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Shinji Shimoda

Publications and source records attributed to Shinji Shimoda.

32 records · Page 2Linked to original sources
PubMed2005

Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis.

BACKGROUND/AIMS: The presence of antibodies to the 210-kDa glycoprotein of the nuclear pore complex (gp210) is highly indicative of primary biliary cirrhosis (PBC). However, the significance of anti-gp210 antibody titers for monitoring PBC remains unresolved. METHODS: We used an ELISA with a gp210 C-terminal peptide as an antigen to assess serum antibody titers in 71 patients with PBC. RESULTS: Patients were classified into three groups: Group A in whom anti-gp210 titers were sustained at a high level, Group B in whom anti-gp210 status changed from positive to negative under ursodeoxycholic acid (UDCA) therapy, Group C in whom anti-gp210 antibodies were negative at the time of diagnosis. The rate of progression to end-stage hepatic failure was significantly higher in group A (60%) as compared to groups B (0%) and C (4.2%). The sustained antibody response to gp210 was closely associated with the severity of interface hepatitis. The significance of anti-gp210 antibody was confirmed by National Hospital Organization Study Group for Liver Disease in Japan. CONCLUSIONS: The serial quantitation of serum anti-gp210-C-terminal peptide antibodies is useful for monitoring the effect of UDCA and for the early identification of patients at high risk for end-stage hepatic failure.

Antibodies↗
PubMed2005

The immune response to mitochondrial autoantigens.

Similar to other autoimmune diseases, there are intense humoral and cellular responses to intracytoplasmic antigens in primary biliary cirrhosis (PBC). The autoantigens against antimitochondrial antibodies (AMAs) in PBC are located on the inner mitochondrial membrane and are identified as members of the 2-oxo-acid dehydrogenase complexes (2-OADCs), of which the E2 subunit of pyruvate dehydrogenase complex (PDC-E2) is the major autoantigen; AMAs are is present in approximately 90 to 95% of PBC sera. An orchestrated immune response against the intrahepatic biliary epithelial cell (BEC) through 2-OADC-specific CD4 (+) helper T cells and CD8 (+) CTL are thought to be the major players in the immunological destruction of BECs in PBC. We believe that a prior/primary event of specific intrahepatic BEC malfunction (possibly caused by environmental insults such as xenobiotics and microorganisms) is responsible for the breaking of self-tolerance to 2-OADC and leads to BEC destruction. The generation of 2-OADC-specific T cells further accelerates the damage of BEC. In addition, immunoglobulin A AMAs may participate in the destruction of BECs by damaging mitochondria.

Autoantigens↗
PubMed2005

Mitochondrial antigens as targets of cellular and humoral auto-immunity in primary biliary cirrhosis.

Several factors point toward an auto-immune pathogenesis for primary biliary cirrhosis(PBC), mostly based on the presence of serum auto-antibodies to mitochondrial antigens(AMAs) and autoreactive T cells (both helper and cytotoxic). Interestingly, epitopes recognized by AMA and T-cell clones are located within overlapping areas of the antigens. Moreover,a role for an imbalance in cytokine pattern and for natural-killer lymphocytes has also been proposed. Despite several experimental reports, no clear evidence is available regarding the interaction of these factors leading to bile duct destruction. This article reviews the current reports regarding the auto-immune reaction against mitochondrial auto-antigens in PBC.

Antigen-Presenting Cells↗
PubMed2005

Influence of interferon therapy on signal-averaged and ambulatory electrocardiograms in patients with chronic active hepatitis.

Although interferon (IFN) shows cardiotoxicity and arrhythmogenesis, the influence of IFN on signal-averaged electrocardiography remains to be clarified. The aim of this study was to test a clinical hypothesis that IFN therapy for hepatitis C virus may induce ventricular late potentials (LPs) and related arrhythmias in patients with chronic active hepatitis. Signal-averaged and ambulatory electrocardiograms were recorded sequentially in patients with chronic active hepatitis C (n = 22) throughout the entire period of IFN therapy. The filtered QRS duration (fQRS) and low amplitude (< 40 microV) signal duration (LAS40) were significantly increased (95.5 +/- 8.5 to 99.6 +/- 9.4 msec, P < 0.0001, and 32.8 +/- 3.1 to 36.3 +/- 3.0 msec, P < 0.0001, respectively), whereas the root mean square voltage in the terminal 40 msec of the fQRS (RMS40) was significantly decreased (25.5 +/- 5.4 to 22.3 +/- 5.2 microV, P < 0.005) 1 month after starting the IFN therapy. The ventricular LP was negative in all subjects before starting therapy, but became positive in 7 patients after the therapy commenced. There were no differences in clinical baseline characteristics between the LP-positive (n = 7) and LP-negative (n = 15) groups. Significant increases in mean heart rate, fQRS, and LAS40 were observed after starting the therapy, irrespective of the appearance of the ventricular LP, whereas a decrease in RMS40 was observed only in the LP-positive group. No sustained ventricular arrhythmias were documented in the ambulatory electrocardiography and no cardiac events were encountered in the follow-up period. Therefore, the results indicate a reversible and subclinical risk of IFN-induced arrhythmogenesis.

Adult↗
PubMed2005

Human cord blood--derived cells generate insulin-producing cells in vivo.

Here we report the capacity of human cord blood (CB)-derived cells to generate insulin-producing cells. To investigate in vivo capacity of human CB-derived cells, T cell-depleted mononuclear cells were intravenously transplanted into nonobese diabetic/severe combined immunodeficient/beta2-microglobulinnull mice within 48 hours of birth. At 1-2 months post-transplantation, immunofluorescence staining for insulin and fluorescence in situ hybridization (FISH) analysis using a human chromosome probe indicated that human CB-derived cells generated insulin-producing cells at a frequency of 0.65%+/-0.64% in xenogeneic hosts. Reverse transcription-polymerase chain reaction analysis confirmed the transcription of human insulin in the pancreatic tissue of the recipient mice. To clarify the mechanism underlying CB-derived insulin-producing cells, double FISH analysis using species-specific probes was performed. Almost equal proportions of human chromosome+ murine chromosome- insulin+ cells and human chromosome+ murine chromosome+ insulin+ cells were present in recipient pancreatic islets. Taken together, human CB contains progenitor cells, which can generate insulin-producing cells in recipient pancreatic tissues across a xenogeneic histocompatibility barrier by fusion-dependent and -independent mechanisms.

Animals↗
PubMed2004

Body surface area is an independent factor contributing to the effects of lamivudine treatment.

BACKGROUND:: It has been suggested that lamivudine therapy may be even more effective if administered at higher doses than is dictated by the current standard regimen. We analyzed the correlation between the effects of lamivudine and body surface area (BSA). METHOD:: We evaluated 134 patients with chronic hepatitis B who had been treated with lamivudine for more than 12 months. The effect of the treatment was evaluated from the levels of serum alanine aminotransferase (ALT) and HBV-DNA. Several variables that could influence the response to treatment, including ALT, albumin, and bilirubin levels, platelet counts, BSA, HBV-DNA, and HBeAg were analyzed. RESULTS:: Univariate logistic analysis selected platelet counts, BSA, HBV-DNA and HBeAg in the biological evaluation, and bilirubin, BSA, HBV-DNA and HBeAg in the virological evaluation (chi(2)>1.0). Using these factors, multivariate analysis revealed that BSA (chi(2)=12.8, p=0.0004) was the only factor that could contribute significantly to the improvement of ALT levels, and that BSA (chi(2)=4.4, p=0.0354) and HBeAg (chi(2)=8.1, p=0.0044) were independent factors that could influence the suppression of HBV-DNA. CONCLUSION:: We revealed that BSA is a significantly predictor of the effect of lamivudine therapy, suggesting that lamivudine dosage should be based on the individual BSA.

Journal Article↗
PubMed2004

Human cord blood- and bone marrow-derived CD34+ cells regenerate gastrointestinal epithelial cells.

In the present study, we aimed to clarify the capacity of human cord blood- and bone marrow-derived progenitor cells to generate gastrointestinal epithelial cells in clinical and experimental transplantation settings. First, in a clinical transplantation setting, gastrointestinal tissues derived from female pediatric or juvenile recipients of allogeneic sex-mismatched bone marrow and cord blood transplantation were examined for the presence of donor-derived epithelial cells. Gastrointestinal specimens of allogeneic recipients included Y chromosome+ cytokeratin+ epithelial cells at a frequency of 0.4-1.9%. To further determine the capacity of purified human progenitor cells, human cord blood- or bone marrow-derived CD34+ cells were transplanted into newborn NOD/SCID/beta2-microglobulin(null) mice as an experimental transplantation assay. When gastrointestinal tissues derived from recipient mice were subjected to FISH and immunofluorescence analyses, human epithelial cells were identified at a frequency of 0.24-0.58% at 3 months posttransplantation. Finally, double FISH analyses using species-specific probes revealed that human chromosome+ epithelial cells did not possess any murine chromosomes, indicating that donor-derived epithelial cells were not generated only by cell fusion. On the basis of these findings, it is concluded that purified human cord blood and bone marrow CD34+ progenitor cells can generate gastrointestinal epithelial cells across allogeneic and xenogeneic histocompatibility barriers.

Animals↗
PubMed2004

Is primary biliary cirrhosis a model autoimmune disease?

Primary biliary cirrhosis (PBC) has been coined a model autoimmune disease. In fact, it does share many similarities with other autoimmune diseases, but there are striking differences that illustrate the uniqueness of the immunopathology. Firstly, similar to other autoimmune diseases, there is an intense humoral and cellular response to an intracytoplasmic antigen. There is also an overlap of the epitopes recognized by autoreactive CD4(+), CD8(+) T cells as well as B cells. Patients with PBC are also predominantly female, and there is a higher family history of other autoimmune diseases. In contrast, however, there are no specific HLA associations in PBC. Further, there are no spontaneous or induced animal models of PBC. In addition, early in the biliary lesions of PBC, there is an eosinophilic infiltration and, often, there are granulomas. Finally, unlike several other human autoimmune diseases, patients with PBC have recognition of but one major epitope, and there is no evidence for determinant spreading. Hence, although the immune response of PBC has been vigorously defined, there remain major gaps in understanding the most difficult issue of all, namely etiology.

Autoantigens↗
PubMed2003

Distinct costimulation dependent and independent autoreactive T-cell clones in primary biliary cirrhosis.

BACKGROUND & AIMS: Previous work has suggested that CD4+ CD28- or costimulation-independent T cells are increased in autoimmune diseases. In this study, we compared frequency and qualitative characteristics of autoreactive costimulation-independent or CD4+ CD28- T cells in primary biliary cirrhosis (PBC) by taking advantage of the well-defined immunodominant autoepitope of the E2 component of pyruvate dehydrogenase (PDC-E2). METHODS: We determined the frequency of costimulation-independent autoreactive T cells that respond to PDC-E2 163-176 and the frequency of CD4+ CD28- T cells. Finally, we determined the role of biliary epithelial cells (BEC) as both an antigen-presenting cell or, alternatively, as a target cell for T-cell-mediated cytotoxicity. RESULTS: The precursor frequency of costimulation-independent CD4+ T cells that respond to PDC-E2 163-176 and the frequency of CD4+ CD28- T cells were dramatically elevated in PBC. Furthermore, 2 types of T-cell clones that respond to PDC-E2 163-176 emerged from this study. One type was costimulation dependent and the other costimulation independent. Both types of clones lyse BEC in a similar effector target (E/T) ratio distribution. However, BEC did not help the proliferation of any T-cell clones. Furthermore, costimulation-independent T-cell clones do not become anergic by BEC. CONCLUSIONS: In PBC, costimulation-independent autoreactive T cells, which do not become anergic, increase and maintain the autoimmune response. In controls, although autoantigens are expressed on BEC and autoantigen-reactive T cells exist around BEC, autoantigen-reactive T cells are costimulation dependent and will become anergic and maintain peripheral tolerance.

Antigen-Presenting Cells↗
PubMed2003

Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis.

BACKGROUND & AIMS: The mechanism for development of primary biliary cirrhosis (PBC) remains enigmatic, but molecular mimicry has been implicated because of well-known cross-reactivity of human mitochondrial autoantigens and equivalent bacterial antigens. Virtually all patients with PBC have antimitochondrial autoantibodies (AMA), but, interestingly, approximately 50% also manifest antinuclear antibodies (ANA). METHODS: To determine whether generation of ANA are due to molecular mimicry of mitochondrial peptides, we established 6 T-cell clones selected by a peptide corresponding to the E2 subunit of mitochondrial pyruvate dehydrogenase complex and analyzed for reactivity to mimicry peptides derived from mitochondrial and nuclear autoantigens, including control sequences. RESULTS: For mitochondrial autoantigens, 1 peptide from the E2 subunit of the pyruvate dehydrogenase complex, 1 peptide from the E2 subunit of the oxo-glutarate dehydrogenase complex, 1 peptide from the E2 subunit of the branched-chain 2-oxoacid dehydrogenase complex, and 1 peptide from the E3-binding protein cross-reacted with these T-cell clones. For the nuclear autoantigens, 5 peptides from gp210 and 1 from Sp100 cross-reacted with these clones. Furthermore, 1 of 3 T-cell clones selected by recombinant gp210 protein reacted with a mimicry peptide corresponding to amino acids 188-201 of gp210, indicating that this part of the protein is a naturally processed immunodominant T-cell epitope. CONCLUSIONS: These results demonstrate molecular mimicry between mitochondrial and nuclear autoantigens in PBC and that a mimicry peptide may become an immunodominant T-cell epitope. These data have significance not only for PBC but also for the production of ANA in other disease processes.

Amino Acid Sequence↗
PubMed2003

Promiscuous T cells selected by Escherichia coli: OGDC-E2 in primary biliary cirrhosis.

The etiology of primary biliary cirrhosis (PBC) remains enigmatic. One theory that has attracted attention proposes that PBC is induced via molecular mimicry with Escherichia coli. If molecular mimicry is responsible for the immunogenic response in PBC, then T cell clones specific for E. coli antigens should stimulate and be cross-reactive with peptides specific for the human immunodominant autoepitopes. To address this issue, we developed T cell clones specific for E. coli OGDC-E2 peptide. Importantly, we demonstrate the presence of T cell clones specific for E. coli OGDC-E2 that react promiscuously with the human mitochondrial equivalents. Indeed, there was a significant increase in the liver derived T cell precursor frequency of such reactivity and such liver clones were only found in patients with PBC. In conclusion, these data suggest that PBC is a multi-hit disease involving a genetic predisposition, a mucosal response, and activation of promiscuous T cells; such activation may occur either directly from bacterial antigens, or indirectly through chemically-modified bacterial antigens. Dissection of the mechanisms involved will lead not only to understanding the immunogenetic basis of PBC, but likely its pathogenic etiology.

Acyltransferases↗
PubMed2003

T cell immunity and primary biliary cirrhosis.

T lymphocytes play a pivotal role in the autoimmune response in primary biliary cirrhosis (PBC). Recent studies have shown that there is overlapping in the PDC-E2-specific T and B cell epitopes. In addition, helper T and cytotoxic T cell epitopes all contain a shared peptide sequence. In addition, recognition of exogenous antigens including bacterial antigens by autoantigen-specific T cell and the mechanism of molecular mimicry provide a clue to clarifying the pathogenesis of PBC. Furthermore, the findings that autoantigen-immune complexes cross present and also that the presentation of autoantigen is of a higher relative efficiency, define a unique role of autoantibodies in the pathogenesis of the autoimmune disease. The mechanism of immune-mediated bile duct damage in PBC, including the possible role of T cell-mediated cytotoxicity and molecular mimicry is discussed.

Animals↗
PubMedDate not supplied

Accuracy in measurement of distance using limited cone-beam computerized tomography.

PURPOSE: The purpose of this study was to evaluate the accuracy of measurement of distance on the images produced by limited cone-beam computerized tomography (CT). MATERIALS AND METHODS: Five cadaver mandibles were examined by spiral computerized tomography (SCT) and limited cone-beam computerized tomography (LCBCT). The vertical distance from a reference point to the alveolar ridge was measured by caliper on the sliced mandible, and measurement error on the CT images was calculated in percentages based on the actual values and the measurement values obtained from the CT images. RESULTS: Measurement error was determined to range from 0 to 1.11 mm (0% to 6.9%) on SCT and from 0.01 to 0.65 mm (0.1% to 5.2%) on LCBCT, with measurement errors of 2.2% and 1.4%, respectively (P < .0001). DISCUSSION: This study suggests that distance can be measured accurately using LCBCT. The size of the rectangular solid images obtained using LCBCT (30 mm wide and 42.7 mm long) is thought to be adequate for observation of mandibular bony structure and for preoperative assessment before dental implant placement. CONCLUSION: In this experiment on cadaver mandibles, LCBCT was shown to be a useful tool for preoperative evaluation in dental surgery because the relatively small field size of its images limits the patient's exposure to radiation.

Alveolar Process↗