Role of IL-17 and Th17 Cells in Liver Diseases

Unbalanced Th1/Th2 T-cell responses in the liver are a characteristic of hepatic inflammation and subsequent liver fibrosis. The recently discovered Th17 cells, a subtype of CD4+ T-helper cells mainly producing IL-17 and IL-22, have initially been linked to host defense against infections and to autoimmunity. Their preferred differentiation upon TGFβ and IL-6, two cytokines abundantly present in injured liver, makes a contribution of Th17 cells to hepatic inflammation very likely. Indeed, initial studies in humans revealed activated Th17 cells and Th17-related cytokines in various liver diseases. However, functional experiments in mouse models are not fully conclusive at present, and the pathogenic contribution of Th17 cells to liver inflammation might vary upon the disease etiology, for example, between infectious and autoimmune disorders. Understanding the chemokines and chemokine receptors promoting hepatic Th17 cell recruitment (possibly CCR6 or CCR4) might reveal new therapeutic targets interfering with Th17 migration or differentiation in liver disease

Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer

Liver fibrosis is a chronic, highly prevalent disease that may progress to cirrhosis and substantially increases the risk for development of hepatocellular carcinoma (HCC). Fibrotic livers are characterized by an inflammatory microenvironment that is composed of various immunologically active cells, including liver-resident populations (e.g., Kupffer cells, hepatic stellate cells and sinusoidal endothelium) and infiltrating leukocytes (e.g., monocytes, monocyte-derived macrophages, neutrophils and lymphocytes). While inflammatory injury drives both fibrogenesis and carcinogenesis, the tolerogenic microenvironment of the liver conveys immunosuppressive effects that encourage tumor growth. An insufficient crosstalk between dendritic cells (DCs), the professional antigen presenting cells, and T cells, the efficient anti-tumor effector cells, is one of the main mechanisms of HCC tumor tolerance. The meticulous analysis of patient samples and mouse models of fibrosis-HCC provided in-depth insights into molecular mechanisms of immune interactions in liver cancer. The therapeutic modulation of this multifaceted immunological response, e.g., by inhibiting immune checkpoint molecules, in situ vaccination, oncolytic viruses or combinations thereof, is a rapidly evolving field that holds the potential to improve the outcome of patients with HCC. This review aims to highlight the current understanding of DC-T cell interactions in fibrogenesis and hepatocarcinogenesis and to illustrate the potentials and pitfalls of therapeutic clinical translation

Role of IL-17 and Th17 Cells in Liver Diseases

Unbalanced Th1/Th2 T-cell responses in the liver are a characteristic of hepatic inflammation and subsequent liver fibrosis. The recently discovered Th17 cells, a subtype of CD4 + T-helper cells mainly producing IL-17 and IL-22, have initially been linked to host defense against infections and to autoimmunity. Their preferred differentiation upon TGFβ and IL-6, two cytokines abundantly present in injured liver, makes a contribution of Th17 cells to hepatic inflammation very likely. Indeed, initial studies in humans revealed activated Th17 cells and Th17-related cytokines in various liver diseases. However, functional experiments in mouse models are not fully conclusive at present, and the pathogenic contribution of Th17 cells to liver inflammation might vary upon the disease etiology, for example, between infectious and autoimmune disorders. Understanding the chemokines and chemokine receptors promoting hepatic Th17 cell recruitment (possibly CCR6 or CCR4) might reveal new therapeutic targets interfering with Th17 migration or differentiation in liver disease

Combination of G-CSF and a TLR4 inhibitor reduce inflammation and promote regeneration in a mouse model of ACLF

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterised by high short-term mortality, systemic inflammation, and failure of hepatic regeneration. Its treatment is an unmet medical need. This study was conducted to explore whether combining TAK-242, a Toll-like receptor-4 (TLR4) antagonist, with Granulocyte-Colony Stimulating Factor (G-CSF) targets inflammation whilst enhancing liver regeneration. METHODS: Two mouse models of ACLF were investigated. Chronic liver injury was induced by carbon tetrachloride followed by either lipopolysaccharide (LPS) or galactosamine (GalN) as extrahepatic or hepatic insults, respectively. G-CSF and/or TLR4-antagonist, TAK-242, were administered daily. The treatment duration was 24h and 5d in the LPS model and 48h in the GalN model, respectively. RESULTS: In a LPS-induced ACLF mouse model treatment with G-CSF was associated with a significant mortality of 66% after 48 hours compared with 0% without G-CSF. Addition of TAK-242 to G-CSF abrogated mortality (0%) and significantly reduced liver cell death, macrophage infiltration and inflammation. In the GalN model, both G-CSF and TAK-242, when used individually, reduced liver injury but their combination was significantly more effective. G-CSF treatment, with or without TAK-242, was associated with activation of the pro-regenerative and anti-apoptotic STAT3 pathway. LPS-driven ACLF was characterized by p21 over-expression suggesting hepatic senescence and inhibition of hepatocyte regeneration. While TAK-242 treatment mitigated the effect on senescence, G-CSF, when co-administered with TAK-242, resulted in a significant increase of markers of hepatocyte regeneration. CONCLUSION: TLR4 inhibition with TAK-242 rescued G-CSF-driven cell death, inflammation, enhanced tissue repair, and significantly induced regeneration thus suggesting that the combination of G-CSF and TAK-242 is a novel approach for the treatment of ACLF. LAY SUMMARY: The combinatorial therapy of Granulocyte-Colony Stimulating Factor and TAK-242, a Toll-like Receptor-4 inhibitor, achieves the dual aim of reducing hepatic inflammation and inducing liver regeneration for the treatment of acute-on-chronic liver failure

Immune Regulatory 1 Cells: A Novel and Potent Subset of Human T Regulatory Cells

A subset of T regulatory cells (Tregs), identified by TIRC7 (T cell immune response cDNA 7) expression is designated as Immune Regulatory 1 Cells (IR1 cells). TIRC7 is an immune checkpoint inhibitor, co-localized with the T- cell receptor, HLA-DR and CTLA-4 during T-cell activation, which delivers regulatory signals via binding to its ligand, HLA-DR α2 domain. IR1 cells express FOXP3, and multiple other markers associated with immune suppression. They constitute as much as 10% of Tregs. IR1 cells strongly inhibit proliferation in mixed lymphocyte reactions, where they express high levels of IL-10. Ex vivo expansion of Tregs over 2 weeks in the presence of an agonist TIRC7 antibody disproportionately expands the IR1 Treg subset, while maintaining high expression of suppressive markers including CD39, IL-10, LAP and GARP. Ex vivo expanded IR1 cells are a potent, homogeneous, stable set of suppressor Tregs with the potential to modulate immune dysregulation. The characteristics of IR1 cells suggest a therapeutic advantage over polyclonal Tregs for therapeutic interventions. Early restoration of immune homeostasis using IR1 cells has the potential to fundamentally alter the natural history of conditions characterized by abnormalities in the T regulatory cell compartment

Chemokine receptor CCR6-dependent accumulation of IL-17 producing gamma-delta T cells in injured liver restricts hepatic inflammation and fibrosis

Chronic liver injury promotes hepatic inflammation, representing a prerequisite for organ fibrosis, a common consequence of various liver diseases. In this study we investigated the contribution of the chemokine receptor CCR6 and its ligand CCL20 to chronic liver injury and hepatic fibrosis. CCR6 is known to be expressed on some T helper cells and gamma/delta T cells, monocyte derived dendritic cells and B cell subsets. It plays an important role in mucosal immunity and has been implicated in the migration of Th17, regulatory (Treg) and gamma/delta T cells, but its role in liver disease is largely unknown. Therefore we analyzed human liver samples of patients with chronic liver disease of various etiologies for expression of CCR6 and CCL20. Additionally, wildtype (wt) and CCR6 knock-out (Ccr6-/-) mice were treated with the hepatotoxic agent carbon tetrachloride (CCl4) thrice weekly over a period of 4 weeks or subjected to methionine-choline-deficient (MCD) diet for 8 weeks to induce liver fibrosis. Liver damage, inflammation, and fibrosis development were then assessed by biochemical methods, histology, immunostaining, flow cytometry, and quantitative realtime PCR. CCR6 and CCL20 expression was significantly up-regulated in the livers of patients with chronic liver diseases (n=50) and fibrotic murine livers. Ccl20 was strongly induced in primary murine hepatocytes upon injury. In both models of chronic liver injury, Ccr6-/- mice developed more severe fibrosis than wildtype mice. Furthermore, in CCl4-induced liver injury Ccr6-/- mice showed strongly enhanced liver inflammation compared to wt mice, as indicated by increased overall hepatic immune cell infiltration. While CCR6-deficiency did not affect the composition of hepatic T helper cell subtypes, expression of interleukin-17 (IL-17) was significantly reduced in livers of Ccr6-/- mice. Wt mice showed an accumulation of IL-17-producing gamma/delta T cells in the liver upon CCl4 treatment, which was markedly reduced in livers of Ccr6-/- mice. Concordantly, the adoptive transfer of wt gamma/delta T cells, but not of CD4+ T cells, into Ccr6-/- mice reduced hepatic inflammation and fibrosis in chronic injury, but this function was independent of their IL-17 production. Moreover, hepatic gamma/delta T cells colocalized with hepatic stellate cells (HSC) in vivo and directly inhibited HSC function by limiting their collagen synthesis and facilitating apoptosis in a Fas-dependent manner in vitro. Thus, IL-17 producing gamma/delta T cells specifically require CCR6 to migrate to the liver upon chronic injury and are able to protect the liver from excessive inflammation and fibrosis by inhibiting HSC