Biomedical subjects
M Imawari
Publications and source records attributed to M Imawari.
Cytotoxic T lymphocyte responses in hepatitis C virus infection.
To clarify whether abnormal cytotoxic T lymphocyte (CTL) responses to hepatitis C virus (HCV) contribute to viral persistence and the development of subsequent chronic liver disease, we studied CTL responses of peripheral blood lymphocytes (PBLs) to HCV in patients with human leukocyte antigen (HLA) B44. CTLs were generated from PBLs by repeated stimulation with a synthetic HCV nucleoprotein peptide. The recognition of the peptide by CTLs was not strong and was restricted by an HLA B44 molecule. The minimal optimal epitope was a 9-mer peptide of HCV nucleoprotein residues 88 to 96. The CTLs also recognized an HCV antigen produced by a recombinant vaccinia virus construct. The CTLs could be induced from PBLs in 4 of 9 patients with past or ongoing HCV infection. Two of the 4 patients who demonstrated the CTL responses had cleared HCV from the circulation. In one of the 4 patients, the infecting strain of HCV was a mutant: this patient's CTLs recognized the variant peptide less efficiently than the wild-type peptide. In the remaining one patient, the amino acid sequence of serum HCV nucleoprotein residues 88 to 96 was that of a wild-type HCV but the titer of HCV RNA in serum was low. All 5 patients who did not demonstrate the CTL responses had high titers of a wild-type HCV in their serum. Thus, insufficient CTL responses to HCV and emergence of HCV variants that escape recognition by CTLs or otherwise prevent the CTL response may contribute to HCV persistence resulting in the subsequent development of chronic liver disease.
Positive and negative regulations of albumin gene expression by retinoids in human hepatoma cell lines.
All-trans-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid (designated "acyclic retinoid") induced upregulation of the albumin gene expression at its transcriptional level, whereas all-trans-retinoic acid (RA) induced downregulation of the expression in both PLC/PRF/5 and HuH7 human hepatoma cell lines. These up- and down regulations of the albumin gene expression coordinated with high and low levels of mRNA for hepatocyte nuclear factor-1 (HNF-1), which is one of the most potent transcription factors for the albumin gene, implying that retinoids may regulate albumin gene expression through HNF-1 expression in opposite ways. The PLC/PRF/5 and HuH7 hepatoma cell lines expressed retinoid X receptor-alpha (RXR alpha) mRNA, whose expression was constitutive. Acyclic retinoid and all-trans-RA both induced upregulation of retinoic acid receptor-beta (RAR beta), and both suppressed cell proliferation-related phenotypic expressions by the alpha-fetoprotein gene and the c-myc oncogene. 9-cis-RA, whose receptor is known to be RXR alpha, also induced upregulation of albumin and HNF-1 expression. These results suggest that acyclic retinoid may act through both RXR alpha and RAR beta, whereas all-trans-RA conveys only RAR beta-mediated functions, at least in these two hepatoma cell lines.
Retroperitoneal fibrosis leading to extrahepatic portal vein obstruction.
A very rare case of highly probable retroperitoneal fibrosis leading to extrahepatic portal obstruction is described. The patient was a 44-year-old woman with right pleural effusion and splenomegaly. Computed tomography indicated a large accumulation of soft tissues in the retroperitoneum, and abdominal angiography showed extensive portal obstruction. A twenty-year-long abuse of analgesics is suspected to have caused the retroperitoneal fibrosis.
HLA B44-restricted cytotoxic T lymphocytes recognizing an epitope on hepatitis C virus nucleocapsid protein.
Cytotoxic T lymphocytes have been reported to be involved in the immune clearance of virus-infected cells and in the pathogenesis of viral infection. We studied the cytotoxic T lymphocyte response to the putative nucleocapsid protein of hepatitis C virus in patients with chronic hepatitis C. Cytotoxic T lymphocytes specific for hepatitis C virus nucleocapsid protein were generated from peripheral blood lymphocytes by means of repeated stimulation with a synthetic hepatitis C virus nucleocapsid protein peptide. The cytotoxic T lymphocytes were CD8 positive and recognized an epitope in hepatitis C virus nucleocapsid protein residues 81 to 100 in association with a human leukocyte antigen class I molecule, B44. The peptide-induced cytotoxic T lymphocytes recognized target cells synthesizing hepatitis C virus nucleocapsid protein endogenously, though less efficiently than peptide-pulsed target cells. The human leukocyte antigen B44-restricted cytotoxic T lymphocyte response was observed in three of five patients with chronic hepatitis C and a human leukocyte antigen B44 molecule but in neither of two hepatitis C virus-negative healthy individuals with human leukocyte antigen B44 molecules. The results demonstrate the presence of hepatitis C virus-specific cytotoxic T lymphocytes in the peripheral blood of patients with chronic hepatitis C and provide a strategy to study the role of cytotoxic T lymphocytes in the viral clearance and the pathogenesis of hepatitis C virus infection.
Correlation between the serum level of hepatitis C virus RNA and disease activities in acute and chronic hepatitis C.
The influence of viremia on hepatic injury in patients infected with hepatitis C virus was examined by analysis of the relationship between alanine aminotransferase activity and the amount of hepatitis C virus RNA in sequential serum samples from I untreated patient with acute hepatitis C and 3 untreated patients with chronic hepatitis C. Semiquantitative analysis by the competitive-reverse-transcription/polymerase-chain-reaction method indicated that the quantity of hepatitis C virus RNA in the serum affected the disease activities of acute and chronic hepatitis C through their natural clinical courses in all these patients. The nucleotide sequence encoding the putative envelope region of the viral genome in the patient with acute hepatitis C was examined. Blood samples taken serially at 2 times of exacerbation of the hepatitis revealed 2 nucleotide mutations, resulting in changes of predicted amino acid residues. This finding suggests that nucleotide mutations in the envelope region of the viral genome may be responsible for the recurrent hepatic injury attributed to recurrence of viremia in patients with hepatitis C. From these aspects, the serial divergence of the virus genome in infected individuals, especially in the region encoding the viral envelope protein, may possibly play an important role in developing chronic infection of hepatitis C virus.
Treatment of hepatocellular carcinoma associated with advanced cirrhosis by transcatheter arterial chemoembolization using autologous blood clot: a preliminary report.
Twenty-two patients with hepatocellular carcinoma were treated by a new method of transcatheter arterial chemoembolization using an autologous blood clot as an embolizing agent. All had underlying advanced cirrhosis (14 Child's class B and 8 Child's class C patients). The median follow-up interval was 11 mo (range = 2 to 30 mo). The results of the treatment were compared with those of conventional chemoembolization using gelatin sponge particles for 19 Child's class B patients as historical controls. The survival rate for Child's class B patients treated by the new procedure estimated by the Kaplan-Meier method was 100% at 2 yr, whereas the survival rate for Child's class B patients treated by conventional chemoembolization was 89% at 1 yr and 72% at 2 yr. The survival rate for Child's class C patients was 75% at 1 yr and 50% at 2 yr. Side effects such as pyrexia of more than 38 degrees C or an elevation of the serum bilirubin level of more than 1.5-fold were less common in patients treated by the new method than in those treated by conventional chemoembolization, and thus the new procedure could be performed even for Child's class C patients. The autologous blood clot did not collapse the hepatic arteries even when the embolization was performed repeatedly, and thus fine collateral vessels feeding recurrent hepatocellular carcinoma did not develop. The results suggest that the new chemoembolization using an autologous blood clot is a promising therapeutic procedure in the management of hepatocellular carcinoma associated with advanced cirrhosis.
Comparison of hepatectomy and transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma: necessity for prospective randomized trial.
Transcatheter arterial chemoembolization is now widely used in cases of surgically unresectable hepatocellular carcinoma. However, it is unclear whether patients with surgically resectable hepatocellular carcinoma should always be treated with hepatectomy as opposed to transcatheter arterial chemoembolization. Sixty-six patients with hepatocellular carcinoma underwent hepatectomy, whereas 29 patients with more advanced hepatocellular carcinoma were treated with transcatheter arterial chemoembolization at our hospital from 1984 to 1990. All cases were associated with cirrhosis of Child class A or B. All of them underwent hepatectomy or transcatheter arterial chemoembolization for the first time. Their outcomes were determined on March 31, 1991. The backgrounds and survival curves for hepatectomy and transcatheter arterial chemoembolization were compared in both Child A and Child B patients. For both Child A and B patients, no significant difference was found between hepatectomy and transcatheter arterial chemoembolization with respect to age, sex, cause of underlying cirrhosis, liver function assessed by indocyanine green test and maximum diameter of the main tumor. The incidence of multiple hepatocellular carcinoma, more advanced hepatocellular carcinoma (TNM stage III or IV) or both was significantly higher in the transcatheter arterial chemoembolization group than in the hepatectomy group for both Child A and Child B patients. The survival curves of both the hepatectomy and the transcatheter arterial chemoembolization groups showed no significant difference for both Child A and Child B patients. A prospective study is therefore warranted to elucidate whether hepatectomy or transcatheter arterial chemoembolization is more effective for treating resectable hepatocellular carcinoma associated with cirrhosis.
Expression of androgen receptor mRNA in human hepatocellular carcinomas and hepatoma cell lines.
The expression of androgen receptor messenger RNA in hepatocellular carcinomas and hepatoma cell lines was studied using Northern-blot analysis and the complementary DNA-polymerase chain reaction method. Androgen receptor messenger RNAs were detected (although in low levels) in both hepatocellular carcinoma tissues and noncancerous tissues of the liver in all eight cases we studied, except for the tumor sample of one case. None of the hepatoma cell lines studied, however, expressed detectable levels of androgen receptor messenger RNA except for the SK-HEP-1 hepatoma cell line.
Multiple diffuse hemangiomas of the large intestine.
A 54-year-old male case with multiple, diffuse hemangiomas of the large intestine is described. Large diffuse hemangiomas were located at the rectosigmoid and the ascending colon. Some polypoid lesions were located on the transverse colon. Tiny calcifications representing phleboliths were detected in those lesions. No skin hemangiomas were present. Although he did not manifest systemic bleeding tendency, blood examinations demonstrated the presence of mild consumption coagulopathy.
Development and growth pattern of small hepatocellular carcinomas in woodchucks--analysis of an animal model of human hepatocellular carcinoma by ultrasonography.
Woodchucks are very useful animal models of human hepatocellular carcinoma. It is important to detect carcinomas in their early stage to study the pathogenesis of hepatocellular carcinoma. By ultrasonography (echogram) we found tumors less than 10 mm in diameter. Echographically all of the tumors except one were hypo-echoic in their early stages. One tumor showed a hyper-echoic pattern which grew very rapidly. Pathologically they were all well differentiated hepatocellular carcinoma and there were no differences between hypo- and hyper-echoic tumors. When volumes of tumors were less than 10 cm3 they grew very slowly but when tumors were larger than 10 cm3 their volume increased very rapidly. The ultrasonographic patterns of large tumors were iso-echoic and mosaic, as in human hepatocellular carcinoma.
A human T-cell clone cytotoxic for hepatocytes from patients with chronic non-A, non-B hepatitis.
A human T-cell clone (TA-NB-2) which could lyse hepatocytes from patients with chronic non-A, non-B (NANB) hepatitis was established (Proc Natl Acad Sci USA 1989;86:2883-2887). TA-NB-2 cells belonged to CD3+ CD8+ cytotoxic T lymphocytes, and recognized the target hepatocytes by T-cell receptor without restriction by major histocompatibility complex (MHC) antigens. TA-NB-2 cells significantly lysed hepatocytes from 22 of 23 patients with chronic NANB hepatitis, whereas they lysed hepatocytes from only one of 17 control patients with chronic type B hepatitis, acute hepatitis B or acute hepatitis A. TA-NB-2 cells also significantly lysed hepatocytes from 4 of 5 patients with autoimmune liver disease. The results suggest that TA-NB-2 cells specifically recognize a NANB hepatitis-related antigen expressed on NANB hepatitis virus-infected hepatocytes by T-cell receptor in non-MHC-restricted manner. The results also suggest that most, if not all, cases of chronic NANB hepatitis are caused by one agent and that a portion of cases of autoimmune liver disease may be induced by infection with a NANB hepatitis virus.
Adoptive immunotherapy of primary and metastatic liver cancer via hepatic artery catheter.
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A functional retinoic acid receptor encoded by the gene on human chromosome 12.
A cDNA clone derived from a human hepatocellular carcinoma has been isolated on the basis of homology to the alpha human retinoic acid receptor (RAR alpha) gene. Expression of this cDNA produces a high affinity nuclear binding protein for retinoic acid. The product of this clone when expressed in transfected cells is able to activate transcription of a reporter plasmid through specific DNA sequences in response to the addition of retinoic acid to the medium. Dose-dependent profiles upon trans-activation of the reporter indicate that apparent sensitivity to retinoic acid of this protein is approximately 10-fold higher than that of human RAR alpha and is comparable to that of the second human RAR, RAR beta. This gene has been mapped to human chromosome 12, which is distinct from those coding for either alpha or beta RAR, and thus encodes a third human RAR.
[Studies on radioimmunoassay kit for measuring urinary neopterin].
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Establishment of a human T-cell clone cytotoxic for both autologous and allogeneic hepatocytes from chronic hepatitis patients with type non-A, non-B virus.
A human T-cell clone (TA-NB-2) that could lyse both autologous and allogeneic hepatocytes from chronic hepatitis patients with type non-A, non-B virus (NANB) was established. This clone produced CD3+ CD8+ cytotoxic T lymphocytes and expressed an antigen specific for alpha and beta subunits of T-cell receptor. The cytotoxic activity of the clone was abrogated by incubation with anti-CD3 monoclonal antibody. Anti-HLA monoclonal antibodies did not block the lysis of the target hepatocytes by TA-NB-2 cells. The cytotoxicity of TA-NB-2 clone against hepatocytes from patients with chronic NANB hepatitis was 39.8 +/- 13.2% (mean +/- SD; n = 17) (range, 14.2-60.5%), whereas that against hepatocytes from control patients with chronic type-B hepatitis, acute hepatitis B, acute hepatitis A, or alcoholic liver cirrhosis was 4.0 +/- 7.7% (n = 12) (range, -10.8 to 14.0%). The results suggest that TA-NB-2 cells specifically recognize a hepatitis NANB-related antigen expressed on hepatitis NANB-infected hepatocytes by T-cell receptor and that the recognition is not restricted by the major histocompatibility complex antigens. The results also suggest that most, if not all, cases of chronic hepatitis due to NANB are caused by one agent; TA-NB-2 clone may be useful as a tool to identify this particular hepatitis-related antigen.
[Significance of serum ammonia nitrogen analysis in clinical tests].
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[A case of asymptomatic intrahepatic primary sclerosing cholangitis associated with atypical ulcerative colitis].
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