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The adult human liver hosts a complex repertoire of liver resident and transient natural killer (NK) cell populations with diverse phenotypes and functions. Liver resident NK cells are CD56 bright NK cells defined by a unique expression profile of transcription factors and cell surface markers (Eomes hi Tbet lo TIGIT + CD69 + CXCR6 + CD49e - ). Despite extensive characterization of the phenotype of liver resident NK cells, it remains unclear how factors within the liver microenvironment induce and maintain this unique phenotype. In this study, we have explored the factors regulating the phenotype of liver resident NK cells. Isolation of healthy liver resident NK cells from donor liver perfusate and in vitro culture results in the gradual loss of the characteristic Tbet lo phenotype, with the cells increasing Tbet expression significantly at day 7. This phenotypic loss could be halted through the dose-dependent addition of liver conditioned media (LCM), generated from the ex vivo culture of liver biopsies from healthy organ donors. TGF-β, but not IL-10, replicated the Tbet suppressive effects of LCM in both liver resident and peripheral blood NK cells. Furthermore, blocking TGF-β receptor signaling using the inhibitor SB431542, reversed the effect of LCM treatment on liver resident NK cells, causing the loss of tissue resident Eomes hi Tbet lo phenotype. Our findings identify liver-derived TGF-β as an important component of the liver microenvironment, which acts to regulate and maintain the phenotype of liver resident NK cells.

The adult human liver is enriched with natural killer (NK) cells, accounting for 30-50% of hepatic lymphocytes, which include tissue-resident hepatic NK-cell subpopulations, distinct from peripheral blood NK cells. In murine liver, a subset of liver-resident hepatic NK cells have altered expression of the two highly related T-box transcription factors, T-bet and eomesodermin (Eomes). Here, we investigate the heterogeneity of T-bet and Eomes expression in NK cells from healthy adult human liver with a view to identifying human liver-resident populations. Hepatic NK cells were isolated from donor liver perfusates and biopsies obtained during orthotopic liver transplantation (N = 28). Hepatic CD56(bright) NK cells were Eomes(hi) T-bet(lo) , a phenotype virtually absent from peripheral blood. These NK cells express the chemokine receptor CXCR6 (chemokine (C-X-C motif) receptor 6), a marker of tissue residency, which is absent from hepatic CD56(dim) and blood NK cells. Compared to blood populations, these hepatic CD56(bright) NK cells have increased expression of activatory receptors (NKp44, NKp46, and NKG2D). They show reduced ability to produce IFN-γ but enhanced degranulation in response to challenge with target cells. This functionally distinct population of hepatic NK cells constitutes 20-30% of the total hepatic lymphocyte repertoire and represents a tissue-resident immune cell population adapted to the tolerogenic liver microenvironment., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background & Aims: Extensive populations of liver immune cells detect and respond to homeostatic perturbation caused by damage, infection or malignancy. Dendritic cells (DCs) are central to these activities, governing the balance between tolerance and immunity. Most of our knowledge about human liver DCs is derived from studies on peritumoral tissue. Little is known about the phenotype and function of DCs, in particular the recently described CD141(+) subset, in healthy human liver and how this profile is altered in liver disease., Methods: During liver transplantation, healthy donor and diseased explant livers were perfused and hepatic mononuclear cells isolated. Dendritic cell subset frequency and phenotype were characterised in liver perfusates by flow cytometry and the function of CD141(+) DCs was evaluated by mixed lymphocyte reactions (MLRs) and measuring cytokine secretion., Results: Almost one third of liver CD11c(+) myeloid DCs (mDCs) expressed CD141 compared to <5% of circulating mDCs. Hepatic CD141(+) DCs demonstrated pro-inflammatory function in allogeneic MLRs, inducing T cell production of interferon gamma (IFN-γ) and interleukin (IL)-17. While CD123(+) plasmacytoid DCs (pDCs) and CD1c(+) mDCs were expanded in diseased liver perfusates, CD141(+) DCs were significantly depleted. Despite their depletion, CD141(+) DCs from explant livers produced markedly increased poly(I:C)-induced IFN lambda (IFN-λ) compared with donor DCs., Conclusions: Accumulation of CD141(+) DCs in healthy liver, which are significantly depleted in liver disease, suggests differential involvement of mDC subsets in liver immunity., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The cellular mechanisms involved in mediating cytoprotection against ischemia-reperfusion (IR) injury are not well understood. In animal models, NF-E2-related factor-2 (Nrf2) protects against IR injury by transcriptional activation of phase II antioxidants. Here, we investigate how the expression of Nrf2 mRNA in human donor livers in the setting of liver transplantation (LT) correlates with the histological damage associated with IR injury and whether or not this influences the outcome of LT., Methods: Pairs of biopsies were acquired from 14 donor livers; the first biopsy of each pair was taken at the start of the retrieval operation, prior to the IR phase of LT and the second at the end of transplantation. RNA was extracted from snap frozen tissue and cDNA was prepared. Nrf2 mRNA expression was determined using real-time polymerase chain reaction (PCR). The modified Suzuki scoring system was used for histological grading of IR injury and relevant donor, recipient, and after LT clinical data were compiled., Results: Nrf2 expression was observed in all biopsies, both before and after IR. Some donor organs had greater expression of Nrf2 mRNA before IR injury, and these organs had lower Suzuki scores and better liver functions (ALT) after LT. Donors of livers with greater Nrf2 levels were significantly younger (40.5 yrs, range 28-53 yrs) than those with low Nrf2 levels (55.5 yrs, range 48-61 yrs), P<0.05., Conclusion: Livers from older donors have lower levels of Nrf2 perhaps exposing these organs to more IR-related damage.

Background: The presence of dual pathology can cause diagnostic dilemmas. We present a case of adenocarcinoma of the ampulla of Vater with concurrent amiodarone hepatotoxicity., Methods: Painless jaundice associated with a palpable gallbladder was investigated clinically, radiologically, endoscopically and via liver biopsy., Results: Liver biopsy showed amiodarone hepatotoxicity. Endoscopic biopsy identified an ampullary adenoma. However, the endoscopic ultrasound and intra-operative findings suggested a malignancy, which was confirmed postoperatively., Conclusions: While the classic findings of Courvoisier's Law are borne out in this case, the etiology of jaundice is twofold. Although dual pathology is uncommon it should always be considered.

The hepatic immunological environment, dominated by NK and NKR(+) T cells, seems specialised to respond to malignant challenge. Ineffective immune responses to malignancy are likely determined by factors including alterations in the local cytokine profile. This study examines the cytokine milieu of normal and tumour-bearing liver, quantifying pro-/anti-inflammatory cytokines using modified ELISAs and real-time quantitative PCR. Cytokine protein was localised using immunohistochemistry. We demonstrate an active cytokine environment in normal liver, with high levels of inflammatory and regulatory cytokines. Inflammatory IFN-gamma was increased in tumour-bearing liver (p<0.0001). However, a much greater increase in anti-inflammatory IL-10, produced by non-parenchymal cells (p<0.0005), resulted in a reduced IFN-gamma:IL-10 ratio in tumour-bearing liver (p<0.02). In contrast, immunosuppressive TGF-beta and IL-13 were significantly downregulated (p<0.02). Furthermore, IL-2 was not increased and IL-15 was reduced (p<0.02). The IFN-gamma inducing cytokine, IL-18 was increased in tumour-bearing liver (p<0.02), while pro-inflammatory TNF-alpha was suppressed (p<0.05). These results suggest that, whilst there is a significant inflammatory immune response in tumour-bearing liver, evidenced by increased levels of IFN-gamma, disproportionate increase in IL-10 may be a key factor in facilitating tumour progression. Therapies aimed at antagonising IL-10-mediated immunosuppression may prove a useful strategy in the future treatment of metastatic disease.

Management of patients with colorectal liver metastases has evolved considerably due to a better understanding of the biology of the disease with concurrent improvements in surgical techniques, oncological strategies and radiological interventions. This review article examines the factors that have contributed to this radical change. Management will be discussed in relation to chemotherapy, surgery and interventional radiology. The addition of chemotherapy and biological agents has greatly extended the reach and scope of surgery. Parenchymal sparing resections, repeat resections, two stage hepatectomy and Associating Liver Partition and Portal Vein ligation are all available to the hepatobiliary surgeon who deals with colorectal liver metastases. Interventional radiology techniques like liver venous deprivation may also replace established surgical practice. Whilst traditionally it was thought that only a few liver metastases could be treated effectively, nowadays tumour number is no longer a limiting factor provided enough functioning liver can be spared and the patient can tolerate the operation. [ABSTRACT FROM AUTHOR]

The adult human liver hosts a complex repertoire of liver resident and transient natural killer (NK) cell populations with diverse phenotypes and functions. Liver resident NK cells are CD56bright NK cells defined by a unique expression profile of transcription factors and cell surface markers (EomeshiTbetloTIGIT+CD69+CXCR6+CD49e−). Despite extensive characterization of the phenotype of liver resident NK cells, it remains unclear how factors within the liver microenvironment induce and maintain this unique phenotype. In this study, we have explored the factors regulating the phenotype of liver resident NK cells. Isolation of healthy liver resident NK cells from donor liver perfusate and in vitro culture results in the gradual loss of the characteristic Tbetlo phenotype, with the cells increasing Tbet expression significantly at day 7. This phenotypic loss could be halted through the dose-dependent addition of liver conditioned media (LCM), generated from the ex vivo culture of liver biopsies from healthy organ donors. TGF-β, but not IL-10, replicated the Tbet suppressive effects of LCM in both liver resident and peripheral blood NK cells. Furthermore, blocking TGF-β receptor signaling using the inhibitor SB431542, reversed the effect of LCM treatment on liver resident NK cells, causing the loss of tissue resident Eomeshi Tbetlo phenotype. Our findings identify liver-derived TGF-β as an important component of the liver microenvironment, which acts to regulate and maintain the phenotype of liver resident NK cells. [ABSTRACT FROM AUTHOR]