrahepatic immune cells including regulatory T cells (Tregs) reside in the hepatic microenvironment which is enriched with proinflammatory cytokines, chemokines and metabolites. In addition, the hepatic microenvironment has the unique ability to establish and maintain immune tolerance despite the continuous influx of the gut derived microbial products via the portal vein. Regulatory T cells play a crucial role in maintaining the hepatic tolerogenic state; however, the phenotypic stability, function and survival of Tregs in the inflamed liver microenvironment is still poorly understood. Despite this, Tregs immunotherapy remains as an appealing therapeutic option in autoimmune and immune mediated liver diseases. In order to advance cell therapy, it is important for us to further our understanding of the hepatic microenvironment, with the aim of developing ways to modify the hostile, inflamed environment to one which is more favourable. By doing so, T cell stability and function would be enhanced, resulting in improved clinical outcomes.

Expression of E-cadherin by CD8+ T cells promotes their invasion into biliary epithelial cells.

The presence of CD8+ T cells in the cytoplasm of biliary epithelial cells (BEC) has been correlated with biliary damage associated with primary biliary cholangitis (PBC). Here, we characterise the mechanism of CD8+ T cell invasion into BEC. CD8+ T cells observed within BEC were large, eccentric, and expressed E-cadherin, CD103 and CD69. They were also not contained within secondary vesicles. Internalisation required cytoskeletal rearrangements which facilitated contact with BEC. Internalised CD8+ T cells were observed in both non-cirrhotic and cirrhotic diseased liver tissues but enriched in PBC patients, both during active disease and at the time of transplantation. E-cadherin expression by CD8+ T cells correlated with frequency of internalisation of these cells into BEC. E-cadherin+ CD8+ T cells formed ß-catenin-associated interactions with BEC, were larger than E-cadherin- CD8+ T cells and invaded into BEC more frequently. Overall, we unveil a distinct cell-in-cell structure process in the liver detailing the invasion of E-cadherin+ CD103+ CD69+ CD8+ T cells into BEC.

Use of immunosuppression in non-transplant hepatology.

Human liver possesses a persistent and tightly regulated immune response. Maintaining this homeostatic state is the key to prevent pathological processes, as a failure in clearing dangerous stimuli, is associated with tissue damage. A dysregulation of the liver immune homeostasis is involved in many disease processes and the use of the immunosuppression aims to control the inflammatory response, where the physiologic mechanisms failed. The use of steroids which targets broadly the inflammatory cascade and the immune system activation have been extensively employed in both acute and chronic liver diseases. They currently are the backbone of the treatment of autoimmune diseases such as autoimmune hepatitis or IgG4 sclerosing cholangitis. The steroid use in acute liver injury, especially alcohol mediated and drug induced liver injury (DILI), have been debated, despite the biological rationale. The immunosuppression molecules currently employed in liver diseases target the immune system broadly, causing multiple side effects either intrinsic in the mechanisms of the drug or secondary to off-target toxicity. The future of immunosuppressant treatment is moving towards more selective strategies, targeting disease specific pathways. This review aims to explore the rationale of use of immunosuppression in non-transplant hepatology. A broad summary of the immune biology of liver immune mediated diseases will be provided to the readers in order to highlight the potential therapeutic targets. An extensive description of the molecules employed in liver diseases will follow and the clinical evidences in AIH, IgG4 related cholangitis, alcoholic hepatitis and DILI will be reviewed.

Natural Killer Cells and Regulatory T Cells Cross Talk in Hepatocellular Carcinoma: Exploring Therapeutic Options for the Next Decade.

Despite major advances in immunotherapy, hepatocellular carcinoma (HCC) remains a challenging target. Natural Killer (NK) cells are crucial components of the anti-HCC immune response, which can be manipulated for immunotherapeutic benefit as primary targets, modulators of the tumour microenvironment and in synchronising with tumour antigen specific effector CD8 cells for tumour clearance. Regulatory T cells shape the anti-tumour response from effector T cells via multiple suppressive mechanisms. Future research is needed to address the development of novel NK cell-targeted immunotherapy and on restraining Treg frequency and function in HCC. We have now entered a new era of anti-cancer treatment using checkpoint inhibitor (CPI)-based strategies. Combining GMP-NK cell immunotherapy to enhance the frequency of NK cells with CPI targeting both NK and CD8 T cells to release co-inhibitory receptors and enhance the cells anti-tumour immunity of HCC would be an attractive therapeutic option in the treatment of HCC. These therapeutic approaches should now be complemented by the application of genomic, proteomic and metabolomic approaches to understanding the microenvironment of HCC which, together with deep immune profiling of peripheral blood and HCC tissue before and during treatment, will provide the much-needed personalised medicine approach required to improve clinical outcomes for patients with HCC.

Gut-Liver Immune Traffic: Deciphering Immune-Pathogenesis to Underpin Translational Therapy.

The tight relationship between the gut and liver on embryological, anatomical and physiological levels inspired the concept of a gut-liver axis as a central element in the pathogenesis of gut-liver axis diseases. This axis refers to the reciprocal regulation between these two organs causing an integrated system of immune homeostasis or tolerance breakdown guided by the microbiota, the diet, genetic background, and environmental factors. Continuous exposure of gut microbiome, various hormones, drugs and toxins, or metabolites from the diet through the portal vein adapt the liver to maintain its tolerogenic state. This is orchestrated by the combined effort of immune cells network: behaving as a sinusoidal and biliary firewall, along with a regulatory network of immune cells including, regulatory T cells and tolerogenic dendritic cells (DC). In addition, downregulation of costimulatory molecules on hepatic sinusoids, hepatocytes and biliary epithelial cells as well as regulating the bile acids chain also play a part in hepatic immune homeostasis. Recent evidence also demonstrated the link between changes in the gut microbiome and liver resident immune cells in the progression of cirrhosis and the tight correlation among primary sclerosing cholangitis (PSC) and also checkpoint induced liver and gut injury. In this review, we will summarize the most recent evidence of the bidirectional relationship among the gut and the liver and how it contributes to liver disease, focusing mainly on PSC and checkpoint induced hepatitis and colitis. We will also focus on completed therapeutic options and on potential targets for future treatment linking with immunology and describe the future direction of this research, taking advantage of modern technologies.

Type 2 Autoimmune Hepatitis and Nonadherence to Medication Correlate With Premature Birth and Risk of Postpartum Flare.

Autoimmune hepatitis (AIH) is an immune-mediated chronic liver disease that affects all ages, including women of childbearing age. Optimal management during pregnancy is poorly defined. We aimed to explore the clinical and biochemical course of AIH in the antenatal and postpartum periods, and assess factors associated with premature birth and postpartum flares. Pregnant women with AIH reviewed in the autoimmune liver disease clinic at the Queen Elizabeth Hospital Birmingham between 2009 and 2020 were identified retrospectively, and clinical, biochemical, and immunological data 1 year before conception to 1 year postpartum were collected. Analysis was performed to identify trends in blood markers over the antenatal period, with an interrupted time series approach used to assess postpartum trends. Data were available for n = 27 pregnancies (n = 20 women), with median gestation of 38 weeks (30% premature) and most having type 1 AIH (78%) and delivering via caesarean section (63%). Levels of alanine transaminase, aspartate transaminase, and immunoglobulin G all declined significantly during gestation, followed by significant step-change increases after delivery. Postpartum flare developed in 58% of pregnancies. AIH type 2 was associated with a higher rate of premature births (67% vs. 19%, P = 0.044), and a trend toward a higher rate of postpartum flare (100% vs. 48%, P = 0.053). Although not significant, medication nonadherence was associated with almost double the risk of prematurity (40% vs. 24%, P = 0.415) and postpartum flare (80% vs. 44%, P = 0.109). Conclusion: Biochemical and immunological remission of AIH occurs during pregnancy, although subsequent postpartum flare is common. Type 2 AIH is associated with a higher risk of premature birth and postpartum flare, although further research is required to validate and explain this finding.

Autoimmune Hepatitis: Tolerogenic Immunological State During Pregnancy and Immune Escape in Post-partum.

The maternal immune system engages in a fine balancing act during pregnancy by simultaneously maintaining immune tolerance to the fetus and immune responses to protect against invading organisms. Pregnancy is an intricately orchestrated process where effector immune cells with fetal specificity are selectively silenced. This requires a sustained immune suppressive state not only by expansion of maternal Foxp3+ regulatory T cells (Tregs) but also by leaning the immune clock toward a Th2 dominant arm. The fetus, known as a semi-allograft or temporary-self, leads to remission of autoimmune hepatitis during pregnancy. However, this tolerogenic immune state reverts back to a Th1 dominant arm, resulting in post-partum flare of AIH. Various hormones play a significant role in endocrine-immune axis during pregnancy. The placenta functions as a barrier between the maternal immune system and the fetus also plays a pivotal role in creating a tolerogenic environment during pregnancy. We review the evidence of immune tolerance during pregnancy and immune escape at post-partum period, focusing on patients with autoimmune hepatitis.