T Uchiyama

Kyoto University, Kyoto, Kyoto-fu, Japan

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Publications (333)1464.67 Total impact

  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2012; · 10.16 Impact Factor
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    ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) is an effective treatment for adult T-cell leukemia (ATL), raising the question about the role of graft-versus-leukemia effect against ATL. In this study, we retrospectively analyzed the effects of acute and chronic graft-versus-host disease (GVHD) on overall survival, disease-associated mortality, and treatment-related mortality among 294 ATL patients who received allogeneic HCT and survived at least 30 days posttransplant with sustained engraftment. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated that the development of grade 1-2 acute GVHD was significantly associated with higher overall survival (hazard ratio [HR] for death, 0.65; P = .018) compared with the absence of acute GVHD. Occurrence of either grade 1-2 or grade 3-4 acute GVHD was associated with lower disease-associated mortality compared with the absence of acute GVHD, whereas grade 3-4 acute GVHD was associated with a higher risk for treatment-related mortality (HR, 3.50; P < .001). The development of extensive chronic GVHD was associated with higher treatment-related mortality (HR, 2.75; P = .006) compared with the absence of chronic GVHD. Collectively, these results indicate that the development of mild-to-moderate acute GVHD confers a lower risk of disease progression and a beneficial influence on survival of allografted patients with ATL.
    Blood 03/2012; 119(9):2141-8. · 9.78 Impact Factor
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    British Journal of Haematology 06/2011; 153(6):796-9. · 4.94 Impact Factor
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    ABSTRACT: Light chain deposition disease (LCDD) is a rare disease for which an optimal treatment is not yet available. Here, we report the clinical course of a 32-year-old woman with LCDD who was successfully treated with thalidomide. She presented with nephrotic syndrome. Based on the renal biopsy findings and the presence of monoclonal immunoglobulin light chains in her serum and urine, LCDD was diagnosed. Prednisolone and cytotoxic chemotherapy used for multiple myeloma proved ineffective. We initiated administration of thalidomide (100 mg daily) and dexamethasone (20 mg for 4 days per month). After 8 months of treatment, she achieved complete hematological remission, defined as the disappearance of monoclonal protein and a normalized free light chain ratio, which led to improvement of her renal insufficiency. She has shown sustained hematological and organ response for 31 months with thalidomide therapy. Thus, thalidomide therapy seems to be a promising approach to the treatment of LCDD.
    International journal of hematology 05/2011; 93(5):673-6. · 1.17 Impact Factor
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    ABSTRACT: To evaluate the clinical significance of subcategory and severity of chronic graft-versus-host disease (GVHD) as defined by the National Institutes of Health (NIH) consensus criteria, we retrospectively studied 211 patients with hematologic neoplasms who survived beyond 100 days after allogeneic hematopoietic cell transplantation. Endpoints included chronic GVHD-specific survival (cGSS), duration of immunosuppressive treatment, and non-relapse mortality (NRM). A total of 96 patients fulfilled the NIH diagnostic criteria for cGVHD. In univariable analysis, patients with NIH overlap syndrome tended to exhibit lower cGSS compared to those with NIH classic cGVHD [hazard ratio (HR) = 2.76, P = 0.060], while patients with severe cGVHD at onset had a significantly lower cGSS compared to those with mild-to-moderate cGVHD (HR = 3.10, P = 0.034). The duration of immunosuppressive treatment was not significantly affected by either subcategory or severity of NIH cGVHD. In multivariable analysis treating cGVHD as a time-dependent covariate, development of overlap syndrome (HR = 3.90, P = 0.014) or severe cGVHD at peak worsening (HR = 6.21, P < 0.001) was significantly associated with higher risk of NRM compared to the absence of cGVHD. Our results suggest that both the subcategory and severity of NIH cGVHD are partly correlated with cGSS and may play a useful role in distinguishing patients at high risk for NRM, warranting validation of this approach through future prospective studies.
    International journal of hematology 04/2011; 93(4):532-41. · 1.17 Impact Factor
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    ABSTRACT: The prognosis for elderly patients with acute myeloid leukemia (AML) remains dismal. To explore the potential of immunotherapy for improving clinical outcomes for these patients, we performed a phase I clinical trial of dendritic cell (DC)-based immunotherapy for elderly patients with AML. Autologus monocytes were obtained after reducing tumor burden by chemotherapy. Immature DCs induced with granulocyte-macrophage colony-stimulating factor and interleukin-4 were pulsed with autologous apoptotic leukemic cells as antigens. DCs were administered intradermally to four patients five times at 2-week intervals. To facilitate DC migration to lymph nodes, injection sites were pretreated with killed Streptococcus pyogenes OK-432 one day before. DCs were coinjected with OK-432 to induce maturation and interleukin-12 production in vivo. Antileukemic responses were observed by an interferon-γ enzyme-linked immunospot assay or a tetramer assay in two of four patients. In a human leukocyte antigen-A∗2402-positive patient, induction of CD8(+) T-cell responses to WT1- and human telomerase reverse transcriptase - derived peptides were observed, indicating cross-priming in vivo. The two patients with antileukemic immunity showed longer periods of disease stabilization than the other two patients. This study demonstrates the immunogenicity of autologous DCs that cross-present leukemia-associated antigens from autologous apoptotic leukemic cells in vivo in elderly patients with AML.
    Experimental hematology 01/2011; 39(4):424-433.e2. · 3.11 Impact Factor
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    ABSTRACT: Sepsis is a generalized inflammatory disease, caused by the hyperinflammatory response of the host, rather than by invading organisms. Endothelial cells play a crucial role in the pathogenesis of sepsis. In this study, we investigated the effects of interleukin-8 (IL-8), a known neutrophil chemoattractant, on lipopolysaccharide (LPS) -induced reactive oxygen species (ROS) production by endothelial cells, and its significance in the pathogenesis of LPS-mediated sepsis. The results revealed that IL-8 directly induced ROS production in human umbilical vein endothelial cells (HUVECs), and also mediated LPS-induced ROS production by HUVECs. Stimulation of HUVECs by LPS strongly enhanced tissue factor expression, a hallmark of severe sepsis, which was suppressed by IL-8 knockdown. We further discovered that NADPH oxidase (Nox) 1 expression in LPS-stimulated HUVECs was markedly repressed by IL-8 knockdown, and Nox1 knockdown reduced tissue factor expression, suggesting that the LPS/IL-8 signalling in endothelial cells was predominantly mediated by Nox1. In conclusion, LPS stimulation of endothelial cells causes activation of the IL-8-Nox1 axis, enhances the production of ROS, and ultimately contributes to the progression of severe sepsis.
    Immunology 11/2010; 131(3):331-9. · 3.71 Impact Factor
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    ABSTRACT: Viral infectivity factor, an accessory protein encoded in the HIV-1 genome, induces G2 cell cycle arrest; however, the biological significance and mechanism(s) remain totally unclear. Here we demonstrate that the TP53 pathway is involved in Vif-mediated G2 cell cycle arrest. Vif enhances the stability and transcriptional activity of TP53 by blocking the MDM2-mediated ubiquitination and nuclear export of TP53. Furthermore, Vif causes G2 cell cycle arrest in a TP53-dependent manner. HXB2 Vif lacks these activities toward TP53 and cannot induce G2 cell cycle arrest. Using mutagenesis, we demonstrate that the critical residues for this function are located in the N-terminal region of Vif. Finally, we construct a mutant NL4-3 virus with an NL4-3/HXB2 chimeric Vif defective for the ability to induce cell cycle arrest and show that the mutant virus replicates less effectively than the wild-type NL4-3 virus in T cells expressing TP53. These data imply that Vif induces G2 cell cycle arrest through functional interaction with the TP53/MDM2 axis and that the G2 cell cycle arrest induced by Vif has a positive effect on HIV-1 replication. This report demonstrates the molecular mechanisms and the biological significance of Vif-mediated G2 cell cycle arrest for HIV-1 infection.
    Proceedings of the National Academy of Sciences 11/2010; 107(48):20798-803. · 9.81 Impact Factor
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    ABSTRACT: Increasing evidence shows that NK cells regulate adaptive immunity, but the underlying mechanisms are not well understood. In this study, we show that activated human NK cells suppress autologous naive CD4 T cell proliferation in response to allogeneic dendritic cells (DCs) by selectively killing Ag-activated T cells. Naive CD4 T cells, which were initially resistant to NK cell-mediated cytotoxicity, became substantially susceptible to NK cells within a day after priming with DCs. Ag-activated T cells showed various degrees of susceptibility to NK cells. After 1 d of priming with LPS-matured DCs, T cells were less susceptible to NK cells than were T cells primed with TNF-α-matured DCs. Subsequently at day 3, Ag-activated T cells regained resistance to NK cells. The level of HLA-E expression on Ag-activated T cells was closely correlated with resistance to NK cells. HLA-E was highly expressed at day 1 by T cells primed with LPS-matured DCs but not by T cells primed with TNF-α-matured DCs. An Ab blockade revealed a critical role for the HLA-E-NKG2A interaction in the protection of Ag-activated T cells from NK cells. Collectively, this study demonstrates that NK cells impact adaptive immunity through the finely controlled kinetics of HLA-E expression on T cells. Thus, HLA-E may be a new target for immunoregulation.
    The Journal of Immunology 10/2010; 185(10):6031-40. · 5.52 Impact Factor
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    ABSTRACT: Dendritic cells (DCs) play a pivotal role in the pathogenesis of inflammatory disorders, so suppressing the activity of DCs is instrumental in treating such diseases. In the present study, we show that a proteasome inhibitor, bortezomib, suppresses the survival and immunostimulatory function of human plasmacytoid DCs (pDCs) by targeting 2 critical points, intracellular trafficking of nucleic acid-sensingToll-like receptors (TLRs) and endoplasmic reticulum (ER) homeostasis. Among the immune cells in blood, pDCs were the most susceptible to the killing effect of bortezomib. This correlates with a decrease in the spliced form of a transcription factor XBP1, which rescues cells from apoptosis by maintaining ER homeostasis. Bortezomib suppressed the production of interferon-α and interleukin-6 by pDCs activated with a TLR9-stimulating CpG DNA and a TLR7-stimulating influenza virus, which appears to be partially independent of apoptosis. Bortezomib inhibited translocation of TLR9 from the ER to endolysosomes but not of an ER membrane protein, Unc93B1, that delivers TLR9 to endolysosomes. Thus, bortezomib suppresses the activity of pDCs by inhibiting intracellular trafficking of TLRs through disrupting the coordinated translocation of TLRs and Unc93B1 and by disturbing ER homeostasis. This study suggests that proteasome inhibitors may alleviate inflammatory disorders such as lupus and psoriasis that involve pDCs.
    Blood 10/2010; 117(2):500-9. · 9.78 Impact Factor
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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used as a curative option for adult T-cell leukemia (ATL), an intractable mature T-cell neoplasm causally linked with human T-cell leukemia virus type I (HTLV-I). We compared outcomes of 386 patients with ATL who underwent allogeneic HSCT using different graft sources: 154 received human leukocyte antigen (HLA)-matched related marrow or peripheral blood; 43 received HLA-mismatched related marrow or peripheral blood; 99 received unrelated marrow; 90 received single unit unrelated cord blood. After a median follow-up of 41 months (range, 1.5-102), 3-year overall survival for entire cohort was 33% (95% confidence interval, 28%-38%). Multivariable analysis revealed 4 recipient factors significantly associated with lower survival rates: older age (> 50 years), male sex, status other than complete remission, and use of unrelated cord blood compared with use of HLA-matched related grafts. Treatment-related mortality rate was higher among patients given cord blood transplants; disease-associated mortality was higher among male recipients or those given transplants not in remission. Among patients who received related transplants, donor HTLV-I seropositivity adversely affected disease-associated mortality. In conclusion, allogeneic HSCT using currently available graft source is an effective treatment in selected patients with ATL, although greater effort is warranted to reduce treatment-related mortality.
    Blood 08/2010; 116(8):1369-76. · 9.78 Impact Factor
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    ABSTRACT: Although fluoroquinolones or other antibiotics are commonly used to prevent bacterial infections after hematopoietic cell transplantation (HCT), because of the growing presence of multidrug-resistant microorganisms, it is important to identify patients who are more likely to benefit from antibacterial prophylaxis. To evaluate risk factors for early bacterial infection after allogeneic HCT, we retrospectively analyzed clinical data for 112 consecutive adult patients with hematological malignancies who received transplants without any antibacterial prophylaxis. The cumulative incidence of bacterial infection at 30 days after transplantation was 16%. Among various pre-transplant factors, only high serum ferritin (>700 ng/mL, 47 patients) and high C-reactive protein (CRP) (>0.3 mg/dL, 28 patients) levels were significantly associated with the development of bacterial infection in a multivariate analysis (hazard ratio (95% confidence interval): ferritin, 4.00 (1.32-12.17); CRP, 3.64 (1.44-9.20)). In addition, septic shock and sepsis with organ failure were exclusively observed in patients who had high ferritin and/or high CRP levels. These results suggest that pretransplant serum ferritin and CRP levels can be useful markers for predicting the risk of early bacterial infection after allogeneic HCT. It may be prudent to limit antibacterial prophylaxis to patients with predefined risk factors to ensure the safety of HCT with the use of fewer antibiotics.
    Bone marrow transplantation 05/2010; 46(2):208-16. · 3.00 Impact Factor
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    ABSTRACT: We report a case of a 41-year-old male with human immunodeficiency virus (HIV)-associated lymphoproliferative disease (LPD) who was successfully treated with highly active antiretroviral therapy (HAART). He presented with epigastralgia, and an upper endoscopic examination revealed submucosal tumors and ulcerations in his stomach. Histopathologic examination of a biopsy specimen resulted in a diagnosis of diffuse large B-cell lymphoma. He also showed systemic lymphadenopathy; whereas, a concurrent inguinal lymph node biopsy produced a diagnosis of follicular hyperplasia. He was treated with CHOP chemotherapy but the response was poor. He demonstrated several immunological abnormalities, such as eosinophilia and bone marrow insufficiency, and was suspected to be in an immunocompromised state. He was examined for HIV infection and turned out to be positive. The gastric and inguinal lymph node specimens were re-evaluated and diagnoses of HIV-LPD and HIV lymphadenitis were made, respectively. He was treated with HAART and achieved complete remission and has remained tumor-free for 20 months. To the best of our knowledge, there is no previous report in which HIV-LPD was successfully treated with antiretroviral therapy alone. It is assumed that HAART resulted in the restoration of anti-tumor immunity in this case, which led to the eradication of LPD cells.
    International journal of hematology 03/2010; 91(4):692-8. · 1.17 Impact Factor
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    ABSTRACT: Studies in mice have shown that CD70 on dendritic cells (DCs) is sufficient to convert T-cell tolerance into immunity and hence induce anti-tumour immune responses. Therefore, it is important to investigate (i) optimal stimuli to induce CD70 on human monocyte-derived DCs (MoDCs), which are widely used for tumour immunotherapy, and (ii) the role of CD70 in functional differentiation of naive CD4(+) and CD8(+) T cells stimulated with MoDCs. We show that interferon-alpha (IFN-alpha) is a key cytokine to differentiate monocytes into DCs with the capacity to express CD70 upon maturation. CD70 expression on IFN-alpha-induced MoDCs was elicited by different categories of maturation-inducing factors (Toll-like receptor ligands, CD40 ligand and pro-inflammatory mediators), among which prostaglandin E(2) was most effective. Naive T cells stimulated with MoDCs also expressed CD70. Stimulation with MoDCs promoted naive CD4(+) T cells to acquire the ability to produce T helper type 1 and 2 cytokines in a CD70-dependent manner. In contrast, the CD70-CD27 interaction diminished the production of an immunoregulatory cytokine IL-10. The CD27 signal did not play a dominant role in the induction of effector molecules in naive CD8(+) T cells during the stimulation with MoDCs. This study adds a novel function to the versatile cytokines, type I IFNs, that is, the induction of CD70 on MoDCs. CD70 promotes naive CD4(+) T cells to acquire immunostimulatory activity through the DC-T-cell and T-cell-T-cell interactions during the stimulation with MoDCs. Hence, the CD70-CD27 interaction may play an important role in inducing effective immune responses in DC-based immunotherapy.
    Immunology 02/2010; 130(1):137-49. · 3.71 Impact Factor
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    ABSTRACT: Adult T-cell leukemia/lymphoma (ATLL) has a very poor prognosis. We have developed the humanized defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal antibody KW-0761 as a next generation immunotherapeutic agent. The first aim of the present study was to evaluate whether the antitumor activity of KW-0761 would likely be sufficient for therapeutic clinical application against ATLL. The second aim was to fully elucidate the mechanism of antibody-dependent cellular cytotoxicity (ADCC) mediated by this defucosylated monoclonal antibody. The antitumor activity of KW-0761 against ATLL cell lines was evaluated in vitro using human cells and in mice in vivo. Primary ATLL cells from 23 patients were evaluated for susceptibility to autologous ADCC with KW-0761 by two independent methods. KW-0761 showed potent antitumor activity against ATLL cell lines both in vitro and in the ATLL mouse model in vivo. In addition, KW-0761 showed potent antitumor activity mediated by highly enhanced ADCC against primary ATLL cells both in vitro and ex vivo in an autologous setting. The degree of KW-0761 ADCC against primary ATLL cells in an autologous setting was mainly determined by the amount of effector natural killer cells present, but not the amount of the target molecule CCR4 on the ATLL cell surface. KW-0761 should be sufficiently active for therapeutic clinical application for ATLL. In addition, combination treatment strategies that augment natural killer cell activity should be promising for amplifying the effect of KW-0761. In the near future, the actual efficacy of KW-0761 will be established in pivotal clinical trials.
    Clinical Cancer Research 02/2010; 16(5):1520-31. · 7.84 Impact Factor
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    Bone marrow transplantation 12/2009; 45(8):1369-71. · 3.00 Impact Factor
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    ABSTRACT: Overproduction of hepcidin by interleukin-6 (IL-6) is considered to be the main factor responsible for the development of anemia in inflammatory conditions. Since oncostatin M (OSM), a member of the IL-6 family, plays an important role in immune and inflammatory responses, we assessed the effect of OSM on hepcidin expression, as well as that of leukemia inhibitory factor (LIF), another member of the IL-6 family. We found that hepcidin expression was markedly induced by OSM and LIF in a time- and dose-dependent manner in hepatoma cell lines, and this expression was induced independent of IL-6/IL-6 receptor signaling. Luciferase assay revealed that OSM and LIF stimulated a -1.3-kb hepcidin promoter. This effect was markedly reduced when the signal transducer and activator of transcription (STAT) site of the promoter was mutated, and was almost completely abolished in the presence of AG-490, a Janus kinase (JAK) inhibitor. Hence, the JAK/STAT pathway plays a major role in OSM- and LIF-induced activation of the hepcidin promoter. In conclusion, we demonstrated that OSM and LIF can induce hepcidin expression mainly through the JAK/STAT pathways. Further studies are warranted to evaluate the clinical significance of OSM and LIF in the development of anemia in various inflammatory diseases.
    International journal of hematology 11/2009; 90(5):545-52. · 1.17 Impact Factor
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    ABSTRACT: B7-H1 is a member of the B7 family that inhibits the function of T-cells through its receptor programmed death-1 (PD-1). We examined B7-H1 expression in anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL) and found that it was constitutively expressed in both clinical samples and cell lines. In anaplastic lymphoma kinase-positive (ALK(+)) ALCL cells, B7-H1 expression was suppressed by the blocking of extracellular signal-regulated kinase (ERK) signaling and upregulated by the augmentation of ERK activity by phorbol 13-myristate 12-acetate stimulation, suggesting that B7-H1 expression is regulated by ERK signaling pathway in ALCL. ERK is one of the downstream mediators of nucleophosmin (NPM)/ALK signaling in ALK(+)ALCL, and pharmacological inhibition of ALK was shown to dephosphorylate ERK and down-regulate B7-H1. The involvement of NPM/ALK in B7-H1 expression was also demonstrated by introducing the construct into human non-ALCL lymphoid cell lines, which resulted in B7-H1 expression. In the case of HL, B7-H1 expression was shown to be dependent on the ERK and p38 mitogen-activated protein kinase (MAPK) signaling pathways. These results suggest that B7-H1 expression is controlled by common ERK signaling pathways in ALCL and HL cells. Our findings provide a potentially effective immunotherapeutic strategy for these B7-H1-expressing tumors.
    Cancer Science 09/2009; 100(11):2093-100. · 3.48 Impact Factor
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    ABSTRACT: The BCL2/IGH translocation is a hallmark of follicular lymphoma and germinal center B-cell type diffuse large B-cell lymphoma. Although a strong determinant of these histological subtypes, this translocation is insufficient by itself for lymphomagenesis, so that other genetic alterations are required. To clarify how the BCL2 translocation contributes to the development of specific lymphoma subtypes, we used chimeric mouse models and a bone marrow transplantation system to examine the biological features of BCL2-overexpressing B cells. These cells showed a cell-autonomous differentiation preference for follicular B cells. Their cell cycle progression was enhanced in wild-type but not in Emu-BCL2 transgenic mice, indicating that the low proliferative activity of B cells in Emu-BCL2 transgenic mice is partly due to their specific microenvironment, which is caused by the abnormal B cells themselves. Moreover, in vitro experiments demonstrated that Emu-BCL2(+) B cells have reduced responsiveness to terminal differentiation stimulation. According to these results, we hypothesize that B cells that have undergone BCL2/IGH translocation might possibly be forced to localize in follicles, and accumulate genetic abnormalities by being subjected to recurrent stimulation. Our findings lead us to propose that B cells carrying the BCL2/IGH translocation comprise a distinctive cell population that leads to the development of germinal center B-cell type lymphoma.
    Cancer Science 09/2009; 100(12):2361-7. · 3.48 Impact Factor
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    ABSTRACT: Atrial natriuretic peptide is a cardiovascular hormone secreted mainly by the cardiac atria and regulates the volume-pressure homeostasis. The action of ANP is mediated by GC-A. We previously reported that human monocyte-derived dendritic cells express GC-A and respond to ANP with polarization toward a Th2-inducing phenotype. In the present study, we explored the possibility that pDC are subjected to immunoregulation via the ANP/GC-A system. We examined GC-A expression on blood pDC and found that GC-A was not expressed on fresh pDC but was induced after stimulation with CpG-oligodeoxynucleotide AAC-30, IL-3, or interleukin-3 plus CD40 ligand. Activated pDC responded to ANP with an increase in cGMP production, indicating that GC-A expressed on pDC was functional. We investigated whether tonsillar pDC express GC-A by immunohistochemistry and immunofluorescence staining. We found that GC-A(+) HLA-DR(+) cells were present in the T-cell areas and the perivascular areas. Flow cytometric analysis with tonsillar cells confirmed that lineage(-) CD123(high) pDC express GC-A. These results indicate that the ANP/GC-A system is involved in immune regulation through pDC in secondary lymphoid organs.
    Microbiology and Immunology 08/2009; 53(7):403-11. · 1.55 Impact Factor

Publication Stats

9k Citations
1,464.67 Total Impact Points


  • 1977–2012
    • Kyoto University
      • • Department of Hematology and Oncology
      • • Graduate School of Medicine / Faculty of Medicine
      • • Institute for Virus Research
      Kyoto, Kyoto-fu, Japan
  • 2011
    • Aichi Cancer Center
      Ōsaka, Ōsaka, Japan
  • 2010
    • Tazuke Kofukai Medical Research Institute, Kitano Hospital
      Ōsaka, Ōsaka, Japan
  • 2006
    • Osaka City University
      • Graduate School of Medicine
      Ōsaka-shi, Osaka-fu, Japan
  • 2004
    • University Hospital Medical Information Network
      Edo, Tōkyō, Japan
  • 1989–2002
    • The University of Tokushima
      • • Department of Clinical Neuroscience
      • • Department of Virology
      Tokusima, Tokushima, Japan
  • 1988–1991
    • Niigata University
      • Department of Biology
      Niigata-shi, Niigata-ken, Japan
  • 1986
    • Kumamoto University
      Kumamoto, Kumamoto Prefecture, Japan