N Yamashita

Musashino University, Edo, Tōkyō, Japan

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Publications (71)243.89 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Acetylcholine (ACh) exerts various anti-inflammatory effects through α 7 nicotinic ACh receptors (nAChRs). We have previously shown that secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1), a positive allosteric modulator of α 7 nAChR signaling, is down-regulated both in an animal model of asthma and in human epithelial cells treated with an inflammatory cytokine related to asthma. Our aim of this study was to explore the effect of SLURP-1, signal through α 7 nAChR, in the pathophysiology of airway inflammation. Cytokine production was examined using human epithelial cells. Ciliary beat frequency (CBF) of murine trachea was measured using a high speed camera. The IL-6 and TNF- α production by human epithelial cells was augmented by siRNA of SLURP-1 and α7 nicotinic ACh receptor. The cytokine production was also dose-dependently suppressed by human recombinant SLURP-1 (rSLURP-1). The ciliary beat frequency and amplitude of murine epithelial cells were augmented by PNU282987, a selective α7 nAChR agonist. Those findings suggested that SLURP-1 and stimulus through α7 nicotinic ACh receptors actively controlled asthmatic condition by stimulating ciliary beating and also by suppressing airway inflammation.
    Biochemical and Biophysical Research Communications 07/2013; · 2.28 Impact Factor
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    ABSTRACT: To advance the control of airway epithelial cell function and asthma, we investigated the effects of a new curcumin derivative, CNB001, which possesses improved pharmacological properties. Normal human bronchial epithelial (NHBE) cells were stimulated with synthetic double-stranded RNA, Poly(I:C). CNB001 significantly suppressed IL-6, TNF-α, and GM-CSF production by NHBE cells, and did so more effectively than did curcumin or dexamethasone (DEX). CNB001 significantly inhibited the decrease of E-cadherin mRNA expression and increase of vimentin mRNA expression observed in NHBE cells induced by a combination of TGF-β1 and TNF-α, which are markers of airway remodeling. In NHBE cells stimulated by TGF-β1, CNB001 significantly downregulated the level of active serine peptidase inhibitor clade E member (SERPINE) 1, which is also reported to be related to airway remodeling. Whereas DEX alone significantly increased the active SERPINE1 level, the combination of DEX and CNB001 significantly suppressed active SERPINE1. In addition, CNB001 significantly suppressed neutrophil infiltration, IL-6, TNF-α, IL-13 and active SERPINE1 production in bronchoalveolar lavage fluid of the murine asthma model, which was not observed in the case of DEX. In conclusion, the curcumin derivative, CNB001, is a promising candidate to treat asthma associated with neutrophilic airway inflammation and remodeling.
    Experimental and Molecular Pathology 04/2012; 93(1):18-25. · 2.13 Impact Factor
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    ABSTRACT: House dust mite (HDM), the most common allergen, activate both the IgE-associated and innate immune responses. To clarify the process of sensitization, we investigated the role of the CCL21, CCL19, and CCR7 axis in a mouse model of HDM-induced allergic asthma. HDM inhalation without systemic immunization resulted in a HDM-specific IgE response. CCR7-knockout (CCR7KO) mice exhibited greater airway inflammation and IgE responses compared to wild-type mice. We examined FoxP3 expression in these mice to clarify the contribution of regulatory cells to the responses. FoxP3 expression was higher in the lungs but not in the lymph nodes of CCR7KO mice compared to wild-type mice. In CCR7KO mice, FoxP3-positive cells were found in lung, but we observed higher release of IL-13, IL-5, TGF-β, IL-17, and HMGB1 in bronchoalveolar lavage fluid. We demonstrate here that immuno-regulation through CCR7 expression in T cells plays a role in HDM-specific sensitization in the airway.
    Cellular Immunology 04/2012; 275(1-2):24-32. · 1.74 Impact Factor
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    ABSTRACT: Whereas acetylcholine (ACh) acts as a bronchoconstrictor and stimulator of mucus secretion from bronchial epithelium, it acts via alpha7 nicotinic Ach receptors (nAChRs) on macrophages in the airways to exert anti-inflammatory effects by reducing synthesis of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha). Moreover, the effects of ACh are modified by secreted ly-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1), a positive allosteric modulator of alpha7 nAChR signaling. Our aim was to explore the roles played by SLURP-1 in the pathophysiology of asthma by assessing SLURP-1 expression in the OVA-sensitized murine asthma model and in cultured human bronchial epithelial cells. Using real-time PCR we found that expression of SLURP-1 mRNA is down-regulated in the lungs of asthmatic model mice, as compared to healthy mice. In addition, immunohistochemical studies confirmed the diminished expression of SLURP-1 in the bronchioles of asthmatic mice, and showed it was due to extensive metaplasia of mucus-secreting cells and the concomitant loss of ciliated epithelial cells. Expression of SLURP-1 mRNA and protein was also significantly down-regulated in human epithelial cells stimulated with the pro-inflammatory cytokine interleukin-13 (IL-13), which is related to asthmatic condition. Thus SLURP-1 appears to be down-regulated in both an animal model of asthma and human epithelial cells treated with an inflammatory cytokine related to asthma. Those findings suggest that diminished expression of SLURP-1 in asthma attenuates its negative regulation of airway inflammation, and that perhaps changes in SLURP-1 expression could serve as a marker of airway damage in asthma.
    Biochemical and Biophysical Research Communications 08/2010; 398(4):713-8. · 2.28 Impact Factor
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    ABSTRACT: To achieve a good control for asthma, cooperation of pharmacists is necessary. It is important to establish the system that the patients easily obtain advice about asthma from pharmacists and to spread the guideline. For the first step, we explore the knowledge and usage of asthmatic guideline among pharmacists in the drug stores in this study. The questionnaires were distributed to 465 drug stores in the Seibu, minato-ku and bunnkyo-ku, Tokyo. The knowledge of guideline was 79% but the existence of guideline booklet at the pharmacy was 24%. The major demand at the pharmacy was to distribute pamphlet around 10 pages which contained treatment at the pregnancy and prevention of asthma. To spread usage of asthmatic guideline at the pharmacy, newly-devised plan is required.
    Arerugī = [Allergy] 12/2009; 58(12):1602-9.
  • Ken Ohta, Hiroyuki Nagase, Naomi Yamashita
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    ABSTRACT: Insulin-like growth factor-I (IGF-I) is known to act on fibroblasts as a progression factor to push the cells from G1 phase to mitosis in the cell cycle and activate them to synthesize collagen. Subepithelial fibrosis, i.e. collagen deposition at the lamina reticularis, is part of the process of so-called remodeling and is a characteristic finding in the asthmatic airway. To study the role of IGF in the evolution of asthma, we used a model that involved immunization of mice with ovalbumin (OVA) and alum, followed by an inhaled challenge of ovalbumin. IGF-I neutralizing antibody was continuously infused with an osmotic pump. Pulmonary function was analyzed using whole-body plethysmography before and after acetylcholine administration. It was found that OVA inhalation induced IGF-I expression at the site of the airway. IGF-I neutralizing antibody inhibited the elevation of airway resistance, airway inflammation, and an increase in airway wall thickening. The depression of ICAM-1 and IGFBP expression was accompanied by a diminution in airway inflammation. In conclusion, these results suggest that IGF-I is likely to be an important mediator of inflammation and remodeling in the asthmatic airway.
    11/2009: pages 291-303;
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    ABSTRACT: Although inhaled steroids are the treatment of first choice to control asthma, administration of systemic steroids is required for treatment of asthmatic exacerbation and intractable asthma. To improve efficacy and reduce side effects, we examine the effects of betamethasone disodium phosphate (BP) encapsulated in biocompatible, biodegradable blended nanoparticles (stealth nanosteroids) on a murine model of asthma. These stealth nanosteroids were found to accumulate at the site of airway inflammation and exhibit anti-inflammatory activity. Significant decreases in BALF eosinophil number were maintained for 7 days with a single injection of nanosteroids containing 40 microg BP. Airway responsiveness was also attenuated by the injection of stealth nanosteroids. A single injection of 40 microg of free BP and 8 microg of free BP once daily for 5 days did not show any significant effects. We conclude that stealth nanosteroids achieve prolonged and higher benefits at the site of airway inflammation compared to free steroids.
    Cellular Immunology 09/2009; 260(1):33-8. · 1.74 Impact Factor
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    ABSTRACT: Mammalian secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1) is a positive allosteric ligand for alpha7 nicotinic acetylcholine (ACh) receptors (alpha7 nAChRs) that potentiates responses to ACh and elicits proapoptotic activity in human keratinocytes. Mutations in the gene encoding SLURP-1 have been detected in patients with Mal de Meleda, a rare autosomal recessive skin disorder characterized by transgressive palmoplantar keratoderma. On the basis of these findings, SLURP-1 is postulated to be involved in regulating tumor necrosis factor-alpha (TNF-alpha) release from keratinocytes and macrophages via alpha7 nAChR-mediated pathways. In the present study, we assessed SLURP-1 expression in lung tissue from C57BL/6J mice to investigate the functions of SLURP-1 in pulmonary physiology and pathology. Immunohistochemical and in situ hybridization analyses revealed expression of SLURP-1 protein and mRNA, respectively, exclusively in ciliated bronchial epithelial cells. This was supported by Western blotting showing the presence of the 9.5-kDa SLURP-1 protein in whole-lung tissue and trachea. In addition, high-affinity choline transporter (CHT1) was detected in apical regions of bronchial epithelial cells and in neurons located in the lamina propria of the bronchus, suggesting that bronchial epithelial cells are able to synthesize both SLURP-1 and ACh. We also observed direct contact between F4/80-positive macrophages and bronchial epithelial cells and the presence of invading macrophages in close proximity to CHT1-positive nerve elements. Collectively, these results suggest that SLURP-1 contributes to the maintenance of bronchial epithelial cell homeostasis and to the regulation of TNF-alpha release from macrophages in bronchial tissue.
    Journal of Neuroscience Research 05/2009; 87(12):2740-7. · 2.97 Impact Factor
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    ABSTRACT: Key role of angiogenesis in tumor growth and metastasis based on accumulating evidence and recent progress of immunotherapy have led us to investigate vaccine therapy targeting tumor angiogenesis. C57BL/6J mice were vaccinated with a syngeneic endothelial cell line Tpit/E by subcutaneous injection once a week. Prior to ninth vaccination, the mice were challenged with B16/F10 melanoma cells by subcutaneous inoculation on the back for the tumor growth model or by tail venous injection for the lung metastasis model. Development of subcutaneous tumor and lung metastasis was monitored by computed tomography scanning, which enabled accurate evaluation with the minimized sacrifice of mice. Vaccination with Tpit/E cells inhibited subcutaneous tumor growth and appearance of lung metastasis compared to control. Survival period was elongated in the Tpit/E vaccination in both of the two models. We also obtained hybridomas secreting specific antibodies to Tpit/E cells from a mouse vaccinated with the cells, indicating that specific immune response to the syngeneic endothelial cells was elicited. These results suggest that vaccination with an autologous endothelial cell line may be effective against melanoma.
    Journal of Experimental & Clinical Cancer Research 02/2009; 28:13. · 3.07 Impact Factor
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    ABSTRACT: Emphysema, one of chronic obstructive pulmonary disease (COPD), is characterized as destruction of airway wall and small airway inflammation. To assess the kinetics of disease progression in murine model of elastase-induced emphysema, we used micro-computed tomography (CT) compared with morphological changes. Two week after elastase administration, a significant increase in the volume of low-density areas, recognized as -800--600 Hounsfield units by micro-CT, was observed. Coefficient of correlation between mean linear intercept (Lm) and low-density area examined by CT, was 0.79 (p<0.01). Micro-CT can quantitatively and sequentially detect murine emphysematous changes, offering a practical method to sequentially analyze the therapeutic effects of treatments in a murine model of emphysema.
    Biological & Pharmaceutical Bulletin 07/2008; 31(7):1434-8. · 1.85 Impact Factor
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    ABSTRACT: Dendritic cells (DCs) are crucial for the induction of immunity and tolerance. Despite an improved understanding of the DC-mediated control of T(H)1-biased immunity, little is known about how DCs regulate T(H)2-mediated immunity. The effects of immunostimulatory mature DCs (maDCs) and regulatory DCs (DCregs) on T(H)2-driven allergic immunity involving IgE production were examined. A murine model of airway hyperresponsiveness; the adoptive transfer of maDCs, DCregs, and T cells; and T-cell function were studied. Antigen-pulsed maDCs inhibited antigen-specific IgE production but enhanced the production of antigen-specific IgG1 and IgG2a. Analysis of Ifng-/- mice and Il21r-/- mice revealed that the inhibitory effect of antigen-pulsed maDCs on antigen-specific IgE production involved IL-21-producing T follicular helper cells but not IFN-gamma-producing T(H)1 cells. In contrast, antigen-pulsed DCregs impaired the production of antigen-specific IgE, IgG1, and IgG2a. In vivo blockade experiments showed that antigen-specific CD4+CD25+Foxp3+ regulatory T cells mainly mediated the suppressive effect of antigen-pulsed DCregs on the production of antigen-specific IgE. Antigen-pulsed maDCs promoted airway inflammation, whereas antigen-pulsed DCregs markedly suppressed the pathogenesis. DCregs abolish T(H)2-mediated IgE production and allergic inflammation based on antigen-specific dominant tolerance, whereas maDCs exacerbate the pathogenesis despite inhibiting the IgE response through the activation of diverse types of T(H) cell responses.
    The Journal of allergy and clinical immunology 02/2008; 121(1):95-104.e7. · 12.05 Impact Factor
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    ABSTRACT: Asthma is a chronic inflammatory disease characterized by airway wall remodeling in which vascular remodeling is thought to be a main contributor. Vascular endothelial growth factor (VEGF) is known as a major regulator of angiogenesis and enhancer of vascular permeability. Here, we define the spatial nature of vascular remodeling and the role of VEGF and its receptors (Flt-1 and Flk-1) in the allergic response in mice (A/J) susceptible to the development of allergen-induced airway hyperresponsiveness using morphometric and quantitative approaches. Increased vascularity, vasodilatation, and endothelial cell proliferation were found in the tracheal and bronchial walls in the early and late phases of asthma. Vascular changes were observed not only in small vessels but also in larger vessels. In contrast to normal control, lung tissue from the asthma model showed dual expression for CD31 and von Willebrand factor in the endothelial cells and alpha-smooth muscle actin and desmin in the mural cells of the vessels, suggesting a phenotypic and functional transformation. The mRNA levels of VEGF isoforms, VEGF(164) and VEGF(188), were significantly increased in the tracheal and lung tissue, respectively. In addition, the mRNA level of VEGF receptor Flk-1 was significantly increased in the trachea. These results establish the existence of vascular remodeling in the airways in a mouse model of allergic asthma and support a key role for the expression of unique VEGF isoform genes as mediators of structural changes.
    Pathobiology 02/2008; 75(1):42-56. · 1.95 Impact Factor
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    ABSTRACT: beta-agonists are frequently used as bronchodilators for asthma as not only a reliever but also a controller, and their utility has increased with the development of long-acting beta(2) selective drugs. Although anti-inflammatory effects of beta(2) selective-agonists have been reported in vitro, side effects on augmentation of airway hyperresponsiveness by chronic use of beta(2) selective-agonists have been described in several reports. In this study, we investigated the effects of procaterol, a second-generation beta(2)-agonist, on airway inflammation in vivo using an antigen-specific murine model of asthma. Mice immunized with ovalbumin (OVA) + alum and challenged with inhaled ovalbumin were orally administered procaterol during the challenge. After inhalation, the mice were tracheostomized and placed in a body box under controlled ventilation to measure airway resistance before and after acetylcholine inhalation. Administration of procaterol at a clinical dose equivalent did not augment airway hyperresponsiveness, inflammation of the airway wall, or subsequent airway wall thickening induced by OVA inhalation. BALF cell analysis revealed that the eosinophil number in the BALF was significantly reduced in procaterol-treated mice compared to untreated mice. Oral administration of procaterol at a clinical dose did not augment airway responsiveness, but did reduce eosinophil inflammation.
    Allergology International 10/2007; 56(3):241-7.
  • Journal of Allergy and Clinical Immunology - J ALLERG CLIN IMMUNOL. 01/2007; 119(1).
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    ABSTRACT: The pathophysiological characteristics of bronchial asthma consist of chronic inflammation of airways, airway hyperresponsiveness, and bronchoconstriction. Studies have shown that T helper type 2 (Th2) cytokines produced by both T cells and mast cells in the airway contribute substantially to the initiation of inflammation in both experimental and human bronchial asthma. GATA-3 is a transcription factor essential to the production of Th2 cytokines by T lymphocytes. To clarify the role of GATA-3-expressing T cells in the pathophysiology of bronchial asthma, we utilized transgenic (Tg) mice carrying the GATA-3 gene and the ovalbumin (OVA)-specific T cell receptor gene (GATA-3-Tg/OVA-Tg). Mice were intranasally administrated OVA without systemic immunization. Airway responses were analyzed with noninvasive and invasive whole body plethysmographs. GATA-3-Tg/OVA-Tg mice exhibited significantly higher IL-13 and IL-4 protein expression in the airway. Although there were no differences in the types of infiltrating cells between GATA-3-Tg/OVA-Tg and GATA-3-non-Tg/OVA-Tg mice and no significant increase in IgE level in either group compared with nontreated mice, the response after ACh inhalation was significantly elevated in GATA-3-Tg/OVA-Tg on the seventh day of intranasal treatment with OVA. This hyperresponsiveness was inhibited by 5-lipoxygenase inhibitor and IL-13 neutralization, suggesting that airway responses were induced through IL-13 and leukotriene pathway. In conclusion, airway hyperresponsiveness, a characteristic of bronchial asthma, is regulated at the level of GATA-3 transcription by T lymphocytes in vivo.
    AJP Lung Cellular and Molecular Physiology 07/2006; 290(6):L1045-51. · 3.52 Impact Factor
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    ABSTRACT: Dendritic cells are the most powerful of the antigen-presenting cells and are known to play important roles in sensitization and inflammation in allergen-specific asthma. Various cytokines and chemokines are involved in the maturation and activation of dendritic cells. Among them is CC chemokine ligand (CCL)21, a key chemokine in the entry of naive T cells and antigen-stimulated dendritic cells into the T-cell zones of secondary lymphoid organs, which is a critical process in antigen-specific T-cell activation. We studied the role of CCL21 in airway inflammation in asthma by using BALB/c-plt/plt (plt) mice, which possess genetic defects in expression of both CCL21 and CCL19. Plt and control BALB/c mice were immunized with ovalbumin and alum 4 times and thereafter were subjected to a 2-week regimen of ovalbumin inhalation. In plt mice, ovalbumin-specific IgE response was delayed compared with control BALB/c mice, but they had the same level of response after final immunization. Although airway inflammation and response to acetylcholine were significantly reduced compared with BALB/c mice, significant eosinophilic inflammation and hyperresponsiveness were also observed in plt mice after 2 weeks of inhalation. Four weeks after cessation of inhalation, airway inflammation and hyperresponsiveness in plt mice were greater than in BALB/c mice. At the time of resolution of airway inflammation, IL-10 production was enhanced in BALB/c mice but not in plt mice. The chemokines CCL21 and CCL19 were critical for resolution of airway inflammation. The findings about the chemokines for induction and resolution of inflammation are key to establishing a new strategy for asthma immunotherapy.
    Journal of Allergy and Clinical Immunology 06/2006; 117(5):1040-6. · 12.05 Impact Factor
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    ABSTRACT: Airway structural changes (remodelling) in asthma include increased smooth muscle mass, mucus gland hypertrophy, deposition of extracellular matrix components, thickening of reticular basement membrane, and angiogenesis. The extent of remodelling correlates with severity of asthma, and since patients with extensive remodelling may be resistant to steroids therapy, prevention of airway remodelling is a promising therapeutic strategy for curing patients with severe asthma. Mast cells play a pivotal role in allergic inflammatory diseases including asthma and rhinitis. Both early-phase mediators such as tryptase and chymase and late-phase mediators such as cytokines released by mast cells are capable of modulating airway smooth muscle cell function and inducing goblet cell hyperplasia. Nasal remodelling in patients with rhinitis seems far less extensive than that which occurs in bronchi of asthmatic patients. Because cytokine production by smooth muscle cells may partly explain the differences in remodelling at these two sites, further investigation of the interaction between human mast cells and airway smooth muscle cells is required to identify new therapeutic strategies for reducing airway remodelling in asthma.
    Clinical & Experimental Allergy Reviews. 05/2006; 6(4):80 - 84.
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    ABSTRACT: The control of airway inflammation is crucial for management of asthma. Theophylline has been demonstrated to have an anti-inflammatory effect as a long-term-medication for asthma in various studies. In the present study we attempted to clarify if aminophylline, a theophylline derivative, could act as an anti-inflammatory agent as well as a bronchodilator in the treatment for acute asthma exacerbations. Patients are initially treated either with an intravenous infusion of aminophylline or with inhalation of salbutamol. Pro-inflammatory mediators such as eosinophil cationic protein (ECP), histamine, serotonin, thromboxane B2, leukotriene C4 were measured before and one hour after the initial treatment. Clinical parameters such as peak expiratory flow (PEF) and SpO2 were also checked during the studies. Significant improvements of PEF and SpO2 with both aminophylline and salbutamol treatment were seen. Furthermore, significant decreases of ECP, histamine, and serotonin were observed with aminophylline but not with salbutamol. Suppressing the release of pro-inflammatory mediators may play a role, at least in part, in the beneficial effects of aminophylline in the treatment of acute exacerbations in asthma. Additionally, this study indicated that treatment with aminophylline is at least as beneficial as nebulized salbutamol in the restoration of lung function.
    Respiratory Medicine 04/2006; 100(3):542-50. · 2.59 Impact Factor
  • Journal of Allergy and Clinical Immunology - J ALLERG CLIN IMMUNOL. 01/2006; 117(2).
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    ABSTRACT: A single nucleotide polymorphism (SNP) C-509T within the tumor growth factor beta1 (TGFbeta1) gene has been associated with atopic asthma and asthma severity. To further understand the mechanisms involved, the association of C-509T with allergy, T-lymphocyte proliferation and plasma TGFbeta1 concentration has been explored in a case-control study with allergic and non-allergic subjects. The recruited subjects including allergic (n = 38) and nonallergic (n = 25) participants have been genotyped for C-509T using allele discrimination assay. Association of C-509T with allergy status was examined using logistic regression analysis in both dominant and recessive models. Association of C-509T with T-cell proliferation in control and antigen-stimulated peripheral blood mononuclear cells (PBMCs), plasma TGFbeta1 and total IgE level were tested by multiple regression analysis. Results: Individuals with homozygous mutant TT genotype showed a higher risk of allergy (TT: odds ratio = 5.099, 95% confidence limit: 1.355-19.190, p = 0.016) after covariates were adjusted. A trend to increased plasma TGFbeta1 in subjects with T allele has been discovered. In the meantime, the T allele is associated with lower T cell proliferation in controls and maximum response to above antigens. A low T-cell proliferation is correlated with higher plasma TGFbeta1 concentration (p < 0.01). The in vitro studies confirmed the suppressing effect of TGFbeta1 on T-cell proliferation at physiological range. A significant inhibitory effect on IL-4 production was also observed. A C to T base change in TGFbeta1 SNP C-509T has been associated with a higher risk of allergy. The mechanisms are not clear. Elevated TGFbeta1 levels associated with the C-509T polymorphism might suppress immune activation as well as Th2 cytokine production.
    International Archives of Allergy and Immunology 10/2005; 138(2):151-60. · 2.25 Impact Factor

Publication Stats

1k Citations
243.89 Total Impact Points

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Institutions

  • 2005–2013
    • Musashino University
      Edo, Tōkyō, Japan
  • 2009
    • Kanazawa University
      • Graduate School of Natural Science and Technology
      Kanazawa-shi, Ishikawa-ken, Japan
  • 1999–2007
    • Teikyo University Hospital
      Edo, Tōkyō, Japan
    • Kyushu University
      • Faculty of Medical Sciences
      Fukuoka-shi, Fukuoka-ken, Japan
  • 2003
    • Teikyo University
      Edo, Tōkyō, Japan
  • 1993–1999
    • St. Marianna University School of Medicine
      • • Department of Immunology
      • • Department of Medicine
      • • Institute of Medical Science
      Kawasaki, Kanagawa-ken, Japan
  • 1987–1991
    • The University of Tokyo
      • Faculty & Graduate School of Medicine
      Tokyo, Tokyo-to, Japan