Atsushi Ogata

Osaka University, Suika, Ōsaka, Japan

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Publications (100)448.02 Total impact

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    ABSTRACT: Background/Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in patients with rheumatoid arthritis (RA) but have several side effects including mucosal damage in the small intestine. We aimed to evaluate whether the small bowel injury is ameliorated by switching from nonselective NSAIDs to celecoxib in patients with RA. Methods: Sixteen patients with RA who were treated with nonselective NSAIDs were enrolled in this study. Nonselective NSAIDs were converted to celecoxib for 12 weeks. Capsule endoscopy was performed before and after treatment with celecoxib. Videos were screened by gastroenterologists blinded to the patients' treatment. Results: Before the administration of celecoxib, reddened folds, denuded areas, petechiae/red spots and mucosal breaks were observed in 63, 63, 88 and 69% of the patients, respectively. In the 14 patients who completed this study, conversion to celecoxib significantly reduced the number of petechiae/red spots, the number of mucosal breaks, and Lewis scores. RA activity and cytokine levels in the peripheral blood were not significantly different before and after treatment with celecoxib. Conclusions: The incidence of small bowel injury by nonselective NSAIDs is high in patients with RA. Conversion from nonselective NSAIDs to celecoxib can be useful for protecting patients with RA from small bowel injury. © 2014 S. Karger AG, Basel.
    Digestion 02/2014; 89(2):124-132. · 1.94 Impact Factor
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    ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation, systemic inflammation, and immunological abnormalities. Because cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 play a major role in the development of RA, their targeting could constitute a reasonable novel therapeutic strategy for treating RA. Indeed, worldwide clinical trials of TNF inhibiting biologic disease modifying antirheumatic drugs (bDMARDs) including infliximab, adalimumab, golimumab, certolizumab pegol, and etanercept as well as the humanized anti-human IL-6 receptor antibody, tocilizumab, have demonstrated outstanding clinical efficacy and tolerable safety profiles, resulting in worldwide approval for using these bDMARDs to treat moderate to severe active RA in patients with an inadequate response to synthetic disease modifying antirheumatic drugs (sDMARDs). Although bDMARDs have elicited to a paradigm shift in the treatment of RA due to the prominent efficacy that had not been previously achieved by sDMARDs, a substantial percentage of patients failed primary or secondary responses to bDMARD therapy. Because RA is a heterogeneous disease in which TNF-α and IL-6 play overlapping but distinct pathological roles, further studies are required to determine the best use of TNF inhibitors and tocilizumab in individual RA patients.
    Targets & therapy 01/2014; 8:141-153.
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    ABSTRACT: Interleukin-6 (IL-6) is a cytokine with redundant and pleiotropic activities, and its synthesis is tightly regulated by transcriptional and posttranscriptional mechanisms. When infections and tissue injuries occur, IL-6 synthesis is promptly induced and provides an emergent signal that contributes to host defense through the stimulation of acute-phase responses, immune reactions, and hematopoiesis. After the environmental stress is removed from the host, the production of IL-6 is terminated. However, dysregulated continual synthesis of IL-6 is involved in the development of chronic inflammatory autoimmune diseases. For this reason, tocilizumab, a humanized anti-IL-6 receptor antibody, was developed. Worldwide clinical trials have demonstrated the outstanding efficacy of tocilizumab in rheumatoid arthritis, systemic juvenile idiopathic arthritis, and Castleman's disease; thus, a new era has come for the treatment of these diseases, which were previously considered intractable. Moreover, favorable results from off-label use of tocilizumab strongly suggest that it will be widely applicable for various refractory inflammatory autoimmune diseases. In this context, the mechanism for the continual synthesis of IL-6 needs to be elucidated in order to investigate the pathogenesis of specific diseases and to facilitate the development of more specific therapeutic strategies.
    Seminars in Immunology 01/2014; · 5.93 Impact Factor
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    ABSTRACT: Objective. To evaluate the efficacious noninferiority of subcutaneous tocilizumab injection (TCZ-SC) monotherapy to intravenous TCZ infusion (TCZ-IV) monotherapy in Japanese patients with rheumatoid arthritis (RA) with an inadequate response to synthetic and/or biologic DMARDs. Methods. This study had a double-blind, double-dummy, parallel-group, comparative phase 3 design. Patients were randomized to receive TCZ-SC 162 mg every 2 weeks or TCZ-IV 8 mg/kg every 4 weeks; no DMARDs were allowed during the study. The primary endpoint was to evaluate the noninferiority of TCZ-SC to TCZ-IV regarding ACR20 response rates at week 24 using an 18% noninferiority margin. Additional efficacy, safety, pharmacokinetic and immunogenicity parameters were assessed. Results. At week 24, ACR20 response was achieved in 79.2% (95% CI, 72.9-85.5) of the TCZ-SC group and in 88.5% (95% CI, 83.4-93.5) of the TCZ-IV group; the weighted difference was -9.4% (95% CI, -17.6 to -1.2), confirming the noninferiority of TCZ-SC to TCZ-IV. Remission rates of DAS28-ESR and CDAI at week 24, respectively, were 49.7% and 16.4% in the TCZ-SC group and 62.2% and 23.1% in the TCZ-IV group. Serum trough TCZ concentrations were similar between groups over time. The incidences of all adverse and serious adverse events were 89.0% and 7.5% in the TCZ-SC group and 90.8% and 5.8% in the TCZ-IV group, respectively. Anti-TCZ antibodies were detected in 3.5% of the TCZ-SC group; no serious hypersensitivity was reported in these patients. Conclusion. TCZ-SC monotherapy demonstrated comparable efficacy and safety to TCZ-IV monotherapy. TCZ-SC could provide additional treatment options for patients with RA. © 2013 American College of Rheumatology.
    Arthritis care & research. 08/2013;
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    ABSTRACT: Objectives: The retention of the anti-rheumatic agent tocilizumab (TCZ) has not been well documented in patients with rheumatoid arthritis (RA). We conducted an observational study to compare the retention of TCZ and anti-tumour necrosis factor (TNF) drugs in the treatment of patients with RA. Method: We reviewed continuation rates and causes of discontinuation of biological agents (biologics) by assessing medical records of patients with RA who were administered biologics at our institute from September 1999 to April 2012, using the Osaka University Biologics for Rheumatic Diseases (BiRD) registry. Results: A total of 401 patients were included. TCZ, infliximab (IFX), etanercept (ETN), and adalimumab (ADA) were administered to 97, 103, 143, and 58 patients, respectively. There were some differences between the baseline characteristics of the groups. The median duration (range) of TCZ, IFX, ETN, and ADA administration was 2.5 (0.1-12.6), 1.9 (0.0-7.7), 2.9 (0.0-11.3), and 1.3 (0.0-3.4) years, respectively. Continuation rates for TCZ and ETN were significantly higher than those for IFX and ADA. Multivariate analyses showed that discontinuation due to lack or loss of efficacy was significantly less common in the TCZ group than in the other groups. Discontinuation due to overall adverse events was not significantly different between treatment groups. Conclusion: TCZ and ETN show better retention than IFX or ADA in the treatment of RA.
    Scandinavian journal of rheumatology 03/2013; · 2.51 Impact Factor
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    ABSTRACT: Systemic sclerosis (SSc) presents stiffness of extremities due to sclerosis of the tissue especially at fingers, hands, and forearms. Here we report the case of a patient with diffuse cutaneous SSc who was administered anti-interleukin-6 receptor antibody tocilizumab (TCZ). Skin condition of SSc is evaluated by pinching the skin according to the Rodnan skin score, but sometimes tissue atrophy results in overestimation of the condition. To understand how the extremities softened after initiation of TCZ, we observed mobility of extremities. Range of motion (ROM) of joints was measured every four months after initiation of TCZ. The patient presented not only reduction of Rodnan score but also amelioration of mobility of extremities. The Rodnan skin score reduced from 35 to 7 within sixteen months, and ROM of most joints except ankle was expanded.
    Modern Rheumatology 03/2013; · 1.72 Impact Factor
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    ABSTRACT: Semaphorin 4A (Sema4A) has an essential role in photoreceptor survival. In humans, mutations in Sema4A are thought to contribute to retinal degenerative diseases. Here we generate a series of knock-in mouse lines with corresponding mutations (D345H, F350C or R713Q) in the Sema4A gene and find that Sema4A(F350C) causes retinal degeneration phenotypes. The F350C mutation results in abnormal localization of the Sema4A protein, leading to impaired endosomal sorting of molecules indispensable for photoreceptor survival. Additionally, protein structural modelling reveals that the side chain of the 350th amino acid is critical to retain the proper protein conformation. Furthermore, Sema4A gene transfer successfully prevents photoreceptor degeneration in Sema4A(F350C/F350C) and Sema4A(-/-) mice. Thus, our findings not only indicate the importance of the Sema4A protein conformation in human and mouse retina homeostasis but also identify a novel therapeutic target for retinal degenerative diseases.
    Nature Communications 01/2013; 4:1406. · 10.74 Impact Factor
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    ABSTRACT: Objective. To evaluate what types of DNA damages are detected in rheumatoid arthritis (RA). Methods. The DNA adducts such as 8-oxo-hydroxy-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), 1,N(6)-etheno-2'-deoxyadenosine ( ε dA), and heptanone-etheno-2'-deoxycytidine (H ε dC) in genomic DNAs, derived from whole blood cells from 46 RA patients and 31 healthy controls, were analyzed by high-performance liquid chromatography tandem mass spectrometry, and their levels in RA patients and controls were compared. In addition, correlation between DNA adducts and clinical parameters of RA was analyzed. Results. Compared with controls, the levels of H ε dC in RA were significantly higher (P < 0.0001) and age dependent (r = 0.43, P < 0.01), while there was no significant difference in 8-oxo-dG and ε dA accumulation between RA patients and controls. H ε dC levels correlated well with the number of swollen joints (r = 0.57, P < 0.0001) and weakly with the number of tender joints (r = 0.26, P = 0.08) of RA patients, while they did not show a significant association with serological markers such as C-reactive protein and matrix metalloproteinase 3. Conclusion. These findings indicate that H ε dC may have some influence on the development of RA and/or its complications.
    Autoimmune diseases. 01/2013; 2013:183487.
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    ABSTRACT: BACKGROUND:: Easily measured and clinically useful biomarkers for inflammatory bowel disease (IBD) are required to advance patient care. We previously reported that the agalactosyl fraction among fucosylated IgG oligosaccharides is increased in IBD, especially Crohn's disease (CD). The present study aimed to establish a simple detection system for aberrant glycosylated IgG based on lectin-oligosaccharide interactions. METHODS:: Lectins with higher affinity to serum IgG from IBD patients than healthy volunteers (HV) were screened by lectin microarray. Binding of selected lectins to agalactosyl IgG was definitively confirmed using step-by-step glycosidase treatment. Using the selected lectins, a lectin-enzyme-linked immunosorbent assay system was established and its clinical utility was investigated in a total of 410 (249 Japanese and 161 American) IBD patients, disease controls, and HVs. RESULTS:: Agaricus bisporus Agglutinin (ABA) and Griffonia simplicifolia Lectin-II (GSL-II) had higher affinity for serum agalactosyl IgG from IBD patients, especially those with CD, compared to HV. Agalactosyl IgG levels measured by a lectin-enzyme immunoassay (EIA) with ABA or GSL-II were significantly increased in CD compared with HV and disease controls. Agalactosyl IgG levels significantly correlated with disease activity, showed higher predictability of therapeutic outcomes for CD than C-reactive protein levels, and exhibited higher specificity for diagnosing IBD in combination with anti-Saccharomyces cerevisiae antibody (ASCA). Validation analysis showed that agalactosyl IgG levels were significantly increased in Japanese and American CD patients. CONCLUSIONS:: A lectin-EIA for agalactosyl IgG is a novel biomarker for IBD, especially in patients with CD.
    Inflammatory Bowel Diseases 12/2012; · 5.12 Impact Factor
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    ABSTRACT: OBJECTIVES: To investigate the clinical characteristics and risk factors of Pneumocystis jirovecii pneumonia (PCP) in rheumatoid arthritis (RA) patients treated with adalimumab. METHODS: We conducted a multicenter, retrospective, case-control study to compare RA patients treated with adalimumab with and without PCP. Data from 17 RA patients who were diagnosed with PCP and from 89 RA patients who did not develop PCP during adalimumab treatment were collected. RESULTS: For the PCP patients, the median age was 68 years old, with a median RA disease duration of eight years. The median length of time from the first adalimumab injection to the development of PCP was 12 weeks. At the onset of PCP, the median dosages of prednisolone and methotrexate were 5.0 mg/day and 8.0 mg/week, respectively. The patients with PCP were significantly older (p < 0.05) and had more structural changes (p < 0.05) than the patients without PCP. Computed tomography of the chest revealed ground-glass opacity without interlobular septal boundaries in the majority of the patients with PCP. Three PCP patients died. CONCLUSIONS: PCP may occur early in the course of adalimumab therapy in patients with RA. Careful monitoring, early diagnosis, and proper management are mandatory to secure a good prognosis for these patients.
    Modern Rheumatology 12/2012; · 1.72 Impact Factor
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    ABSTRACT: Multiple sclerosis (MS) is a demyelinating autoimmune disease of the CNS and a leading cause of lasting neurologic disabilities in young adults. Although the precise mechanism remains incompletely understood, Ag presentation and subsequent myelin-reactive CD4(+) T cell activation/differentiation are essential for the pathogenesis of MS. Although semaphorins were initially identified as axon guidance cues during neural development, several semaphorins are crucially involved in various phases of immune responses. Sema4A is one of the membrane-type class IV semaphorins, which we originally identified from the cDNA library of dendritic cell (DC). Sema4A plays critical roles in T cell activation and Th1 differentiation during the course of experimental autoimmune encephalomyelitis, an animal model of MS; however, its pathological involvement in human MS has not been determined. In this study, we report that Sema4A is increased in the sera of patients with MS. The expression of Sema4A is increased on DCs in MS patients and shed from these cells in a metalloproteinase-dependent manner. DC-derived Sema4A is not only critical for Th1 but also for Th17 cell differentiation, and MS patients with high Sema4A levels exhibit Th17 skewing. Furthermore, patients with high Sema4A levels have more severe disabilities and are unresponsive to IFN-β treatment. Taken together, our results suggest that Sema4A is involved in the pathogenesis of MS by promoting Th17 skewing.
    The Journal of Immunology 04/2012; 188(10):4858-65. · 5.52 Impact Factor
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    ABSTRACT: Le rhumatisme psoriasique (PsA) fait partie des spondylarthropathies séronégatives. Comme dans la polyarthrite rhumatoïde (PR), on suppose que l’augmentation de la production d’interleukine 6 (IL-6) joue un rôle dans la pathogénie du PsA. Cependant, l’efficacité du tocilizumab (TCZ), anticorps monoclonal humanisé dirigé contre le récepteur de IL-6 dans le traitement du PsA reste encore à démontrer, contrairement à la PR. Dans cet article, nous présentons deux observations de PsA traités par TCZ. Bien que la CRP sérique se soit normalisée dans les deux cas sous TCZ, les arthrites et les lésions cutanées n’ont pas été améliorées malgré six mois de traitement. En revanche, les atteintes cutanées et articulaires ont régressé sous inhibiteur du facteur de nécrose tumorale (TNF). Ces résultats montrent, d’une part que l’IL-6 a un rôle physiopathologique différent dans la PR et le PsA, d’autre part confirment l’efficacité du traitement par anti-TNF (et non pas celui du TCZ) dans les arthrites et les lésions cutanées du PsA.
    Revue du Rhumatisme. 03/2012; 79(2):168–170.
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    Atsushi Ogata, Toshio Tanaka
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    ABSTRACT: Interleukin (IL)-6 is a cytokine featuring redundancy and pleiotropic activity. While IL-6, when transiently produced, contributes to host defense against acute environmental stress, continuous dysregulated IL-6 production plays a significant pathological role in several systemic autoimmune diseases. In response to the expectation that IL-6 blockade would constitute a novel therapeutic strategy for the treatment of these diseases, tocilizumab, a humanized anti-IL-6 receptor antibody, was developed. Clinical trials have verified the efficacy and the safety of tocilizumab for patients with rheumatoid arthritis, resulting in approval of this innovative biologic for the treatment of rheumatoid arthritis in more than 90 countries worldwide. Pathological analyses of the effect of IL-6 on the development of autoimmune diseases and a considerable number of case reports and pilot studies have also indicated the beneficial effects of this antibody on other systemic autoimmune diseases, including systemic lupus erythematosus, systemic sclerosis, polymyositis, and large-vessel vasculitis.
    International Journal of Rheumatology 01/2012; 2012:946048.
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    ABSTRACT: Because of the pathological role of IL-6 in rheumatoid arthritis (RA), tocilizumab (TCZ), a humanized anti-IL-6 receptor monoclonal antibody, was expected to improve inflammation and joint destruction of RA. Indeed, randomized clinical trials demonstrated the clinical efficacy of TCZ as monotherapy or combined with methotrexate (MTX) for RA patients with inadequate responses to disease-modifying antirheumatic drugs, MTX or tumor necrosis factor (TNF) inhibitors. Although long-term tolerability for TCZ is superior to that for TNF inhibitors, information regarding the potency of drug free remission of TCZ is limited at present. In terms of its safety profile, the general risk of infection when using TCZ is comparable to that of TNF inhibitors. TCZ has some advantage in RA patients who can not use MTX and are non-responders to TNF inhibitors. In conclusion, TCZ is one of the most prospective next generation biologics for the treatment of RA.
    Clinical medicine insights. Arthritis and musculoskeletal disorders. 01/2012; 5:27-42.
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    ABSTRACT: Psoriatic arthritis (PsA) is a clinical manifestation of psoriatic disease. Although the pathogenesis of PsA remains unknown, PsA can be managed by treatments similar to those used for rheumatoid arthritis (RA). Because interleukin-(IL-) 6 has been suggested to have a pathogenic role in PsA, a humanized anti-IL-6 receptor antibody tocilizumab treatment for PsA was recently tried. However, the efficacy of tocilizumab for PsA was not favorable. This suggests that the pathogenic roles of IL-6 in PsA and RA are different. In RA, tumor necrosis factor (TNF) primarily contributes to the arthritis effector phase and IL-6 contributes to the arthritis priming phase. In PsA, the TNF-related effector phase is similar to that in RA, but the IL-6-related priming phase might not be critical. This paper discusses the role of IL-6 in PsA.
    Arthritis. 01/2012; 2012:713618.
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    ABSTRACT: The cytokine interleukin (IL)-6 has a wide range of biological activities. It contributes to host defense against pathogens by inducing immune responses, hematopoiesis, and acute-phase reactions. However, dysregulation of IL-6 production plays a significant pathological role in various autoimmune and chronic inflammatory disorders. Because IL-6 blockade was anticipated to provide a novel strategy for the treatment of such diseases, tocilizumab, a humanized anti-IL-6 receptor antibody, was developed. Clinical trials have demonstrated the efficacy of tocilizumab for patients with moderate to severe rheumatoid arthritis, resulting in approval in more than 90 countries worldwide of this innovative biologic for the treatment of rheumatoid arthritis. Tocilizumab was also approved in Japan for the treatment of Castleman's disease and juvenile idiopathic arthritis. Results of recent pilot or case studies have indicated that tocilizumab may become a novel drug for various other autoimmune disorders, including systemic lupus erythematosus, systemic sclerosis, polymyositis, and vasculitis syndrome, as well as inflammatory disorders such as adult-onset Still's disease, Crohn's disease, amyloid A amyloidosis, polymyalgia rheumatica, and spondylarthritides. It has been demonstrated that an imbalance of CD4-positive T-helper subsets [Th17 and/or Th1 >> regulatory T cells (Treg)] plays a major role in the development of several autoimmune disorders. In murine models of autoimmune disorders, the anti-IL-6 receptor antibody induced Treg and inhibited Th17 and/or Th1 differentiation, indicating that tocilizumab treatment may be able to repair this imbalance in human diseases as well. Drug Dev Res 72:717–732, 2011. © 2011 Wiley Periodicals, Inc.
    Drug Development Research 12/2011; 72(8). · 0.87 Impact Factor
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    Amyloidosis - An Insight to Disease of Systems and Novel Therapies, 11/2011; , ISBN: 978-953-307-795-6
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    ABSTRACT: Psoriatic arthritis (PsA) is considered as one of the seronegative spondylarthropathies. Like rheumatoid arthritis (RA), the increased production of interleukin (IL)-6 suggests a pathogenic role of IL-6 in PsA. However, whether humanized anti-IL-6 receptor antibody such as tocilizumab (TCZ) might be effective for PsA as well as RA has yet to be determined. We report herein two cases of PsA treated using TCZ. Although, TCZ treatment resulted in disappearance of serum CRP in both patients, arthritis and skin lesions were not improved despite 6-month administration of TCZ. In contrast, tumor necrosis factor (TNF) inhibitor proved effective against arthritis and skin lesions in these patients. Collectively, these findings not only indicate that IL-6 has distinct pathological roles in RA and PsA, but also suggest that TNF inhibitor therapy (but not TCZ) is effective for arthritis and skin lesions of PsA.
    Joint, bone, spine: revue du rhumatisme 09/2011; 79(1):85-7. · 2.25 Impact Factor
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    ABSTRACT: A 65-year-old woman who had suffered from chronic graft-versus-host disease (GVHD) presented with extensive purpura and was diagnosed with acquired hemophilia A. Because she was refractory to corticosteroids and her condition was complicated with diabetes mellitus, glaucoma, and hypoglobulinemia, she was treated with tocilizumab. Tocilizumab treatment increased the activity of factor VIII in a rapid and sustained manner, leading to a reduction of the prednisolone dose. Tocilizumab may thus be an optional treatment modality for acquired hemophilia A.
    Modern Rheumatology 08/2011; 21(4):420-2. · 1.72 Impact Factor
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    ABSTRACT: A 47-year-old female patient with Behçet's disease had been treated with colchicine, prednisolone, cyclosporine A, and infliximab. Because she relapsed, however, treatment with tocilizumab, a humanized anti-interleukin 6 receptor antibody, was started. This treatment suppressed the patient's clinical manifestations, including ocular attacks, for 1 year and improved her visual acuity. This experience indicates that tocilizumab may constitute a therapeutic option for refractory Behçet's disease.
    Modern Rheumatology 07/2011; 22(2):298-302. · 1.72 Impact Factor

Publication Stats

2k Citations
448.02 Total Impact Points

Institutions

  • 2009–2014
    • Osaka University
      • Immunopathology Group
      Suika, Ōsaka, Japan
  • 2003–2014
    • Osaka City University
      • Department of Neurosurgery
      Ōsaka, Ōsaka, Japan
  • 2006–2007
    • Osaka Prefectural Medical Center for Respiratory and Allergic Diseases
      Ōsaka, Ōsaka, Japan
  • 1998–2005
    • Hyogo College of Medicine
      • Department of Internal Medicine
      Nishinomiya, Hyogo-ken, Japan
    • The Jikei University School of Medicine
      • Department of Pediatrics
      Tokyo, Tokyo-to, Japan
  • 1996–1999
    • Dana-Farber Cancer Institute
      • Division of Hematologic Malignancies
      Boston, Massachusetts, United States
  • 1997
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 1996–1997
    • Harvard Medical School
      • Department of Medicine
      Boston, MA, United States
  • 1990
    • Kagoshima University
      Kagosima, Kagoshima, Japan