G Toda

The University of Tokyo, Edo, Tōkyō, Japan

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Publications (244)676.42 Total impact

  • Nippon rinsho. Japanese journal of clinical medicine 06/2010; 68 Suppl 6:697-700.
  • Nippon rinsho. Japanese journal of clinical medicine 06/2010; 68 Suppl 6:717-20.
  • Kanzo 01/2009; 50(12):687-702.
  • Kanzo 01/2009; 50(10):584-587.
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    ABSTRACT: Aim: Treatment with ursodeoxycholic acid (UDCA) improves the survival of stage I and II primary biliary cirrhosis (PBC) patients. However, new therapeutic options are needed for patients who are refractory to UDCA and for those whose disease is at an advanced stage. Bezafibrate could be useful in PBC treatment, since it increases phospholipid output into the bile and reduces the cytotoxicity of hydrophobic bile acids, which are increased with cholestasis.Methods: We conducted two prospective, multicenter randomized open studies in non-cirrhotic patients with PBC to evaluate the efficacy of bezafibrate. One study compared UDCA and bezafibrate monotherapy (study 1: 45 patients [37 females], mean age 55.9 years), and the other evaluated the addition of bezafibrate to patients who were refractory to UDCA (study 2: 21 patients [18 females], mean age 54.1 years).Results: Study 1 demonstrated that bezafibrate monotherapy was as effective as UDCA and study 2 revealed that bezafibrate combined with UDCA was effective in improving and maintaining biliary enzymes where the ineffectiveness of long-term treatment with UDCA was confirmed.Conclusion: This multicenter, randomized, open study revealed that combination therapy of bezafibrate and UDCA improved biliary enzymes in non-cirrhotic Japanese patients with PBC refractory to UDCA. Further studies are needed to evaluate whether combination therapy improves histological staging and prognosis.
    Hepatology Research 04/2008; 38(6):557 - 564. · 2.07 Impact Factor
  • Gastroenterology 04/2008; 134(4). · 12.82 Impact Factor
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    ABSTRACT: The occurrence of antibodies to interferon-α2a (anti-IFN-α2a) to recombinant human IFN-α2a was examined in chronic liver disease by a sensitive enzyme-linked immunosorbent assay (ELISA). Naturally occurring IgG and/or IgM anti-IFN-α2a were found in one of 12 cases of chronic persistent hepatitis, four of 18 cases of chronic active hepatitis (CAH), two of 12 cases of liver cirrhosis, six of seven cases of primary biliary cirrhosis, nine of 11 cases of auto-immune CAH and none of 21 normal control subjects. Fifteen patients with viral CAH were treated with recombinant IFN-α2a. Two of them were positive prior to receipt of IFN-α2a and their titres increased after the therapy. Two patients became positive for anti-IFN-α2a after the therapy. Absorption experiments revealed that anti-IFN-α2a cross-reacted with native human leucocyte IFN-α and recombinant IFN-α2b but not with recombinant IFN-β and -γ. The immunoblotting experiment confirmed the binding of antibodies to IFN. The results of anti-IFN-α2a obtained by antiviral, cytopathic effect assay were in good agreement with those of IgG anti-IFN-α2a, but not with those of IgM antibodies obtained by the ELISA. The ELISA described in the present study is a simple, sensitive and quantitative assay for anti-IFN-α2a. It should be useful in assessing sub-specificities of anti-IFN and provide valuable information to predict the effect of IFN therapy and to elucidate the immunological abnormality in liver disease.
    Journal of Gastroenterology and Hepatology 03/2008; 4(5):411 - 418. · 3.33 Impact Factor
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    ABSTRACT: Combined pegylated interferon and ribavirin has improved chronic hepatitis C (CH-C) therapy; however, sustained virological response is achieved in only about half of the patients with a 1b genotype infection. We assessed oral ursodeoxycholic acid (UDCA) on serum biomarkers as a possible treatment for interferon non-responders. CH-C patients with elevated alanine aminotransferase (ALT) were assigned randomly to 150 (n = 199), 600 (n = 200) or 900 mg/day (n = 197) UDCA intake for 24 weeks. Changes in ALT, aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) were assessed. This study is registered at ClinicalTrial.gov, identifier NCT00200343. ALT, AST and GGT decreased at week 4 and then remained constant during drug administration. The median changes (150, 600 and 900 mg/day, respectively) were: ALT, -15.3, -29.2 and -36.2%; AST, -13.6, -25.0 and -29.8%; GGT, -22.4, -41.0 and -50.0%. These biomarkers decreased significantly less in the 150 mg/day than in the other two groups. Although changes in ALT and AST did not differ between the 600 and 900 mg/day groups, GGT was significantly lower in the 900 mg/day group. In subgroup analysis, ALT decreased significantly in the 900 mg/day group when the baseline GGT exceeded 80 IU/l. Serum HCV-RNA did not change in any group. Adverse effects were reported by 19.1% of the patients, with no differences between groups. A 600 mg/day UDCA dose was optimal to decrease ALT and AST levels in CH-C patients. The 900 mg/day dose decreased GGT levels further, and may be preferable in patients with prevailing biliary injuries.
    Gut 01/2008; 56(12):1747-53. · 13.32 Impact Factor
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    ABSTRACT: Interleukin-12 (IL-12), a cytokine with antitumor activity, was examined for the suppressive effect on hepatocellular carcinoma (HCC) in mouse model, and its mechanism of antitumor activity was analyzed. Mice implanted with MIH-2 HCC cells were treated with recombinant mouse IL-12 (500 ng/mouse). Involvement of CD4(+), CD8(+), NK cells and interferon (IFN)-gamma on tumor suppression by IL-12 was examined by treatment of mice with each antibody. Interferon-gamma (IFN-gamma) production by tumor infiltrating cells was analyzed by immunofluorescence microscopy and flow cytometric analysis. Signal transduction for apoptosis induction was examined by immunoblot analysis. The growth of implanted MIH-2 tumors was significantly suppressed by IL-12 and the suppression was inhibited by depletion of CD8(+)T cells. IL-12 treatment caused numerous IFN-gamma-producing CD8(+)T cells to infiltrate into MIH-2 tumors. Antitumor activity of IL-12 was blocked by treating mice with anti-IFN-gamma mAb. CD8(+)T cells from IL-12-treated mice attached to MIH-2 cells and produced IFN-gamma in vitro. Cell attachment might be associated with intercellular adhesion molecule-1 induced by IFN-gamma. In vitro treatment with IFN-gamma induced apoptosis of MIH-2 cells via a mitochondria-dependent pathway. IL-12 suppressed HCC growth in mouse model. IFN-gamma produced by IL-12-activated tumor-infiltrating CD8(+)T cells directly induced apoptosis of HCC cells.
    Journal of Hepatology 12/2006; 45(5):662-72. · 10.40 Impact Factor
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    ABSTRACT: Dendritic cell (DC) vaccines might induce both anti-tumour immunity and autoimmunity. In this report, we demonstrate elevated levels of anti-nuclear antibody (ANA) in the sera of patients with cancer who had received immunotherapy with a dendritic/tumour-fusion vaccine. Twenty-two patients were treated with DC vaccine of fusion cells composed of autologous DCs and tumour cells (DC/tumour-fusion vaccine), which was generated by treating each cell type with polyethylene glycol. Nine of the 22 patients were treated with both the DC/tumour-fusion vaccine and systemic administration of recombinant human interleukin (rhIL)-12. Serum levels of ANA were examined with an enzyme-linked immunosorbent assay kit. One patient with gastric carcinoma (patient 1, DC/tumour-fusion vaccine alone), one patient with breast cancer (patient 2, DC/tumour-fusion vaccine alone) and one patient with ovarian cancer (patient 3, DC/tumour-fusion vaccine + rhIL-12) showed significant elevations of serum ANA levels during treatment. In patient 1 malignant ascitic effusion resolved and serum levels of tumour markers decreased. Patients 2 and 3 remained in good physical condition during treatment for 24 and 9 months, respectively. Immunoblot analysis indicated antibody responses to autologous tumour cells after vaccination in patient 2. None of the treated patients showed clinical symptoms suggesting autoimmune disease. Patients with elevated serum levels of ANA had significantly longer treatment periods than those without it. Elevated serum levels of ANA after DC/tumour-fusion cell vaccine might be associated with anti-tumour immune response induced by the vaccination.
    Clinical & Experimental Immunology 05/2006; 144(1):41-7. · 3.28 Impact Factor
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    ABSTRACT: The liver enzymes, alcohol dehydrogenase (ADH) and aldehyde de-hydrogenase (ALDH), which are responsible for the oxidative metabolism of ethanol, are polymorphic in humans. Cytochrome P450IIE1, an ethanol-inducible isozyme of liver microsomal P450, is also important in ethanol metabolism. Genetic polymorphisms in the 5′-flanking region of the human cytochrome P450IIE1 gene have recently been reported. We hypothesized that the polymorphisms of ADH, ALDH, and P450IIE1 modify the susceptibility to development of alcoholism. We determined the genotypes of the ADH2, ALDH2, and P450IIE1 loci of 96 Japanese alcoholics and 60 healthy male subjects, using leukocyte DNA by the restriction fragment-length polymorphism by polymerase chain reaction. The alcoholics had significantly higher frequencies of the ADH21 and ALDH21 alleles than did the healthy subjects. No significant difference in the frequency of the P45011E1 genotype was observed between the alcoholics and the healthy subjects. In conclusion, genetic polymorphisms of the ADH and ALDH genes, but not of the P45011E1 gene, influence the risk of developing alcoholism in Japanese.
    Alcoholism Clinical and Experimental Research 04/2006; 19(4):951 - 954. · 3.31 Impact Factor
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    ABSTRACT: Background: Alcohol abuse can induce brain atrophy, but it only occurs in some alcoholics. Many inflammatory cytokines such as tumor necrosis factor (TNF) are produced rapidly in the brain by experimental or clinical injury.Method: To investigate whether genetic polymorphism of TNF was related to alcoholic brain atrophy, we determined restriction fragment-length polymorphisms of the TNF-β genes in 72 male alcoholics. Computed tomography was used to determine the severity of brain atrophy.Results: Digestion with Nco I and Msp I after polymerase chain reaction amplification showed that the TNFB1 allele frequency was significantly higher in patients with brain atrophy than in those without brain atrophy (χ2= 10.20, p= 0.0034). A multivariate analysis that included age, total alcohol intake, ADH2 genotype, and TNF-β genotype showed that the ADH21/21 genotype and TNFB1/B1 genotype are independently associated with alcoholic brain atrophy. These findings suggest that the TNFB1 allele may be associated with alcoholic brain atrophy.
    Alcoholism Clinical and Experimental Research 04/2006; 25(s2):7S - 10S. · 3.31 Impact Factor
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    ABSTRACT: We examined patients who showed laboratory and histological evidence of primary biliary cirrhosis (PBC) in the absence of antimitochondrial antibody (AMA) to elucidate the characteristics of AMA negative PBC. From a total of 5,805 patients with symptomatic PBC, 2,419 cases (41.7%) were selected in the present study, who were diagnosed using the following criterion; chronic non-suppurative destructive cholangitis was histologically observed and laboratory data did not contradict PBC. The information collected from records included sex, age, symptoms, physical findings, and complicated autoimmune diseases. We then evaluated these data according to the positivity of AMA. Of the total subjects, 470 cases (19.4%) were found to be negative for AMA. The proportion of female patients was higher among the AMA negative group than among the AMA positive one. Pruritus was found less frequently among patients with AMA negative PBC than among those with AMA positive PBC. Levels of alkaline phosphatase,gamma-glutamyl transpeptidase, and IgM were significantly lower among patients with AMA negative PBC than among those with AMA positive PBC. Complications such as Sjögren's syndrome, rheumatoid arthritis, and scleroderma, including CREST syndrome, were found with significantly higher frequency among patients with AMA negative PBC than among those with AMA positive PBC. Considering serum level of IgM and frequencies of complicated autoimmune diseases, it is possible that Japanese patients with AMA negative PBC are consistent with the disease entity of autoimmune cholangitis reported in western countries.
    Journal of Epidemiology 02/2006; 16(1):30-4. · 2.86 Impact Factor
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    ABSTRACT: Diagnosing autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis, and other autoimmune liver diseases remains an imperfect process. We need a more accurate, evidence-based diagnostic system. We conducted a national survey and identified 988 cases of liver disease which did not satisfy the inclusion criteria for any liver disease of known etiology. We expected these cases to include autoimmune liver disease (AILD) and its variant forms. We selected 269 prototype cases for which histological re-evaluation of liver biopsy by independent expert hepatopathologists and the original diagnosis coincided. We did a multiple logistic regression analysis to determine explanatory variables that would distinguish cases of AIH and PBC from those of non-AIH and non-PBC, respectively. We constructed a multivariable diagnostic formula that gave AIH and PBC disease probabilities and validated it in a study of an additional 371 cases (validation group). Based on the results of the statistical analysis, we selected three laboratory tests and four histological features as independent variables correlated to the diagnosis of both AIH and PBC. For the validation group, assuming that the original diagnosis was correct, the sensitivity and specificity for AIH were 86.3% and 92.4%, respectively. For PBC the sensitivity and specificity were 82.5% and 63.7%, respectively. A detailed analysis of inconsistent cases showed that the diagnosis based on the formula had given the correct diagnosis, for either AIH or PBC, except for 5 cases (1.3%) in which disease probability was low for both. A seven-variable formula based on three laboratory tests and four histological features gives significant information for the diagnosis of AILD.
    Journal of Gastroenterology 01/2006; 40(12):1148-54. · 4.02 Impact Factor
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    ABSTRACT: Vaccination of mice with dendritic cells loaded with Hepa1-6, well-differentiated hepatocellular carcinoma cell line (DC/Hepa1-6), induced cytotoxic T lymphocytes against Hepa1-6. Liver-specific inflammation was generated by vaccination of mice with DC/Hepa1-6 and subsequent administration of interleukin (IL)-12. Vaccination with DCs loaded with MC38 or B16 and administration of IL-12 did not generate significant liver-specific inflammation. Splenic T cells from DC/Hepa1-6-vaccinated mice showed proliferative response by stimulation with S-100 protein of the liver and showed cytotoxic activity to hepatocytes. Hepatic mononuclear cells from DC/Hepa1-6 + IL-12-treated mice also showed cytotoxic activity to hepatocytes. Adoptive transfer of splenocytes from DC/Hepa1-6-vaccinated mice produced hepatic inflammation in recipient mice that had been pretreated with IL-12. IL-12 upregulated the expression of adhesion molecules and chemokines in the liver. In conclusion, CTLs responsive to hepatocytes induced by DC/Hepa1-6 and enhanced expression of adhesion molecules and chemokines in the liver by IL-12 would produce autoimmune hepatic inflammation.
    Clinical Immunology 01/2006; 117(3):280-93. · 3.99 Impact Factor
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    ABSTRACT: Alcohol dehydrogenase (ADH), aldehyde dehydrognase (ALDH), and P450IIE1 are the primary enzymes that catalyze the conversion of ethanol to acetaldehyde and then to acetate. Genetic polymorphisms have been reported in ADH2, ADH3, ALDH2, and the 5′-flanking region of P450IIEI. In this study, we used multivariate analysis to determine which genetic polymorphisms in alcohol metabolizing enzymes were independently associated with the development of alcoholic cirrhosis. Thirty-four noncirrhotic alcoholic patients, including 27 with fatty liver and 7 with nonspecific changes, and 46 patients with alcoholic liver cirrhosis were studied. Restriction fragment length polymorphisms (RFLPs) in the ADH2 and P450IIE1 genes were detected by digestion of polymerase chain reaction (PCR)-amplified DNA with MaeIII and RsaI, respectively. In the ALDH2 gene, RFLPs were detected by differences in the MboII site after PCR amplification. By multivariate analysis of four significant factors including total alcohol intake, ADH, ALDH, and P450IIE1 using the multiple logistic regression model, genotype ADH22/ADH22 (P = .029) and genotype c1/c1 of P450IIE1 (P = .013) were found to be independently associated with alcoholic cirrhosis. The odds ratios for ADH22/ADH22 genotype and the type A genotype of P450IIE1 (c1/c1) were 4.600 and 4.006, respectively. These results suggest that ADH2 and P450IIE1 gene polymorphisms may be independently associated with the development of alcoholic liver cirrhosis in Japan. (HEPATOLOGY 1995; 22:1136–1142.).
    Hepatology 12/2005; 22(4):1136 - 1142. · 11.19 Impact Factor
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    ABSTRACT: Human metastatic colorectal carcinomas (CRCAs) express carcinoembryonic antigen (CEA) and/or MUC1 tumor-associated antigens as potential targets for the induction of active specific immunity. In the present study, freshly isolated metastatic CRCA cells were successfully fused with immature autologous human monocyte-derived dendritic cells (DCs). The created heterokaryons (DC/CRCA) coexpress the CRCA-derived CEA and MUC1 antigens and DC-derived MHC class II and costimulatory molecules. The fusion cells were functional in stimulating the proliferation of autologous T cells. In addition, both CD4(+) and CD8(+) T cells were activated by fusion cells, as demonstrated by the production of high levels of IFN-gamma. More importantly, coculture of fusion cells with patient-derived peripheral blood mononuclear cells (PBMCs) resulted in the induction of antigen-specific cytotoxic T lymphocytes (CTLs). CTLs were effective at lysis of not only autologous CRCA cells but also the CEA and/or MUC1-positive and HLA partially matched target cells. Antigen-specific CTL responses were confirmed by tetrameric analysis. Coculture of PBMCs with fusion cells resulted in increased frequency of CEA- and MUC1-specific CTLs simultaneously. Taken together, these results indicate that freshly isolated human metastatic CRCA cells expressing the CEA and/or MUC1 may represent a potential partner for the creation of DC/tumor fusion cells targeting induction of antigen-specific CTL responses. Our report demonstrates the simultaneous induction of CRCA-specific CTL responses restricted by HLA-A2 and -A24.
    International Journal of Cancer 12/2005; 117(4):587-95. · 5.01 Impact Factor
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    ABSTRACT: The aim of antitumor immunotherapy is to induce CTL responses against autologous tumors. Previous work has shown that fusion of human dendritic cells and autologous tumor cells induce CTL responses against autologous tumor cells in vitro. However, in the clinical setting of patients with colorectal carcinoma, a major difficulty is the preparation of sufficient amounts of autologous tumor cells. In the present study, autologous dendritic cells from patients with colorectal carcinoma were fused to allogeneic colorectal tumor cell line, COLM-6 (HLA-A2(-)/HLA-24(-)), carcinoembryonic antigen (CEA)(+), and MUC1(+) as an alternative strategy to deliver shared colorectal carcinoma antigens to dendritic cells. Stimulation of autologous T cells by the fusion cells generated with autologous dendritic cells (HLA-A2(+) and/or HLA-A24(+)) and allogeneic COLM-6 resulted in MHC class I- and MHC class II-restricted proliferation of CD4(+) and CD8(+) T cells, high levels of IFN-gamma production in both CD4(+) and CD8(+) T cells, and the simultaneous induction of CEA- and MUC1-specific CTL responses restricted by HLA-A2 and/or HLA-A24. Finally, CTL induced by dendritic cell/allogeneic COLM-6 fusion cells were able to kill autologous colorectal carcinoma by HLA-A2- and/or HLA-A24-restricted mechanisms. The demonstration of CTL activity against shared tumor-associated antigens using an allogeneic tumor cell line, COLM-6, provides that the presence of alloantigens does not prevent the development of CTL with activity against autologous colorectal carcinoma cells. The fusion of allogeneic colorectal carcinoma cell line and autologous dendritic cells could have potential applicability to the field of antitumor immunotherapy through the cross-priming against shared tumor antigens and provides a platform for adoptive immunotherapy.
    Clinical Cancer Research 12/2005; 11(21):7891-900. · 8.19 Impact Factor
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    ABSTRACT: When BALA/c mice with BNL hepatocellular carcinoma (HCC) were treated with dendritic cells fused with BNL cells (DC/BNL) and recombinant murine interleukin (IL)-12, tumour development was significantly suppressed, whereas treatment with either DC/BNL or IL-12 alone did not show a tumour-suppressive effect. Antitumour activity induced by DC/BNL + IL-12 was abrogated by depletion of CD4+ T cells, but not by depletion of CD8+ T cells or natural killer cells. Splenic CD4+ T cells and CD8+ T cells from DC/BNL-treated mice showed cytotoxic activity against BNL cells after 3 days of incubation with DC/BNL, although BNL cells do not express major histocompatibility complex (MHC) class II molecules even after treatment with interferon (INF)-gamma. Furthermore, CD4+ T cells killed syngeneic-irrelevant CT26 cells and even allogeneic Hepa1-6 cells. This cytotoxicity was blocked by concanamycin A, but not by an anti-Fas ligand (FasL) monoclonal antibody, indicating that cytotoxic activity was mediated by perforin. Immunofluorescence microscopy demonstrated that abundant CD4+ T cells and MHC class II-positive macrophages, but not CD8(+) T cells, had infiltrated tumour tissue in mice treated with DC/BNL + IL-12. Flow cytometric analysis of tumour-infiltrating cells in mice treated with DC/BNL + IL-12 showed increases in CD4+ T cells and MHC class II+ CD11b+ cells but not in CD8+ T cells or MHC class I+ CD11b+ cells. Our results suggest that, in BNL-bearing mice treated with DC/BNL + IL-12, tumour macrophages activated by INF-gamma produced by IL-12-stimulated T cells might present BNL tumour antigens and activate DC/BNL-primed CD4+ cytotoxic T lymphocytes (CTLs) in a MHC class II-dependent manner, leading to perforin-mediated bystander killing of neighbouring MHC class II-negative tumour cells.
    Immunology 09/2005; 115(4):451-61. · 3.74 Impact Factor
  • Nippon rinsho. Japanese journal of clinical medicine 08/2005; 63 Suppl 7:650-2.

Publication Stats

3k Citations
676.42 Total Impact Points


  • 1975–2008
    • The University of Tokyo
      • • Division of Internal Medicine
      • • Department of Internal Medicine
      • • Department of Pharmaceutical Sciences
      • • School of Medicine
      • • Faculty & Graduate School of Medicine
      Edo, Tōkyō, Japan
  • 2005–2006
    • Sapporo Medical University
      • Department of Public Health
      Sapporo, Hokkaidō, Japan
  • 1993–2006
    • The Jikei University School of Medicine
      • • Department of Internal Medicine H
      • • Division of Gastroenterology and Hepatology
      • • Institute of DNA Medicine
      Tokyo, Tokyo-to, Japan
  • 2001–2004
    • Kashiwa City Hospital
      Kashiwa, Chiba, Japan
    • King's College London
      • Department of Nutrition and Dietetics
      London, ENG, United Kingdom
    • Musashino Red Cross Hospital
      Edo, Tōkyō, Japan
  • 2002
    • Kansai Medical University
      • Third Department of Internal Medicine
      Moriguchi, Ōsaka, Japan
  • 1999
    • National Cancer Center
      • Endoscopy Division
      Edo, Tōkyō, Japan
  • 1991
    • Teikyo University
      • Department of Internal Medicine
      Edo, Tōkyō, Japan