Hepatitis: Yamagiwa S

Yamagiwa S, Kamimura H, Ichida T. · Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachidori, Chuo-ku, Niigata, 951-8510, Japan. · Med Mol Morphol. · Pubmed #19294486 No free full text.

Abstract: The liver is a distinctive immune organ with predominant innate immunity, being rich in innate immune cells such as natural killer (NK) cells. In humans, NK cells comprise about 30%-50% of intrahepatic lymphocytes, whereas peripheral blood lymphocytes contain about 5%-20% NK cells. Accumulating evidence suggests that NK cells play an important role not only in host defense against invading microorganisms and tumor transformation in the liver but also in liver injury and repair. In recent years, significant progress has been made in terms of understanding how NK cells recognize their target cells and carry out their effector functions. It is now clear that NK cells are strictly regulated by numerous activating and inhibitory NK cell receptors that recognize various classes of cell surface ligands, some of which are expressed by normal healthy cells. Therefore, to further elucidate the involvement of NK cells in the pathogenesis of liver diseases, an understanding of recent advances in NK cell biology is crucial. This review provides an overview of recent advances in our knowledge of human NK cell receptors and their ligands in the context of liver diseases.

Sato Y, Oya H, Yamamoto S, Kobayashi T, Watanabe T, Kokai H, Yamagiwa S, Hatakeyama K. · Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, Japan. · Hepatogastroenterology. · Pubmed #19453058 No free full text.

Abstract: BACKGROUND/AIMS: Re-infection of hepatitis C virus (HCV) is very important for prognosis after liver transplantation of HCV cirrhosis. In the mechanism of re-infection of HCV, the peri-transplant immunity including the immunosuppression must be very important for getting the solution of prevention of its infection. (please rewrite this phrase). In this study, we investigated the influences of intraportal DST for HCV-reinfection after living related liver transplantation (LRLT). METHODOLOGY: The 12 patients, who underwent LRLT for the end-stage HCV liver cirrhosis from 1999 to 2007 in our hospital, were estimated about the influence of intraportal DST for re-infection of HCV. The nine persons of all patients had received the intraportal DST after LRLT. RESULTS: These nine patients could be steroid withdrawn within 2 months. The seven persons of all patients that received intraportal DST were treated with perioperative IFN therapy. Two patients had preoperative interferon-beta therapy. The one patient could obtain SVR. The other patient dropped out for the complications. The four patients had interferon-beta therapy in the acute hepatitis phase. Two patients had it in the chronic hepatitis phase. The one patient mentioned before, had preoperative IFN-beta and dropped out. HCV of the one patients without interferon therapy disappeared spontaneously from 3 months. The HCV disappeared in the 6 patients (66.7%) of all nine patients with intraportal DST after LRLT. The five of six patients were SVR. The patient who got preoperative IFN-beta revealed the macrochimerism of donor type CD56+T cell in the graft liver one month after LRLT. The immunological analysis about the patient, who got a spontaneous disappearance of HCV two months after LRLT, demonstrated that CD56+T cells strongly developed the both FasL and TRAIL expressions. CONCLUSION: In this study, the clinical and immunological findings suggested that intraportal DST might affect for the clearance of HCV by the both host immunity and IFN-ribavirin therapy.

Yamagiwa S, Matsuda Y, Ichida T, Honda Y, Takamura M, Sugahara S, Ishikawa T, Ohkoshi S, Sato Y, Aoyagi Y. · Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. · Hepatol Res. · Pubmed #18328072 No free full text.

Abstract: Aim: Previous studies have revealed that functional impairment of innate immune cells, including natural killer (NK) and natural killer T (NKT) cells, might be associated with the persistence of hepatitis C virus (HCV) infection. However, the involvement of innate immune cells, which predominate in the liver, in therapeutic HCV clearance is still unclear. Methods: To clarify the role of intrahepatic innate immune cells in the clinical outcome of patients with chronic hepatitis C (CHC) treated with interferon-alpha plus ribavirin (IFN/RBV), we prospectively investigated the status of NK and NKT cells in paired liver biopsy and peripheral blood (PB) samples obtained from 21 CHC patients before and immediately after IFN/RBV treatment by flow cytometry. Normal liver and PB samples were obtained from 10 healthy donors for living donor liver transplantation. Results: Before treatment, intrahepatic NK and NKT cells constituted a significantly lower proportion in CHC patients than in healthy individuals (P < 0.05). After IFN/RBV treatment, the proportions and absolute numbers of CD3(-)CD161(+) NK and CD3(+)CD56(+) NKT cells in the liver, but not in PB, were significantly increased in sustained responders (SR) as compared with poor responders (P < 0.05). The proportion of CD3(+)CD161(+) NKT cells was also increased in the liver of SR after the treatment. Moreover, there was a striking increase of activated CD152(+) cells among CD3(+)CD56(+) NKT cells in the liver of SR (P = 0.041). Conclusion: These findings demonstrate that sustained response to IFN/RBV treatment for patients with CHC is closely associated with increased dynamism of NK and NKT cells in the liver.

Yamazaki K, Suzuki K, Ohkoshi S, Yano M, Kurita S, Aoki YH, Toba K, Takamura MA, Yamagiwa S, Matsuda Y, Aoyagi Y. · Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences of Niigata University, 1-754, Asahimachi-Dori, Niigata-city 951-8122, Japan. · J Hepatol. · Pubmed #18083266 No free full text.

Abstract: BACKGROUND/AIMS: The preventive effect of interferon (IFN) against hepatocellular carcinoma (HCC) has been confirmed clinically. We sought to determine whether the temporal administration of IFN-beta prevents hepatocarcinogenesis in a mouse model where HCC develops without necroinflammation. METHODS: Hepatocarcinogenic mice that are transgenic for the hepatitis B virus X gene (HBx-Tg) were treated with IFN-beta or saline (control) for three months, from 3 to 6 months of age, and the incidence of HCC was determined at 18 months of age. The effects of IFN-beta on DNA synthesis and apoptosis were tested. RESULTS: The incidence of HCC was significantly lower in the IFN-beta-treated mice than the controls (0 vs. 50%, P<0.01). Inhibition of DNA synthesis in hepatocytes by IFN-beta was observed in the livers of HBx-Tg, without any significant induction of apoptosis. Although the treatment of IFN-beta was temporal, the number of hepatocytes with DNA synthesis remained lower 3 and 12 months later in life. CONCLUSIONS: Temporal administration of IFN-beta has a significant preventive effect on the occurrence of HCC in a mouse model where HCC develops without inflammation. The mechanisms are the inhibition of DNA synthesis and cell cycle progression of hepatocytes.

Honda Y, Yamagiwa S, Matsuda Y, Takamura M, Ichida T, Aoyagi Y. · Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 757, Asahimachi-Dori 1, Niigata 951-8510, Japan. · J Hepatol. · Pubmed #17448566 No free full text.

Abstract: BACKGROUNDS/AIMS: Toll-like receptors (TLRs) have emerged as a key component of the innate immune system that triggers antimicrobial responses. Altered monocyte responses to ligands for TLRs have been reported in patients with primary biliary cirrhosis (PBC), yet the precise mechanism remains unknown. METHODS: We investigated in vitro responses to a TLR4 ligand, lipopolysaccharide (LPS), using peripheral blood mononuclear cells and monocytes from 25 patients with PBC, 10 patients with chronic viral hepatitis (CVH), and 20 healthy individuals. RESULTS: After stimulation with LPS, we found significantly higher amounts of IL-1beta, IL-6, and IL-8 production in PBC patients. Through the TLR4 signaling pathway, activation of NF-kappaB and expression of MyD88 mRNA were significantly increased in PBC patients, and the level of TLR4 expression was significantly increased on PBC monocytes as compared with CVH patients and controls. Of significance, the surface expression of RP105, which has recently been shown to be involved in negative regulation of TLR4 signaling, on PBC monocytes was significantly decreased in comparison with CVH patients (P=0.016) and controls (P<0.001). CONCLUSIONS: These results suggest that expression of RP105 and TLR4 is altered on PBC monocytes, which appear to be hypersensitive to LPS, resulting in increased secretion of pro-inflammatory cytokines.

Ishikawa T, Ichida T, Yamagiwa S, Sugahara S, Uehara K, Okoshi S, Asakura H. · Department of Internal Medicine III, Niigata University School of Medicine, Niigata, Japan. · J Gastroenterol Hepatol. · Pubmed #11903747 No free full text.

Abstract: BACKGROUND AND AIMS: The aims of the present study were to determine the occurrence rate of hepatocellular carcinoma (HCC) and to assess the risk factors for the development of HCC in compensated viral liver cirrhosis. METHODS: Two hundred and thirty-nine cirrhotic patients (65 hepatitis B surface antigen (HBsAg) positive, 165 hepatitis C virus (HCV) antibody positive (anti-HCV), and nine with both HBsAg and anti-HCV positivity) were studied. The Kaplan-Meier method evaluated by a log-rank test was used to estimate the cumulative probability of HCC development. Independent predictors of HCC development were estimated by using the Cox proportional hazard regression analysis. RESULTS: Dual infection manifested as HBsAg and anti-HCV positive was the highest risk of HCC. Multivariate analysis indicated that anti-HCV positive, HBsAg positive, and lactate dehydrogenase were independent predictors of the development of HCC among individuals with viral cirrhosis. In the HBsAg-positive group, a high-titer of HBV-DNA (more than 3.7 log genome equivalents (LGE)/mL) was most predictive of HCC development. In the anti-HCV-positive group, male gender and a high-titer of HCV-RNA (more than 1.0 Meq/mL) were predictive factors for the development of HCC. CONCLUSIONS: Individuals with high viral loads should be monitored for the development of HCC. Clinical efforts at eradicating or reducing the viral load may reduce the risk for HCC.

Yonekura K, Ichida T, Sato K, Yamagiwa S, Uchida M, Sugahara S, Ito S, Abo T, Asakura H. · Department of Internal Medicine III, Niigata University School of Medicine, Japan. · Liver. · Pubmed #11092253 No free full text.

Abstract: AIM: Hepatitis C virus (HCV) is a major cause of post-transfusional and sporadic hepatitis, and leads to chronic liver disease. It has been suggested that virus-specific cytotoxic T lymphocytes are responsible for liver injuries that occur in HCV-infected patients. However, the detailed characteristics of these lymphocytes have not yet been defined. We have previously reported that CD56+ T lymphocytes, as intermediates between natural killer cell and T lymphocytes, predominantly infiltrated the liver and were increased in patients with chronic hepatitis related to HCV (CH-C). MATERIAL AND METHODS: We obtained peripheral blood and liver tissues from 32 patients diagnosed as having CH-C, and 10 other liver disease patients (5 chronic hepatitis related to HBV, 5 alcoholics), and analyzed peripheral blood and liver-infiltrating lymphocytes using flow cytometric and immunohistochemical techniques. RESULTS: The CD56+ T lymphocyte ratio in the liver of patients with a high histology activity index (HAI) score for chronic hepatitis was higher than that of patients with a low HAI score and patients with other liver diseases. In addition, T lymphocytes from patients with chronic hepatitis with a high HAI score carried mostly gamma delta-TCR. There was a correlation between the ratio of CH-C and serum alanine aminotransferase, category I (periportal inflammation and necrosis), and IV (fibrosis) of the HAI scoring system. The ratio was highest in zone 1 of the hepatic lobules. CONCLUSION: The correlation between CD56+ T lymphocyte ratios and hepatocellular damage was examined. These findings suggest strongly that liver-infiltrating CD56+ T lymphocytes play an important pathologic role in hepatocellular injury in CH-C.