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Biomedical subjects

M Imawari

Publications and source records attributed to M Imawari.

At least 37 records · Page 2Linked to original sources
PubMed1999

Hepatitis C virus structural proteins induce liver cell injury in transgenic mice.

To develop an animal model of hepatitis C virus (HCV) infection, transgenic mice carrying part of the HCV cDNA (C980) encoding HCV-core and envelope proteins under control of the mouse class I major histocompatibility complex gene (H-2K) regulatory region were produced. HCV-C980 RNA and HCV-core protein were present in livers from line H36 as determined by RNase protection assay and immunostaining, respectively. More than 40 animals from line H36 were examined histologically. Most of these H36 mice after 10 months of age developed spontaneous focal infiltration of lymphocytes, hepatocyte necrosis, degeneration, and altered foci with mitotic hepatocytes. These pathological lesions were absent in livers from the age-matched control littermates. Liver cells from these H36 mice were sensitive to damage induced by intravenous administration of an anti-Fas antibody. It is suggested that HCV-C980 proteins by themselves may be one causative agent of liver cell injury in subjects with HCV infection.

Animals↗
PubMed1999

A new endoscopic metallic stenting method for duodenal stenosis: a preliminary report.

Palliative duodenal stenting was attempted in three patients with severe duodenal stenosis due to tumor invasion. Two methods were applied for duodenal stenting: the conventional method, which inserts the Ultraflex (stent for esophageal stenosis) along the guidewire under fluoroscopy, and a new method that uses a snare and an endoscope to guide the esophageal stent. The conventional method is often unsuccessful, because the delivery tube is too short, but the latter method appears to be a safe and effective duodenal stenting technique.

Aged↗
PubMed1999

IL-12 induces specific cytotoxicity against regenerating hepatocytes in vivo.

Although impaired liver regeneration is thought to be a major cause of death in patients with fulminant hepatitis, the mechanisms are not well defined. Since IL-12 synthesis has been reported to be up-regulated in murine hepatitis virus infection, we studied the influence of continuous IL-12 stimulation on murine liver regeneration using flow cytometric and functional analyses. In non-hepatectomized mice, interestingly, the number of hepatic NK cells was significantly decreased on day 7, after six IL-12 injections, and day 14, after 13 IL-12 injections. The number of hepatic NKT cells was markedly increased on day 7 and day 14 of daily IL-12 treatment. The cytotoxic activity of hepatic lymphocytes against both YAC-1 and p815 cells was enhanced on day 2, after single IL-12 injection, and day 7, after six IL-12 injections. In contrast, hepatic lymphocytes isolated 24 h after partial hepatectomy with IL-12 pretreatment did not show any cytolytic activity against either YAC-1 cells or p815 cells. However, continuous IL-12 stimulation resulted in a significantly higher serum alanine aminotransferase (sALT) level 24 h after the partial hepatectomy as compared with sALT levels in mice subjected to either partial hepatectomy or IL-12 pretreatment alone. On the other hand, the expression of hepatic TNF-alpha mRNA was markedly enhanced by continuous IL-12 stimulation even 24 h after partial hepatectomy, as compared with that in non-treated mice and hepatectomy alone. Simultaneous administration of anti-tumor necrosis factor (TNF)-alpha mAb completely inhibited IL-12-induced in vivo enhancement of liver damage after partial hepatectomy. In conclusion, IL-12 induces the specific cytolytic activity against regenerating hepatocytes in vivo mainly through the enhancement of TNF-alpha synthesis.

Animals↗
PubMed1997

Perforin, Fas/Fas ligand, and TNF-alpha pathways as specific and bystander killing mechanisms of hepatitis C virus-specific human CTL.

In chronic hepatitis C, Fas expression is up-regulated in the hepatocytes, especially near liver-infiltrating lymphocytes, and Fas ligand is expressed on the lymphocytes. The presence of hepatitis C virus (HCV)-specific CTLs has been demonstrated both in peripheral blood and among liver-infiltrating lymphocytes of patients with chronic hepatitis C. We studied the killing mechanisms of HCV-specific human CTLs using target cells that were sensitive or resistant to agonistic anti-Fas Abs and TNF-alpha. We show that HCV-specific CTL clones kill non-Ag-bearing bystander cells as well as Ag-bearing cells, although the bystander killing is less efficient than the specific target cell killing, and the efficacy of the bystander killing of anti-Fas- and soluble TNF-alpha-sensitive cells is greater than that of resistant cells. We also show that the killing of Ag-presenting, sensitive cells is mediated by Fas ligand and TNF-alpha as well as perforin, although the latter plays a major role in the killing at a low E:T ratio, and that the killing of sensitive bystander cells is primarily mediated by Fas ligand and TNF-alpha on CTLs expressed upon specific Ag stimulation, which may be relevant to the bystander lysis by HCV-specific CTLs of uninfected hepatocytes, in which Fas expression is up-regulated. Activated CTLs also kill bystander cells by the perforin-based mechanism, although it requires a high E:T ratio. The effective bystander killing requires a close intercellular contact between CTLs and target cells, although TNF-alpha released from the CTLs mediates lysis of the bystander cells without a close cell-cell contact.

Antigen Presentation↗
PubMed1997

Impaired induction of cytotoxic T lymphocytes by antagonism of a weak agonist borne by a variant hepatitis C virus epitope.

An epitope that acted as a weak agonist in the cytotoxicity assay was identified as part of the capsid protein of a hepatitis C virus (HCV) variant. In a low concentration, the variant epitope also had a weak antagonistic effect. When a minute amount of this variant epitope was added to the culture for induction, it selectively attenuated the expansion of major cytotoxic T cell populations and drastically reduced the cytotoxic responses against the wild-type epitope. Thus, antagonism to induction suppressed immune responses against both the wild type and the variant, thereby helping the persistence of not only variant itself but also the wild-type HCV. Because this variant was a weak agonist, most cytotoxic T cells induced with the wild-type epitope were cross-reactive with the variant and susceptible to the antagonism to induction. Only the T cells which were not cross-reactive with the variant and not susceptible to the antagonism survived the antagonism in induction. This implied that the specificity of the remaining immune response, if any, was directed exclusively to the wild-type epitope after the emergence of the variant. For viruses like HCV, being heterogeneous itself may contribute significantly toward persistent infection through antagonism to induction.

Antigenic Variation↗
PubMed1997

Cytotoxic T lymphocyte response and viral load in hepatitis C virus infection.

A cytotoxic T lymphocyte (CTL) response to the hepatitis C virus (HCV) nucleoprotein residues 88-96 that are the minimal and optimal epitope for human leukocyte antigen (HLA) B44-restricted CTLs was assessed in 27 HLA B44-positive patients with chronic HCV infection. Serum HCV RNA concentration and the amino acid sequence of the residues 81-100 were also determined. Three patients were infected with HCV with uncommon amino acid substitutions within the epitope. One was infected with HCV with an amino acid substitution in the flanking residues of the epitope. To stimulate CTLs in the peripheral blood, 9-mer peptides that corresponded to the residues 88-96 of the individual patients were synthesized and used. Seven of the 27 patients demonstrated a CTL response to the residues 88-96 with specific cytotoxic activities higher than 20%. The CTL activities were significantly higher in patients with a low titer of serum HCV RNA than in those with a high titer of serum HCV RNA (P = .0006). Some of the patients that demonstrated a CTL response to the residues 88-96 also demonstrated a CTL response to a newly identified HLA B44-restricted CTL epitope or a known HLA A11-restricted CTL epitope or both. No apparent association was observed between the CTL response and the stage of disease, or between the CTL response and the grade of necroinflammatory activity. The results suggest that the HLA B44-restricted CTLs together with other HCV-specific CTLs may inhibit the outgrowth of HCV and that high-titer infection with HCV may suppress the CTL responses.

Adult↗
PubMed1997

Present status of autoimmune hepatitis in Japan--correlating the characteristics with international criteria in an area with a high rate of HCV infection. Japanese National Study Group of Autoimmune Hepatitis.

BACKGROUND/AIMS: A nationwide survey of autoimmune hepatitis (AIH) was carried out in Japan. METHODS: Four hundred and ninety-six patients were enrolled by questionnaires sent to 101 hospitals with hepatology specialists. RESULTS: The clinical features of Japanese AIH were as follows: most patients were middle-aged women; serum autoantibodies, especially antinuclear antibody, were frequently positive, serum IgG level was high, and HLA-DR4 was the major HLA allotype. Liver-kidney microsomal type 1 antibody was positive in nine of 79 patients tested. Eight of these antibody positive patients were also positive for antinuclear antibody and five for anti-smooth muscle antibody. Ninety-two percent of the patients showed piecemeal necrosis and 60% bridging necrosis; plasma cell infiltration in the portal areas was observed in 50% of the patients. Only 12.3% were diagnosed as having liver cirrhosis. A favorable effect of corticosteroid, normalization of serum transaminases, was observed in 89% of 317 patients, who were treated with an initial dose of over 30 mg/day. Sixty-two patients were positive for hepatitis C virus (HCV) markers. In these patients, however, only one patient was liver-kidney microsomal type 1 antibody positive. Corticosteroid was effective in 30 (81%) of 37 HCV-marker-positive patients treated with this agent. Thus the efficacy of corticosteroid did not differ from that in AIH patients without HCV infection (90%). Similarly, interferon treatment was used in 20 patients, all of whom were positive for HCV-RNA, and resulted in 50% efficacy as determined by normalization of the serum transaminase level 6 months after treatment. The International Diagnostic Scoring System for the diagnosis of AIH worked well in these patients, except for HCV-infected individuals, that is, approximately 10% of the total of AIH patients.

Adolescent↗
PubMed1996

Three new cytotoxic T cell epitopes identified within the hepatitis C virus nucleoprotein.

Cytotoxic T lymphocytes (CTLs) may play a role in host defence against hepatitis C virus (HCV) infection, and HCV-specific CTL epitopes may be included in vaccines to induce protective CTLs. We identified three new epitopes within the HCV nucleoprotein recognized by CTLs. HCV nucleoprotein residues 28-37 are the minimal epitope recognized by CTLs in association with the class I human leukocyte antigen B60, and epitopes in HCV nucleoprotein residues 111-130 and 161-180 are both recognized by CTLs in association with the class II human leukocyte antigen DRBI*08032.

Amino Acid Sequence↗
PubMed1995

HLA B44-restricted cytotoxic T lymphocyte responses to the peptides of HCV nucleoprotein residues 81-100 in patients with chronic hepatitis C.

Human leukocyte antigen B44-restricted cytotoxic T lymphocytes (CTLs) recognize an epitope in hepatitis C virus (HCV) nucleoprotein residues 81-100. CTLs that recognize two wild-type peptides 81-100 of HCV genotypes 1b/II and 2a/III were generated from peripheral blood lymphocytes of each of three patients studied. Although CTLs that recognize a wild-type peptide 81-100 of HCV genotypes 1a/I and 2b/IV were not generated from any patient, CTLs that recognize peptide 81-100 of a rare HCV isolate of type 1a/I were generated from two patients. The results suggest that HLA B44-restricted CTLs recognize most, if not all, HCV isolates of types 1b/II and 2a/III and rare variants of type 1a/I and that the wild-type HCV isolates of genotypes 1a/I and 2b/IV may be less immunogenic for HLA B44-restricted CTLs.

Aged↗
PubMed1995

Immune response to hepatitis C virus core protein in mice.

To analyse the immune response to the hepatitis C virus (HCV) core protein, we immunized mice with the protein. BALB/c (H-2d) and C3H/He (H-2k) mice were high responders, while C57BL/6 (H-2b) mice were low responders in terms of Th cell proliferative responses. All the strains showed comparable levels of antibody responses to the HCV core protein. The Th cell lines recognized residues 61-90 of the HCV core protein in the context of I-Ad (BALB/c) and residues 11-30 in the context of I-Ek (C3H/He), respectively. The Th cell lines were restricted by I-Ab in C57BL/6 mice but recognized no synthetic peptide that spanned the region, although derivative clones from the line recognized residues 1-20 and 91-110 of the HCV core protein, respectively. The Th cell lines were Th 1 subset in all three strains based on the profile of lymphokine secretion. The major B cell epitope of the protein was found to be within residues 21-40 of the HCV core protein in all three strains. These observations should be useful for better understanding of the immune response to the HCV core protein in vivo.

Amino Acid Sequence↗
PubMed1995

A minimal and optimal cytotoxic T cell epitope within hepatitis C virus nucleoprotein.

Amino acid residues 81-100 of the hepatitis C virus (HCV) nucleoprotein contain a cytotoxic T cell epitope that is recognized by cytotoxic T lymphocytes (CTLs) in association with human leukocyte antigen B44. With panels of truncated and overlapping peptides, the minimal and optimal epitope recognized by CTLs was shown to be a 9-mer peptide (residues 88-96). The peptide can stimulate effectively CTLs that are able to recognize endogenously synthesized and processed HCV nucleoprotein.

Amino Acid Sequence↗