IL-15 enhances CCR5-mediated migration of memory CD8 + T cells by upregulating CCR5 expression in the absence of TCR stimulation

During microbial infection, bystander CD8+ T cells that are not specific to infecting pathogens can be activated by interleukin (IL)-15. However, the tissue-homing properties of bystander-activated CD8+ T cells have not been elucidated. Here, we examine the effects of IL-15 on the expression of chemokine receptors on CD8+ T cells and their migration. IL-15 upregulates CCR5 in memory CD8+ T cells in the absence of T cell receptor (TCR) stimulation and enhances CCR5-dependent migration. IL-15-induced CCR5 upregulation is abrogated by TCR stimulation, indicating that CCR5 is upregulated in bystander-activated CD8+ T cells. Moreover, CCR5 signals increase proliferation and cytotoxic protein expression in IL-15-treated memory CD8+ T cells, although the increase has a small extent. CCR5 upregulation in bystander-activated CD8+ T cells is associated with severe liver injury in patients with acute hepatitis A. Altogether, the results indicate that CCR5 upregulation by IL-15 mediates the migration of bystander-activated CD8+ T cells.ope

Current status of liver diseases in Korea: Hepatitis B.

Hepatitis B virus (HBV) infection is the one of the most common causes of the liver diseases in Korea. Since the discovery of Australia antigen (hepatitis associated antigen, or HBsAg later), hepatitis associated antigen was tested widely. HBsAg was detected in 6.6~8.6% in 1980's. Later, it decreased to 5.7% in 1990's. Remarkably, seropositivity of the children deceased to 0.2% after the nationwide vaccination program. Although hepatitis B vaccines are highly effective, the failure rate of perinatal prophylaxis in babies born to HBsAg positive mother was reported to be 4.25%. Treatment of chronic hepatitis B was initiated after the introduction of interferon alpha. Lamivudine opened a new era of oral antiviral agent, and it has been widely used in Korea since 1999. Adefovir was proven to have a good efficacy for lamivudine-resistant chronic hepatitis B. Newer potent antiviral agents such as entecavir, clevudine, and telbivudine are available currently. Further studies are warranted for understanding factors influencing natural history, improving treatment outcomes, and overcoming vaccine non-response.ope

Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice

Activation of innate immunity (natural killer [NK] cell/interferon-γ [IFN-γ]) has been shown to play an important role in antiviral and antitumor defenses as well as antifibrogenesis. However, little is known about the regulation of innate immunity during chronic liver injury. Here, we compared the functions of NK cells in early and advanced liver fibrosis induced by a 2-week or a 10-week carbon tetrachloride (CCl(4) ) challenge, respectively. Injection of polyinosinic-polycytidylic acid (poly I:C) or IFN-γ induced NK cell activation and NK cell killing of hepatic stellate cells (HSCs) in the 2-week CCl(4) model. Such activation was diminished in the 10-week CCl(4) model. Consistent with these findings, the inhibitory effect of poly I:C and IFN-γ on liver fibrosis was markedly reduced in the 10-week versus the 2-week CCl(4) model. In vitro coculture experiments demonstrated that 4-day cultured (early activated) HSCs induce NK cell activation via an NK group 2 member D/retinoic acid-induced early gene 1-dependent mechanism. Such activation was reduced when cocultured with 8-day cultured (intermediately activated) HSCs due to the production of transforming growth factor-β (TGF-β) by HSCs. Moreover, early activated HSCs were sensitive, whereas intermediately activated HSCs were resistant to IFN-γ-mediated inhibition of cell proliferation, likely due to elevated expression of suppressor of cytokine signaling 1 (SOCS1). Disruption of the SOCS1 gene restored the IFN-γ inhibition of cell proliferation in intermediately activated HSCs. Production of retinol metabolites by HSCs contributed to SOCS1 induction and subsequently inhibited IFN-γ signaling and functioning, whereas production of TGF-β by HSCs inhibited NK cell function and cytotoxicity against HSCs. CONCLUSION : The antifibrogenic effects of NK cell/IFN-γ are suppressed during advanced liver injury, which is likely due to increased production of TGF-β and expression of SOCS1 in intermediately activated HSCs.ope

High-Dose Vitamin C Promotes Regression of Multiple Pulmonary Metastases Originating from Hepatocellular Carcinoma

We report a case of regression of multiple pulmonary metastases, which originated from hepatocellular carcinoma after treatment with intravenous administration of high-dose vitamin C. A 74-year-old woman presented to the clinic for her cancer-related symptoms such as general weakness and anorexia. After undergoing initial transarterial chemoembolization (TACE), local recurrence with multiple pulmonary metastases was found. She refused further conventional therapy, including sorafenib tosylate (Nexavar). She did receive high doses of vitamin C (70 g), which were administered into a peripheral vein twice a week for 10 months, and multiple pulmonary metastases were observed to have completely regressed. She then underwent subsequent TACE, resulting in remission of her primary hepatocellular carcinoma.ope

Assessment of Hepatic Fibrosis Regression by Transient Elastography in Patients with Chronic Hepatitis B Treated with Oral Antiviral Agents

Transient elastography (TE) has been used as a non-invasive method for liver stiffness measurement (LSM) in patients with chronic liver disease. This study was performed to assess the change of LSM by TE and to assess its clinical usefulness during long-term oral antiviral therapy in patients with chronic hepatitis B (CHB). We retrospectively reviewed 83 CHB patients. The mean interval between two LSM was 411.5 ± 149.5 days. Initial and follow-up LSM was 16.15 ± 12.41 kPa and 11.26 ± 7.36 kPa, respectively (P upper limit of normal [ULN] × 2) and low (≤ ULN × 2) alanine aminotransferase groups during antiviral therapy (P < 0.001; P = 0.001, respectively). Long-term oral antiviral therapy resulted in the improvement of liver stiffness in a substantial portion of patients with CHB. TE may be used a useful clinical tool to assess disease progression in CHB patients.ope

Acute Hepatitis A Complicated with Acute Kidney Injury

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A case of angiomyolipoma of the liver

Angiomyolipoma occurs most commonly in the kidneys; the liver is the second most frequent site of involvement. Hepatic angiomyolipoma is a rare, benign, mesenchymal neoplasm, composed mainly of blood vessels, smooth muscle cells, fat, and myelocomponents. Radiologic findings are non-specific because the various elements of these neoplasms vary in their proportion and distribution within the tumor. Thus, data obtained by imaging technologies such as computed tomography, ultrasonography, or magnetic resonance imaging tend to be merely suggestive; definitive diagnosis usually requires histologic confirmation. We report here a case of angiomyolipoma in an incidental tumor of the liver of a 53-year-old female. Tissue was removed from the tumor by ultrasonography-guided gun biopsy and subjected to immunohistochemical analysis. Data showed that tumor cells were positive for HMB-45 and SMA, but negative for cytokeratin, anti-hepatocyte antigen, and alpha-fetoprotein. The patient did not receive any treatment and is being followed upope

Is liver biopsy still useful in the era of non-invasive tests?

Biopsy, needle ; Complicationsope

Revision and update on clinical practice guideline for liver cirrhosis

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CD11b+ Gr1+ bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice

Clinical trials and animal models suggest that infusion of bone marrow cells (BMCs) is effective therapy for liver fibrosis, but the underlying mechanisms are obscure, especially those associated with early effects of BMCs. Here, we analyzed the early impact of BMC infusion and identified the subsets of BMCs showing antifibrotic effects in mice with carbon tetrachloride-induced liver fibrosis. An interaction between BMCs and activated hepatic stellate cells (HSCs) was investigated using an in vitro coculturing system. Within 24 hours, infused BMCs were in close contact with activated HSCs, which was associated with reduced liver fibrosis, enhanced hepatic expression of interleukin (IL)-10, and expanded regulatory T cells but decreased macrophage infiltration in the liver at 24 hours after BMC infusion. In contrast, IL-10-deficient (IL-10(-/-) ) BMCs failed to reproduce these effects in fibrotic livers. Intriguingly, in isolated cells, CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) BMCs expressed more IL-10 after coculturing with activated HSCs, leading to suppressed expression of collagen and α-smooth muscle actin in HSCs. Moreover, these effects were either enhanced or abrogated, respectively, when BMCs were cocultured with IL-6(-/-) and retinaldehyde dehydrogenase 1(-/-) HSCs. Similar to murine data, human BMCs expressed more IL-10 after coculturing with human HSC lines (LX-2 or hTERT), and serum IL-10 levels were significantly elevated in patients with liver cirrhosis after autologous BMC infusion. Conclusion : Activated HSCs increase IL-10 expression in BMCs (CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) cells), which in turn ameliorates liver fibrosis. Our findings could enhance the design of BMC therapy for liver fibrosis.ope