Hepatitis: Onji M

Tokumoto Y, Onji M. · No affiliation provided · Intern Med. · Pubmed #17202725 links to  free full text

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Hiasa Y, Onji M. · No affiliation provided · J Gastroenterol. · Pubmed #16988775 No free full text.

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Abe M, Akbar SM, Onji M. · Third Department of Internal Medicine, Ehime University School of Medicine, Ehime, Japan. · Hepatol Res. · Pubmed #16890177 No free full text.

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Horiike N, Onji M. · No affiliation provided · J Gastroenterol. · Pubmed #16378184 No free full text.

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Michitaka K, Onji M. · No affiliation provided · J Gastroenterol. · Pubmed #15565417 No free full text.

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Horiike N, Onji M. · No affiliation provided · J Gastroenterol. · Pubmed #12693384 No free full text.

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Onji M. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #17929436 No free full text.

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Akbar SM, Horiike N, Onji M. · Third Department of Internal Medicine, Ehime University School of Medicine, To on City, Ehime 791-0295, Japan. · World J Gastroenterol. · Pubmed #16718812 links to  free full text

Abstract: Hepatitis B virus (HBV) infection is a global public health problem. Of the approximately 2 billion people who have been infected worldwide, more than 400 million are chronic carriers of HBV. Considerable numbers of chronic HBV carriers suffer from progressive liver diseases. In addition, all HBV carriers are permanent source of this virus. There is no curative therapy for chronic HBV carriers. Antiviral drugs are recommended for about 10% patients, however, these drugs are costly, have limited efficacy, and possess considerable side effects. Recent studies have shown that immune responses of the host to the HBV are critically involved at every stage of chronic HBV infection: (1) These influence acquisition of chronic HBV carrier state, (2) They are important in the context of liver damages, (3) Recovery from chronic HBV-related liver diseases is dependent on nature and extent of HBV-specific immune responses. However, induction of adequate levels of HBV-specific immune responses in chronic HBV carriers is difficult. During the last one decade, hepatitis B vaccine has been administered to chronic HBV carriers as a therapeutic approach (vaccine therapy). The present regimen of vaccine therapy is safe and cheap, but not so effective. A dendritic cell-based therapeutic vaccine has recently been developed for treating chronic HBV infection. In this review, we will discuss about the concept, scientific logics, strategies and techniques of development of HBV-specific immune therapies including vaccine therapy and dendritic cell-based vaccine therapy for treating chronic HBV infection.

Onji M, Furukawa S. · Third Department of Internal Medicine, Ehime University School of Medicine. · Nippon Shokakibyo Gakkai Zasshi. · Pubmed #15682811 No free full text.

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Konishi I, Horiike N, Michitaka K, Ochi N, Furukawa S, Minami H, Onji M. · Third Department of Internal Medicine, Ehime University School of Medicine, Shigenobucho, Onsen-gun, Ehime 791-0295. · Intern Med. · Pubmed #15575242 links to  free full text

Abstract: A 44-year-old Japanese woman with a history of living-related renal transplantation was treated with interferon-beta (IFN-beta) for chronic infection with sero-group 2 hepatitis C virus (HCV). Serum HCV-RNA titer was 160 kilo-international units/ml. Treatment with intravenous IFN-beta daily was given for 6 weeks. Serum HCV-RNA was undetectable at 3 weeks after initiating therapy. Renal graft rejection did not occur. Six months after completing therapy, she obtained sustained viral response. This case demonstrates that IFN-beta therapy safely induced clearance of HCV in a renal transplant recipient with stable renal function, low viral load and/or HCV sero-group 2.

Hiasa Y, Onji M. · Third Department of Internal Medicine, Ehime University School of Medicine. · Nippon Rinsho. · Pubmed #15453369 No free full text.

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Michitaka K, Onji M. · Endoscopy Center, Ehime University School of Medicine. · Nippon Rinsho. · Pubmed #15453328 No free full text.

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Horiike N, Onji M. · Third Department of Internal Medicine, Ehime University School of Medicine. · Nippon Rinsho. · Pubmed #15453289 No free full text.

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Akbar SM, Furukawa S, Horiike N, Onji M. · Third Department of Internal Medicine, Ehime University School of Medicine, Japan. · Curr Drug Targets Infect Disord. · Pubmed #15180457 No free full text.

Abstract: Despite the presence of an effective prophylactic vaccine since 1982, more than 350 million people of the world are now chronically infected with hepatitis B virus (HBV). In one scenario, a considerable numbers of chronic HBV carrier would eventually develop serious complications like liver cirrhosis and hepatocellular carcinoma. In another, chronic HBV carriers would be permanent sources of HBV infection and transmit HBV to uninfected healthy individuals. Taken together, chronic HBV infection represents a major global public health problem, especially in the developing nations of the Asia and Africa, where most of the chronic HBV-carriers reside. Unfortunately, there is no good curative therapy approach for these patients. The prospect of treatment of chronic HBV infection by antiviral agents like type-1 interferons and lamivudine is not satisfactory due to their low efficacy, considerable side effects and high costs. Vaccine therapy, an immune therapy, has recently shown considerable optimism for treating patients with chronic HBV infection. In this review, we will first describe the pathogenesis of chronic HBV carrier state to provide scientific and ethical rationales of vaccine therapy in chronic HBV carriers. Next, we will summarize the information that has been compiled from ongoing clinical trials of vaccine therapy in chronic HBV carrier. Finally, we will discuss the mechanism of action of vaccine therapy in patients with chronic HBV infection and HBV transgenic mice, a murine model of chronic HBV carrier state. This information will be valuable for developing next generation therapeutic vaccines for the management of chronic HBV infection.

Akbar SM, Horiike N, Onji M, Hino O. · Third Department of Internal Medicine, Ehime University School of Medicine, Ehime, Japan. · Intervirology. · Pubmed #11509880 No free full text.

Abstract: Many individuals infected with hepatitis B virus (HBV) and hepatitis C virus (HCV) are unable to clear these viruses following an acute infection and become chronically infected. There are more than 400 million HBV and HCV carriers in the world and a considerable number of these patients would eventually develop more severe complications like liver cirrhosis and hepatocellular carcinoma. It is not clearly known how an individual develops a chronic hepatitis virus carrier state; however, a defective immune response of the host is thought to play a critical role in the underlying pathogenetic mechanism. On the other hand, dendritic cells (DCs), the most potent antigen-presenting cells, are widely distributed in both lymphoid and nonlymphoid tissues. Recognition of the microbes or microbial antigens by DCs is one of critical events for the initiation of an immune response. DCs also play a cardinal role during the progression and termination of an immune response. The aim of this overview is to provide information regarding the role of DCs in the pathogenesis of chronic hepatitis due to HBV and HCV in humans and in animal models of HBV and HCV carrier states. First, we summarize our current understanding of the pathogenesis of hepatitis virus carrier states and also of general properties of DCs. Next, we discuss the data on the phenotypes and functions of DCs in both human and murine HBV and HCV carriers. We also discuss vaccine therapy in murine HBV carriers because activation of DCs due to vaccination-initiated HBsAg-specific immune responses in HBV transgenic mice (HBV-Tg), which in turn resulted in complete clearance of hepatitis B surface antigen and hepatitis B e antigen and decreased levels of HBV DNA in some HBV-Tg. Finally, we discuss the extracted questions and future research directions.

Neuman MG, Brenner DA, Rehermann B, Taieb J, Chollet-Martin S, Cohard M, Garaud JJ, Poynard T, Katz GG, Cameron RG, Shear NH, Gao B, Takamatsu M, Yamauchi M, Ohata M, Saito S, Maeyama S, Uchikoshi T, Toda G, Kumagi T, Akbar SM, Abe M, Michitaka K, Horiike N, Onji M. · Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Ontario, Canada. · Alcohol Clin Exp Res. · Pubmed #11391079 No free full text.

Abstract: This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Manuela G. Neuman. The presentations were (1) New aspects of hepatic fibrosis, by D. A. Brenner; (2) Cellular immune response in hepatitis C models, by B. Rehermann; (3) The role of interleukin-10 in acute alcoholic hepatitis, by J. Taieb, S. Chollet-Martin, M. Cohard, J. J. Garaud, and T. Poynard; (4) Cytokine-mediated apoptosis in vitro, by M. G. Neuman; (5) Signaling for apoptosis and repair in vitro, by G. G. Katz, R. G. Cameron, N. H. Shear, and M. G. Neuman; (6) Interferons activate the P42/44 mitogen-activated protein kinase and Janus Kinase signal transducers and activation of transcription (JAK-STAT) signaling pathways in hepatocytes: Differential regulation by acute ethanol via a protein kinase C-dependent mechanism, by B. Gao; (7) Genetic polymorphisms of interleukin-1 in association with the development of Japanese alcoholic liver disease, by M. Takamatsu, M. Yamauchi, M. Ohata, S. Saito, S. Maeyama, T. Uchikoshi, and G. Toda; and (8) Increased levels of macrophage migration inhibitory factor in sera from patients with alcoholic liver diseases, by T. Kumagi, S. M. F. Akbar, M. Abe, K. Michitaka, N. Horiike, and M. Onji.

Fazle Akbar SM, Furukawa S, Yoshida O, Hiasa Y, Horiike N, Onji M. · Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon City, Ehime 791-0295, Japan. · J Hepatol. · Pubmed #17467112 No free full text.

Abstract: BACKGROUND/AIMS: Antigen-pulsed dendritic cells (DCs) are now used for treatment of patients with cancers, however, the efficacy of these DCs has never been evaluated for prophylactic purposes. The aim of this study was (1) to prepare hepatitis B surface antigen (HBsAg)-pulsed human blood DCs, (2) to assess immunogenicity of HBsAg-pulsed DCs in vitro and (3) to evaluate the efficacy of HBsAg-pulsed DCs in hepatitis B (HB) vaccine nonresponders. METHODS: Human peripheral blood DCs were cultured with HBsAg to prepare HBsAg-pulsed DCs. The expression of immunogenic epitopes of HBsAg on HBsAg-pulsed DCs was assessed in vitro. Finally, HBsAg-pulsed DCs were administered, intradermally to six HB vaccine nonresponders and the levels of antibody to HBsAg (anti-HBs) in the sera were assessed. RESULTS: HB vaccine nonresponders did not exhibit features of immediate, early or delayed adverse reactions due to administration of HBsAg-pulsed DCs. Anti-HBs were detected in the sera of all HB vaccine nonresponders within 28 days after administration of HBsAg-pulsed DCs. CONCLUSIONS: This study opens a new field of application of antigen-pulsed DCs for prophylactic purposes when adequate levels of protective antibody cannot be induced by traditional vaccination approaches.

Horiike N, Fazle Akbar SM, Michitaka K, Joukou K, Yamamoto K, Kojima N, Hiasa Y, Abe M, Onji M. · Third Department of Internal Medicine, Ehime University School of Medicine, Shigenobu-Cho, Ehime 791 0295, Japan. · J Clin Virol. · Pubmed #15653419 No free full text.

Abstract: BACKGROUND: Both the hepatitis B virus (HBV) and the immune response of the hosts to HBV play important roles in the pathogenesis of chronic hepatitis B (CHB). Lamivudine is a potent antiviral agent with minimal immune modulator capacity. Moreover, lamivudine causes severe side effects like breakthrough of HBV DNA and breakthrough hepatitis in patients with CHB. On the other hand, vaccine therapy, a recently-developed immune therapy, exhibits potent immune modulatory potentials and almost no side effects, but possesses little antiviral capacity in patients with CHB. OBJECTIVES: The aim of this clinical trial is to evaluate the efficacy of a combination therapy of lamivudine and vaccine in patients with CHB. STUDY DESIGN: Seventy-two patients with CHB (hepatitis B e antigen (HBeAg)-positive, 40; antibody to HBeAg (anti-HBe)-positive, 32). All patients received lamivudine at a dose of 100 mg daily for 12 months. Fifteen patients (HBeAg+, 9; anti-HBe+, 6) receiving oral lamivudine were also given a vaccine containing 20 microg of hepatitis B surface antigen, intradermally, once every 2 weeks for 12 times (combination therapy). RESULTS: Twelve months after the start of therapy, serum HBV DNA became negative in 9 of 9 (100%) HBeAg+ CHB patients receiving combination therapy and in 15 of 31 (48%) HBeAg+ CHB patients receiving lamivudine monotherapy (P < 0.05). The rate of seroconversion from HBeAg to anti-HBe was also significantly higher in patients receiving combination therapy (56% versus lamivudine monotherapy, 16%, P < 0.05). Of the 57 patients receiving lamivudine monotherapy, breakthrough of HBV DNA was found in 10 and breakthrough hepatitis was found in 4; however, these were not seen in any patient receiving combination therapy. CONCLUSIONS: Combination therapy represents a better therapeutic regimen with few complications in patients with CHB.

Tanimoto K, Akbar SM, Michitaka K, Onji M. · Third Department of Internal Medicine, Ehime University School of Medicine, Japan. · Pathol Res Pract. · Pubmed #10220795 No free full text.

Abstract: In order to have insights into the abnormal immune regulation in primary biliary cirrhosis (PBC), different types of antigen presenting cells (APC) were localized immunohistochemically in liver specimens from 26 patients with PBC and compared with the distributions of APC from 11 and 10 patients with chronic hepatitis C (CH-C) and large bile duct obstruction, respectively. In all diagnostic conditions, 30-90% of the infiltrating cells were positive for HLA DR. In PBC, the numbers of interdigitating cells (IDC) were significantly higher than the numbers of CD83-positive dendritic cells (DC) (34.0 +/- 38.8 vs. 5.5 +/- 7.1/specimen, mean +/- SD, p < 0.05). On the other hand, the numbers of IDC (14.2 +/- 20.0/specimen) and CD83-positive DC (7.9 +/- 8.7/specimen) were almost similar in CH-C (p > 0.05). Positive stainings for IDC and CD83-positive DC were rarely seen in large bile duct obstruction. This is the first report on the existence of activated CD83-positive DC in PBC. The significantly increased numbers of IDC and the highly restricted distributions of CD83-positive DC in PBC indicate that activated DC may play a role in the abnormal immune pathogenesis of PBC.

Akbar SM, Hiasa Y, Mishiro S, Onji M. · Department of Medical Sciences, Toshiba General Hospital, 6-3-22 Higashi Oi, Shinagawa, Tokyo 140-8522, Japan. · Expert Opin Pharmacother. · Pubmed #19496738 No free full text.

Abstract: BACKGROUND: The treatment of individuals infected with hepatitis B virus (HBV) is a complex issue in practical settings, despite the explosion of new and effective antiviral agents. OBJECTIVE: To assess the scope and limitations of ongoing treatment guidelines against HBV from a global perspective. METHODS: Present therapeutic guidelines against HBV have been discussed with emphasis on their value in developing countries that harbor about 90% of the total number of global patients who are infected with HBV. RESULTS/CONCLUSION: Treatment of HBV-infected patients should be appropriately followed up and healthcare delivery systems should be able to combat treatment-induced adverse side effects. Current therapeutic guidelines should be optimized based on the socio-economic conditions of developing countries.

Yoshida O, Abe M, Furukawa S, Murata Y, Hamada M, Hiasa Y, Matsuura B, Akbar F, Michitaka K, Onji M. · Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, To-on. · Intern Med. · Pubmed #19252353 links to  free full text

Abstract: Autoimmune hepatitis is a chronic liver disease, and both genetic background and environmental factors are related to its pathogenesis. Here, we report that out of five members of a family with similar human leukocyte antigen haplotypes, two developed autoimmune hepatitis, one was positive for antinuclear antibody, and the remaining two had no features of autoimmunity. The two patients with autoimmune hepatitis had a history of medication use, whereas the other family members did not. Our familial study suggests that in addition to genetic background, medication use and other environmental factors may be related to the onset of autoimmune hepatitis.

Michitaka K, Tokumoto Y, Uesugi K, Kisaka Y, Hirooka M, Konishi I, Mashiba T, Abe M, Hiasa Y, Matsuura B, Horiike N, Shoda T, Onji M. · Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan. · Hepatol Res. · Pubmed #19000057 No free full text.

Abstract: Aim: The aim of this study is to clarify the cerebral functions in patients with chronic hepatitis (CH) as well as those with liver cirrhosis (LC). Methods: We studied 58 patients with CH (20 in fibrosis stage F1, 20 in F2, 18 in F3), 77 with LC (46 rated as Child-Pugh class A, 24 as B, 7 as C), and 20 healthy volunteers (HV). Computer-aided quantitative neuropsychiatric function test systems, including eight neuropsychiatric tests were performed. Results: Subjects with results over the cut-off value for healthy subjects ranged from 11.1-28.6% in CH and 19.5-36.4% in LC. The percentages with abnormality in at least one test in CH and LC were 72.4% and 80.6%, respectively, which were significantly higher than that in the HV group (35.0%) (P = 0.003, P = 0.0003, respectively). Among CH subjects, those with three or more abnormal results in the F1, F2 and F3 subgroups were 15.0%, 20.0% and 38.9%, respectively. Among LC subjects, those with three or more abnormal results in the Child-Pugh class A, B and C subgroups comprised 30.4%, 50.0% and 57.1%, respectively. The rate in the CH F3 subgroup (P = 0.011) and in all three LC subgroups (P = 0.023, P = 0.001, P = 0.002, respectively) were significantly higher than that in the HV group. Conclusion: The percentage of patients with neuropsychiatric function impairment was high in both LC and CH, especially in stage F3. Neuropsychiatric dysfunction may initiate in CH in a considerable number of patients.

Hiasa Y, Kuzuhara H, Tokumoto Y, Konishi I, Yamashita N, Matsuura B, Michitaka K, Chung RT, Onji M. · Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan. · Hepatology. · Pubmed #18459156 No free full text.

Abstract: A derivative of soyasapogenol, 22beta-methoxyolean-12-ene-3beta, 24(4beta)-diol (ME3738), ameliorates liver injury induced by Concanavalin A in mice. We examined whether ME3738 has independent antiviral effects against hepatitis C virus (HCV) using an established HCV replication model that expresses the full-length genotype 1a HCV complementary DNA plasmid (pT7-flHCV-Rz) under the control of a replication-defective adenoviral vector expressing T7 polymerase. Hepatocellular carcinoma (HepG2) cells, human hepatoma (Huh7) cells, or monkey kidney (CV-1) cells were transfected with pT7-flHCV-Rz, and infected with adenoviral vector expressing T7 polymerase. ME3738 or interferon-alpha (IFN-alpha) was added thereafter and then protein and RNA were harvested from the cells at 9 days after infection. HCV-positive and HCV-negative strands were measured by real-time reverse-transcription polymerase chain reaction and HCV core protein expression was measured using an enzyme-linked immunosorbent assay. The messenger RNA levels of innate antiviral response-related genes were assessed using real-time reverse-transcription polymerase chain reaction. ME3738 dose-dependently reduced HCV-RNA and core protein in hepatocyte-derived cell lines. The antiviral effect was more pronounced in HepG2 than in Huh7 cells. ME3738 increased messenger RNA levels of interferon-beta (IFN-beta) and of IFN-stimulated genes (2'-5' oligoadenylate synthetase, myxovirus resistance protein A [MxA]). Interferon-beta knockdown by small interfering RNA abrogated the anti-HCV effect of ME3738. Moreover, the anti-HCV effects were synergistic when ME3738 was combined with IFN-alpha. CONCLUSION: ME3738 has antiviral effects against HCV. The enhancement of autocrine IFN-beta suggests that ME3738 exerts antiviral action along the type I IFN pathway. This anti-HCV action by ME3738 was synergistically enhanced when combined with IFN-alpha. ME3738 might be a useful anti-HCV drug either with or without IFN-alpha.

Yoshida O, Akbar F, Miyake T, Abe M, Matsuura B, Hiasa Y, Onji M. · Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan. · Clin Exp Immunol. · Pubmed #18307521 links to  free full text

Abstract: The primary aim of this study was to evaluate the role of natural killer (NK) cells on antigen-specific adaptive immune responses. After analysing the mechanism of impaired adaptive immune responses of NK-depleted mice, an immune interventional approach was developed to restore adaptive immunity in NK-depleted mice. NK cells were depleted from mice by administration of anti-asialo GM1 antibody (100 mul/mouse), twice, at an interval of 48 h. Hepatitis B surface antigen (HBsAg) was administered intraperitoneally to normal C57BL/6 mice (control mice) and NK-depleted mice. The levels of antibody to HBsAg (anti-HBs) in the sera and HBsAg-specific lymphocytes in the spleen were assessed. The functions of T lymphocytes, B lymphocytes and dendritic cells (DCs) were evaluated in vitro. HBsAg-pulsed DCs were prepared by culturing spleen DCs with HBsAg for 48 h and administered once to NK-depleted mice. The levels of anti-HBs in the sera and HBsAg-specific lymphocytes were significantly lower in NK-depleted mice compared with control mice (P < 0.05). The functions of T and B lymphocytes were similar between control mice and NK-depleted mice. However, the functions of spleen DC and liver DC were significantly lower in NK-depleted mice compared with control mice (P < 0.05). Administration of HBsAg-pulsed DCs, but not HBsAg, induced HBsAg-specific humoral and cellular immune responses in NK-depleted mice. Our study suggests that cross-talk between NK cells and DCs regulates the magnitude of adaptive immunity. In addition, antigen-pulsed immunogenic DCs represent potent immune modulator even if subjects with diminished innate immunity.

Okanoue T, Itoh Y, Minami M, Hashimoto H, Yasui K, Yotsuyanagi H, Takehara T, Kumada T, Tanaka E, Nishiguchi S, Izumi N, Sata M, Onji M, Yamada G, Okita K, Kumada H. · Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan. · Hepatol Res. · Pubmed #18039201 No free full text.

Abstract: Aim: We aimed to identify the candidates for antiviral therapy, among patients who are hepatitis C virus (HCV) carriers with normal serum aminotransferase (ALT), focused on the inhibition of hepatocellular carcinoma (HCC). Methods: Four hundred and sixty-four HCV carriers with normal serum ALT and 129 HCV carriers with persistently normal ALT (PNALT) and platelet (PLT) counts >/=150 000/muL who received liver biopsies were enrolled. HCV carriers with normal serum ALT were divided into four groups according to their ALT levels (</=30 U/L or 31-40 U/L) and PLT counts (>/=150 000/muL or <150 000/muL). Results: In 129 HCV carriers with PNALT, the rate of progression of fibrosis stage was 0.05/year and no HCC was detected during the follow up for 10 years. Approximately 20% of patients with ALT </=40 U/L and PLT counts >/=150 000/muLwere at stage F2-3; however, approximately 50% of patients with ALT </= 40 U/L and PLT counts <150 000/muL were at stage F2-4. An algorithm for the management of HCV carriers with normal serum ALT was advocated based on ALT and PLT counts. Conclusion: The combination of ALT and PLT counts is useful for evaluating the fibrosis stage in HCV carriers with normal serum ALT. Most patients with PLT counts <150 000/muL are candidates for antiviral therapy, especially those with ALT levels >/=31 U/L when we focus on the inhibition of the development of HCC.