Tomomitsu Miyagaki

The University of Tokyo, Tōkyō, Japan

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Publications (64)267.18 Total impact

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    ABSTRACT: Background: Endothelial protein C receptor (EPCR) predominantly expressed on endothelial cells plays a critical role in the regulation of coagulation system and also mediates various cytoprotective effects by binding and activating protein C. So far, the role of EPCR has not been studied in systemic sclerosis (SSc). Objectives: To investigate the potential contribution of EPCR to the development of SSc. Methods: EPCR expression was examined in skin samples and cultivated dermal microvascular endothelial cells by immunostaining, immunoblotting, and/or quantitative reverse transcription PCR. Fli1 binding to the EPCR promoter was assessed by chromatin immunoprecipitation. Serum EPCR levels were determined by enzyme-linked immunosorbent assay in 65 SSc and 20 healthy subjects. Results: EPCR expression was decreased in dermal small vessels of SSc lesional skin compared with those of healthy control skin. Transcription factor Fli1, whose deficiency is implicated in SSc vasculopathy, occupied the EPCR promoter and EPCR expression was suppressed in Fli1 siRNA-treated endothelial cells and dermal small vessels of Fli1(+/-) mice. In SSc patients, decreased serum EPCR levels were associated with diffuse skin involvement, interstitial lung disease and digital ulcers. Furthermore, serum EPCR levels inversely correlated with plasma levels of plasmin-α2-plasmin inhibitor complex (PIC). Importantly, bosentan significantly reversed circulating EPCR and PIC levels in SSc patients and the expression of Fli1 and EPCR in dermal small vessels was elevated in patients treated with bosentan compared to untreated patients. Conclusions: Endothelial EPCR down-regulation due to Fli1 deficiency may contribute to hyper-coagulation status leading to tissue fibrosis and impaired peripheral circulation in SSc. This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 09/2015; DOI:10.1111/bjd.14183 · 4.28 Impact Factor
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    ABSTRACT: Undermined pressure ulcers (PUs) are troublesome complications that are likely to delay wound healing. Early skin incision and debridement can prevent the deterioration of undermined PUs, thus it is necessary to identify devitalised tissue areas to determine the appropriate timing for such interventions. This retrospective cohort study evaluated whether a lower temperature at the wound edge than the wound bed and periwound skin, detected by thermography, can predict undermining development in PUs 1 week after the assessment. Twenty-two participants with category III, IV, or unstageable PUs who were examined by interdisciplinary PU team and were followed up for at least two consecutive weeks were analysed. We found 9/11 PUs without a lower temperature at the wound edge did not develop undermining development, whereas 8/11 PUs with the lower temperature did develop undermining. The relative risk of undermining development after 1 week in PUs with the lower temperature was 4·00 (95% confidence intervals: 1·08-14·7). The sensitivity, specificity, positive predictive value and negative predictive value were 0·80, 0·75, 0·73 and 0·81, respectively. A thermal imaging assessment focusing on a lower temperature pattern at the wound edge may provide sufficient information to predict undermining development. © 2015 Inc and John Wiley & Sons Ltd.
    International Wound Journal 07/2015; DOI:10.1111/iwj.12454 · 2.15 Impact Factor
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    ABSTRACT: We report a 39-year-old man referred to our facility with linear sclerotic lesions along the several Blaschko's lines of the scalp. A year before the referral, he had had an episode of brain hemorrhage, although there was no evidence of vascular malformation or any other risk factors of brain hemorrhage for his young age. On the diagnosis of scleroderma en coup de sabre, prednisolone intake was initiated, and the skin lesions were well controlled. However, in the course of our follow up, he had another episode of brain hemorrhage, again without any evidence of cerebral vascular abnormalities. Organic intracranial abnormalities in this disease are well-documented, but there have been few reports on comorbid recurrent brain hemorrhages. We herein discuss the possible relationship of the skin lesions with the brain hemorrhages in our case, taking notice of the implication of developmental abnormalities behind these apparently independent phenomena inside and outside the cranium. © 2015 Japanese Dermatological Association.
    The Journal of Dermatology 07/2015; DOI:10.1111/1346-8138.13023 · 2.25 Impact Factor
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    ABSTRACT: Interleukin (IL)-33 is a recently identified cytokine, which is a member of the IL-1 family and binds to a heterodimeric receptor comprising ST2 (suppression of tumorigenicity 2) and IL-1 receptor accessory protein. Serum levels of IL-33 have been reported to be upregulated in various T helper (Th)1/Th17-mediated diseases, such as rheumatoid arthritis and inflammatory bowel disease. IL-33 expression is increased in lesional skin in patients with psoriasis, but serum levels in patients with psoriasis have not yet been studied. To study serum IL-33 levels in patients with psoriasis, a Th1/Th17-mediated skin disease, before and after anti-tumour necrosis factor (TNF)-α therapy. Serum IL-33 levels were measured in patients with psoriasis vulgaris (PV), psoriatic arthritis (PsA) or pustular psoriasis (PP), and compared with those of healthy controls. Associations between serum IL-33 levels and serum TNF-α, IL-6, vascular endothelial growth factor and C-reactive protein levels were also studied. In addition, the effect of IL-33 stimulation on IL-6, IL-8, TNF-α and VEGF secretion by human keratinocyte was analysed. Serum IL-33 levels in patients with PV, PsA and PP were significantly higher than those in healthy controls. Serum IL-33 levels correlated with serum TNF-α levels in patients with psoriasis, and decreased after anti-TNF-α therapy. IL-33 stimulated IL-6 and IL-8 secretion by human keratinocytes. These results suggest that serum IL-33 levels generally reflect increased inflammation in patients with psoriasis. © 2015 British Association of Dermatologists.
    Clinical and Experimental Dermatology 05/2015; DOI:10.1111/ced.12670 · 1.09 Impact Factor
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    ABSTRACT: Cutaneous apocrine carcinoma (CAC) is a rare malignancy. It develops predominantly in the regions where apocrine glands are distributed. Some cases of CAC have been reported in the axilla and the inguinal regions, but only a few in the scrotum. We herein report a case of CAC which widely spread over both sides of the whole scrotum with plate-like hard induration, and such a manifestation has never been reported before. CAC is known to have high rates of local recurrence or metastasis, and the efficacy of radiotherapy or chemotherapy has not been established. As therapeutic options for CAC are limited, it is critical to reach the diagnosis and treat at an early stage. © 2015 Japanese Dermatological Association.
    The Journal of Dermatology 05/2015; 42(8). DOI:10.1111/1346-8138.12914 · 2.25 Impact Factor
  • Tomomitsu Miyagaki · Manabu Fujimoto · Shinichi Sato
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    ABSTRACT: B cells have been generally considered to be positive regulators of immune responses because of their ability to produce antigen-specific antibodies and to activate T cells through antigen presentation. Impairment of B cell development and function may cause inflammatory and autoimmune diseases. Recently, specific B cell subsets that can negatively regulate immune responses have been described in mouse models of a wide variety of inflammatory and autoimmune diseases. The concept of those B cells, termed regulatory B cells, is now recognized as important in the murine immune system. Among several regulatory B cell subsets, IL-10-producing regulatory B cells are the most widely investigated. On the basis of discoveries from studies of such mice, human regulatory B cells that produce IL-10 in most cases are becoming an active area of research. There have been emerging data suggesting the importance of human regulatory B cells in various diseases. Revealing the immune regulation mechanisms of human regulatory B cells in human inflammatory and autoimmune diseases could lead to the development of novel B cell targeted therapies. This review highlights the current knowledge on regulatory B cells, mainly IL-10-producing regulatory B cells, in animal models of inflammatory and autoimmune diseases and in clinical research using human samples. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail:
    International Immunology 05/2015; DOI:10.1093/intimm/dxv026 · 2.54 Impact Factor
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    ABSTRACT: Galectin-9 is a member of the galectin family that has a wide spectrum of biological functions. Among them, galectin-9 has been known mainly as a potent chemoattractant for eosinophils. In addition, galectin-9 alters the T-cell balance by negatively regulating T-helper (Th)1 and Th17 cells, resulting in Th2 polarization. Atopic dermatitis (AD) is a skin allergic disease characterized by peripheral eosinophilia, mast cell activation and predominance of Th2 cells. To investigate possible roles of galectin-9 in AD, we measured serum galectin-9 levels in AD patients and investigated galectin-9 expression in lesional skin by immunohistochemistry. Serum galectin-9 levels in patients with AD were significantly higher than those in healthy controls and correlated with the Eczema Area and Severity Index. Serum galectin-9 levels were decreased after treatment, accompanied by improvement of skin lesions. Immunohistochemical study revealed that galectin-9 was expressed on epidermal keratinocytes and mast cells in lesional skin of AD. Our results suggest that elevated galectin-9 expression is associated with progression of AD and that galectin-9 could be a therapeutic target in AD. © 2015 Japanese Dermatological Association.
    The Journal of Dermatology 04/2015; 42(7). DOI:10.1111/1346-8138.12884 · 2.25 Impact Factor
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    ABSTRACT: CCR4 is expressed on tumor cells of mycosis fungoides (MF) and Sézary syndrome (SS). In MF, most infiltrating cells in patches and plaques express CXCR3, while tumor cells express CCR4 in advanced stages. Poteligeo Test IHC (CCR4 staining kit) is a newly developed staining kit that can examine the presence of CCR4 expressed on tumor cells of adult T-cell leukemia/lymphoma, peripheral T-cell lymphoma and cutaneous T-cell lymphoma before treatment of anti-CCR4 antibody using paraffin-embedded samples. In this study, we analyzed CCR4 expression in lesional skin of MF, SS, atopic dermatitis (AD) and psoriasis with this new kit. CCR4 was expressed on infiltrating cells in lesional skin of patch, plaque, tumor MF and SS, and the number of positive cells increased as the disease progressed. Immunohistochemistry with frozen sections also showed some positive cells scattered in the dermis, although the quality was not high enough to quantify positive cells. There were significant positive correlations between CCR4(+) cells and serum lactate dehydrogenase levels. Interestingly, CCR4(+) cells were also detected in AD skin, whose number was larger than that in psoriatic skin. Previous studies showed only scattered CCR4(+) cells in skin samples by standard immunohistochemical staining. The new, sensitive CCR4 staining kit has revealed that CCR4 is expressed on infiltrating cells in lesional skin of early MF and AD as well as advanced MF and SS. These cells can be therapeutic targets for patients who are resistant to standard treatments. © 2015 Japanese Dermatological Association.
    The Journal of Dermatology 03/2015; 42(6). DOI:10.1111/1346-8138.12852 · 2.25 Impact Factor
  • Tomomitsu Miyagaki · Makoto Sugaya
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    ABSTRACT: Atopic dermatitis (AD) and psoriasis are common inflammatory skin diseases. Although clinical pictures of these two diseases are quite different, they share some common pathological backgrounds such as barrier dysfunction and enhanced IL-22 expression. To explain the clinical differences of the diseases, it has been proposed that Th2/Th22-polarized immune status together with an attenuated Th17 axis may cause insufficient induction of antimicrobial peptides and more severe barrier dysfunction in AD. While skin barrier dysfunction is commonly seen in AD and psoriasis, a Th2-dominant cytokine milieu down-regulates immunity against infections, which are commonly seen in lesional skin of AD. In the era of biologics, increase in the understanding or new discoveries of molecules involved in the development of various diseases will instantly lead to a new therapeutic strategy. In this review, we give an overview of recent advances in AD and psoriasis, especially on genetic background, barrier function, and therapeutic targets. Copyright © 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
    Journal of Dermatological Science 02/2015; 78(2). DOI:10.1016/j.jdermsci.2015.02.010 · 3.42 Impact Factor
  • T Miyagaki · M Sugaya · T Oka · H Fujita · S Sato
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    ABSTRACT: Vorinostat is the first histone deacetylase inhibitor approved for cutaneous T cell lymphoma (CTCL).(1) Although in vitro effects of this drug on various types of cells have been studied,(2-5) little is known about how this drug has clinical effects on CTCL patients. As many chemokines are reported to reflect disease activity of CTCL, suggesting their important roles in disease progression,(6) we investigated variation of serum chemokine levels during oral vorinostat therapy in a Sézary syndrome (SS) patient. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 02/2015; 173(2). DOI:10.1111/bjd.13696 · 4.28 Impact Factor
  • The Journal of Dermatology 11/2014; 41(12). DOI:10.1111/1346-8138.12688 · 2.25 Impact Factor
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    ABSTRACT: Early cutaneous T cell lymphoma clinically and histologically resembles benign inflammatory skin diseases, which sometimes makes it difficult to reach a correct diagnosis. It is recently reported that thymocyte selection-associated high mobility group box factor (TOX) serves as a molecular marker for histological diagnosis of early-stage mycosis fungoides (MF). To examine whether TOX could be a marker of tumour cells in different types of cutaneous lymphoma, we investigated immunohistochemical staining for TOX with the lesional skin of patch, plaque, and tumour MF, Sézary syndrome (SS), lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (PCALCL), adult T cell leukemia/lymphoma (ATLL), peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), atopic dermatitis (AD), and normal skin. TOX and CCR4 messenger RNA (mRNA) levels in lesional skin of MF/SS were also examined. Immunohistological staining showed that a high specific nuclear staining of TOX was observed at a high frequency in MF, SS, and PTCL, NOS. Tumour cells in LyP, PCALCL, and ATLL showed a slightly dim nuclear staining of TOX. TOX(+) cells in MF and LyP expressed surface molecules characteristics of tumour cells in these diseases. Lesional skin of SS expressed higher levels of TOX mRNA, compared to normal skin or MF lesional skin. Moreover, TOX expression significantly correlated with CCR4 expression. TOX may be a specific marker for tumour cells in some types of cutaneous lymphoma.
    Archives for Dermatological Research 09/2014; 306(9). DOI:10.1007/s00403-014-1501-7 · 1.90 Impact Factor
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    ABSTRACT: Dear Editor,Paraneoplastic pemphigus (PNP) is a rare autoimmune mucocutaneous disorder which is predominantly associated with lymphoproliferative disorders including non-Hodgkin lymphoma, B-chronic lymphocytic leukemia, Castleman disease, and Waldenström macroglobulinemia [1]. PNP is characterized by painful mucosal erosion with frequent skin eruption, histological changes of acantholysis or lichenoid/interface dermatitis, and serum autoantibodies against plakin family proteins [2, 3]. Although the cause of PNP is not identified in most cases, previous literatures have indicated that PNP may be triggered by specific treatment modalities for lymphoid neoplasms. Patients with lymphoid malignancies were recurrently affected by PNP within several cycles of fludarabine-containing therapy [4–7] or after local radiotherapy [8–10]. Here, we describe the first case of PNP occurring after bendamustine and rituximab therapy for follicular lymphoma.A 77-year-old Japanese woman was diagnosed with f ...
    Annals of Hematology 09/2014; 94(4). DOI:10.1007/s00277-014-2202-1 · 2.63 Impact Factor
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    ABSTRACT: Purpose: Atopic dermatitis is characterized by decreased expression of filaggrin and loricrin. Patients with atopic dermatitis often suffer from skin infections, which are also frequently seen in patients with cutaneous T-cell lymphoma (CTCL). In this study, we aimed to investigate the skin barrier in CTCL. Experimental design: We assessed skin moisture and transepidermal water loss (TEWL) in patients with CTCL. We next examined mRNA expression levels of filaggrin, loricrin, and antimicrobial peptides (AMP) in skin samples of CTCL, using skin from healthy volunteers and patients with atopic dermatitis or psoriasis as controls. Immunostainings for filaggrin, loricrin, and S100 proteins were also performed. Results: Lower levels of skin moisture accompanied by higher levels of TEWL were seen in lesional skin of CTCL than in normal skin. CTCL lesional skin contained lower levels of filaggrin and loricrin mRNA than normal skin, which was also true with atopic dermatitis and psoriatic skin. mRNA expression levels of filaggrin in CTCL skin negatively correlated with disease severity markers. Expression levels of AMPs in lesional skin of CTCL and atopic dermatitis were significantly lower than in psoriatic skin. Immunohistochemistry confirmed decreased expression of filaggrin and loricrin in CTCL, atopic dermatitis, and psoriatic skin and enhanced expression of S100 proteins in psoriatic skin. Conclusions: Our results show that there is barrier dysfunction in CTCL skin, similar to what is seen with atopic dermatitis skin. In addition, low AMP expression in CTCL skin was documented when compared with psoriatic skin, which may explain frequent infections that can occur in patients with CTCL.
    Clinical Cancer Research 06/2014; 20(16). DOI:10.1158/1078-0432.CCR-14-0077 · 8.72 Impact Factor
  • M. Sugaya · H. Suga · T. Miyagaki · H. Fujita · S. Sato
    Clinical and Experimental Dermatology 04/2014; 39(4). DOI:10.1111/ced.12315 · 1.09 Impact Factor
  • International journal of dermatology 02/2014; 53(2):e82-4. DOI:10.1111/j.1365-4632.2012.05494.x · 1.31 Impact Factor
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    Tomomitsu Miyagaki · Makoto Sugaya
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    ABSTRACT: Tumor genesis and development are driven by a combination of intrinsic events such as oncogene activation and tumor-suppressor gene inactivation, and extrinsic events that are dependent on the interaction with the stroma. Different types of growth factors, cytokines and chemokines secreted by the surrounding stromal cells are thought to play key roles in solid tumor progression. Accumulating evidence indicates that the immunological milieu plays an essential role in tumor development, not only in solid tumors, but also in hematopoietic malignancies. Understanding the interactions between tumor cells and microenvironment in mycosis fungoides (MF) and Sézary syndrome (SS) could provide a basis for the development of new treatments for these diseases that are sometimes resistant to current therapies. This article focuses on the wide variety of cell types and immunological milieus, affecting the characteristic features of MF and SS, such as skin-homing of tumor cells, T-helper type 2-dominant tumor microenvironment, accumulation of dermal dendritic cells, epidermal hyperplasia, angiogenesis and pruritus.
    The Journal of Dermatology 01/2014; 41(1):11-8. DOI:10.1111/1346-8138.12305 · 2.25 Impact Factor
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    ABSTRACT: Depsipeptide (FK228), a histone deacetylase inhibitor, was recently approved for use in cutaneous T-cell lymphoma. Roxithromycin (RXM) is a macrolide antibiotic that can induce apoptosis of some T-cell lines. In this study, we investigated whether combination of FK228 and RXM had a synergistic inhibitory effect on cell survival of various lymphoma cells and which signaling pathway was affected by the drugs in the presence or absence of chemokines, which were reported to inhibit apoptosis of some tumor cells. FK228 and RXM additively decreased the number of HUT-78, Ki-JK and EL-4 lymphoma cells at doses over 50 nmol/L and 50 μmol/L, respectively. These drugs inhibited phosphorylation of Akt and extracellular signal-regulated kinase (ERK) of EL-4 cells in a dose-dependent manner. Significant association between ERK phosphorylation and cell number or annexin V(+) cells suggested that the ERK pathway may be critical for survival of EL-4 cells. Combination of 10 or 50 nmol/L of FK228 and 10 μmol/L of RXM decreased cell number of HUT78 and EL-4 compared to a single use of each drug. Our in vitro study suggested that combination of FK228 and RXM may be helpful for enhancing tumor killing effects. Although further study is necessary, this combination may be applicable to patients with cutaneous T-cell lymphoma in the future.
    The Journal of Dermatology 01/2014; 41(1):57-62. DOI:10.1111/1346-8138.12351 · 2.25 Impact Factor
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    ABSTRACT: IL-32 is a pro-inflammatory cytokine expressed by activated natural killer cells, T cells, keratinocytes, and fibroblasts. In this study, we examined the role of IL-32 in cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS). IL-32 mRNA expression levels in lesional skin of MF patch, plaque, and tumor were increased compared to those of normal skin, which positively correlated with CCL17 and CCL18 mRNA expression levels. Serum IL-32 levels positively correlated with disease activity within each patient. Immunostaining showed that keratinocytes expressed IL-32 in lesional skin of MF patch and plaque, while in MF tumor, atypical T cells in the dermis strongly expressed IL-32. We also showed that IL-32 dose-dependently accelerated proliferation of MF and SS cell lines in vitro, which was inhibited by blocking mitogen-activated protein kinase and NF-κB-mediated signaling. Addition of anti-IL-32 antibodies in culture decreased proliferation of SS cells and viability of MF cells, suggesting that IL-32 serves as an autocrine growth factor. In conclusion, our results suggest that IL-32 plays a role in formation and maintenance of CTCL lesions, providing a possible therapeutic target for patients with this disease.Journal of Investigative Dermatology accepted article preview online, 13 November 2013. doi:10.1038/jid.2013.488.
    Journal of Investigative Dermatology 11/2013; 134(5). DOI:10.1038/jid.2013.488 · 7.22 Impact Factor
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    ABSTRACT: Propionibacterium acnes has been implicated as one of the suggested causative antigens for sarcoidosis, a systemic granulomatous disease. By injecting heat-killed P. acnes into the dorsal skin of C57BL/6J mice on days 1, 3, 5, and 14, sarcoid-like granulomatosis was induced in skin and lungs of these mice on day 28. To clarify the role of cell adhesion molecules in cutaneous sarcoidosis, we induced sarcoid-like granulomatosis in mice deficient of intercellular adhesion molecule (ICAM)-1, L-selectin, P-selectin, or E-selectin via repeated P. acnes injection. Histopathologic analysis revealed that granuloma formation was aggravated in the skin and lungs of ICAM-1-deficient mice compared with wild-type mice. Within skin granulomas of ICAM-1-deficient mice, P. acnes immunization up-regulated mRNA expression of tumor necrosis factor-α, although it failed to induce IL-10 mRNA expression in contrast to wild-type mice. Infiltration of regulatory T cells into skin granuloma was similar between wild-type mice and ICAM-1-deficient mice. P. acnes immunization induced IL-10 production by CD4(+)CD25(+)Foxp3(+) regulatory T cells in lymph nodes of wild-type mice in vivo, which was absent in regulatory T cells of ICAM-1-deficient mice. Our results indicate that ICAM-1 is imperative for inducing regulatory T cells to produce IL-10 in vivo, which would prevent granuloma formation.
    American Journal Of Pathology 10/2013; 183(6). DOI:10.1016/j.ajpath.2013.08.021 · 4.59 Impact Factor

Publication Stats

398 Citations
267.18 Total Impact Points


  • 2008–2015
    • The University of Tokyo
      • Department of Surgical Sciences
      Tōkyō, Japan
  • 2012
    • Duke University Medical Center
      • Department of Immunology
      Durham, North Carolina, United States
  • 2011
    • National Center for Global Health and Medicine in Japan
      Edo, Tōkyō, Japan
  • 2010
    • Tokyo University and Graduate School of Social Welfare
      Edo, Tōkyō, Japan