Tomomitsu Miyagaki

The University of Tokyo, Edo, Tōkyō, Japan

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Publications (51)179.48 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Atopic dermatitis (AD) is characterized by decreased expression of filaggrin and loricrin. AD patients 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 messenger RNA (mRNA) expression levels of filaggrin, loricrin, and antimicrobial peptides (AMPs) in skin samples of CTCL, using skin from healthy volunteers and patients with AD 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 compared to normal skin. CTCL lesional skin contained lower levels of filaggrin and loricrin mRNA than normal skin, which was also true with AD and psoriatic skin. mRNA expresion levels of filaggrin in CTCL skin negatively correlated with disease severity markers. Expression levels of AMPs in lesional skin of CTCL and AD were significanlty lower than in psoriatic skin. Immunohistochemistry confirmed decreased expression of filaggrin and loricrin in CTCL, AD, and psoriatic skin, and enhanced expression of S100 prioteins in psoriatic skin. Conclusions: Our results show that there is barrier dysfunction in CTCL skin, similar to what is seen with AD skin. In addition, low AMP expression in CTCL skin was documented when compared to psoriatic skin, which may explain frequent infections that can occur in CTCL patients.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 06/2014;
  • Clinical and Experimental Dermatology 04/2014; · 1.33 Impact Factor
  • International journal of dermatology 02/2014; 53(2):e82-4. · 1.18 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. · 1.77 Impact Factor
  • Source
    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. · 1.77 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; · 6.19 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; · 4.60 Impact Factor
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    ABSTRACT: Visfatin, a novel adipocytokine, is related with chronic inflammatory diseases, especially those characterized by T helper (Th)1-type immune responses. In this study, we examined serum visfatin levels in patients with atopic dermatitis (AD) or cutaneous T-cell lymphoma (CTCL), both of which are Th2-dominant diseases. Serum visfatin levels in patients with AD or advanced stage CTCL were significantly elevated compared to healthy controls. In CTCL patients, serum visfatin levels significantly decreased after treatment. Serum visfatin levels correlated with eosinophil counts in AD patients, whereas they correlated with the visual analogue scale itch scores and serum C-C motif ligand (CCL) 11 and CCL26 levels in CTCL patients. Visfatin expression by adipose tissue in lesional skin of AD and advanced stage CTCL was enhanced compared to that of healthy controls. These results suggest that visfatin may also be important in the development of Th2-dominant diseases as well as in Th1-type diseases.
    European journal of dermatology : EJD. 09/2013;
  • International journal of dermatology 09/2013; 52(9):1147-9. · 1.18 Impact Factor
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    ABSTRACT: Angiogenesis is a crucial process in the growth and progression of cancer, correlating with the metastatic potential of tumour cells. Angiopoietins are ligands for the endothelium-specific tyrosine kinase Tie2 receptor, which comprise 4 structurally related proteins, termed angiopoietin (Ang)-1, Ang-2, Ang-3 and Ang-4. The roles of Ang-1 and Ang-2 have recently been clarified as crucial in angiogenesis. In this report, we measured serum Ang-1 and Ang-2 levels in patients with cutaneous T-cell lymphoma (CTCL). Serum levels of Ang-2, but not Ang-1, in patients with Sézary syndrome were significantly higher than those in patch mycosis fungoides (MF), plaque/tumour MF, and healthy controls. In patients with CTCL, serum Ang-2 correlated with disease activity. Moreover, the numbers of Ang-2+ cells in lesional skin of CTCL were significantly larger than those in normal skin. These results suggest that Ang-2 may have important roles in the development of CTCL.
    Acta Dermato-Venereologica 07/2013;
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    ABSTRACT: Sensitization and challenge using dinitrofluorobenzene (DNFB) induce contact hypersensitivity (CHS) with Th1 cell infiltration, whereas those using FITC generate CHS with Th2 cell infiltration. In this study, we attempted to determine the role of CXCR3, a chemokine receptor, in Th1- and Th2-type CHS induced by DNFB or FITC using CXCR3-deficient (CXCR3(-/-)) mice. Ear swelling was prolonged after DNFB challenge in CXCR3(-/-) mice, which was accompanied by increased Th1 cytokines and decreased TGF-β and IL-10 expression at a late time point of CHS, whereas there was no significant difference between wild-type and CXCR3(-/-) mice in FITC-induced CHS. In Th1-type CHS, the number of regulatory T cells (Tregs) was decreased in the challenged ear of CXCR3(-/-) mice compared with that of wild-type mice, suggesting that CXCR3 would be important in migration of Tregs into the site of inflammation. Moreover, we examined the characteristics of CXCR3(+) Tregs both in vitro and in vivo, revealing that CXCR3(+) Tregs expressed high levels of TGF-β and IL-10 as well as IFN-γ compared with CXCR3(-) Tregs. When CXCR3(-/-) mice were injected with CXCR3(+) Tregs, the prolonged ear swelling induced by DNFB was normalized. Taken together, our results suggest that CXCR3(+) Tregs play a key role for quenching Th1-type CHS.
    The Journal of Immunology 05/2013; · 5.52 Impact Factor
  • International journal of dermatology 03/2013; · 1.18 Impact Factor
  • Journal of Dermatological Science. 02/2013; 69(2):e21.
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    ABSTRACT: A 68-year-old Japanese woman was referred to our hospital with a 1-year history of multiple erosions on the oral mucosa and a few pruritic, bean-sized, reddish-blue plaques on the body. Based on physical examination, pathological findings, and immunofluorescence findings, a diagnosis of lichen planus (LP) was made. Computed tomography scan revealed a thymoma. After thymectomy, cutaneous LP lesions subsided spontaneously. Oral lesions responded well to oral etretinate therapy. We speculate that direct tissue injury by CD8(+) T cells, activated by abnormal regulation of lymphocytes within the thymus, may cause LP.
    Australasian Journal of Dermatology 02/2013; 54(1):e25-7. · 0.97 Impact Factor
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    ABSTRACT: Abstract is missing (Letter).
    Acta Dermato-Venereologica 01/2013;
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    ABSTRACT: Cutaneous involvement is frequent in adult T-cell leukaemia/lymphoma (ATLL), a peripheral T-cell neoplasm caused by human T-cell lymphotropic virus type I (HTLV-I). Patients with ATLL manifest different types of skin lesions, including nodules, plaques, ulcers, erythroderma and purpura. It has been reported that this type of skin eruption is an independent prognostic factor for ATLL. We report here a rare case of a 62-year-old Japanese woman with smouldering-type ATLL, first manifested by lichen planus-like skin lesions on the lower leg. This case report highlights the multiplicity of skin manifestations in ATLL.
    Acta Dermato-Venereologica 12/2012;
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    ABSTRACT: B cells regulate immune responses by producing antigen-specific antibodies. However, specific B-cell subsets can also negatively regulate T-cell immune responses, and have been termed regulatory B cells. Human and mouse regulatory B cells (B10 cells) with the ability to express the inhibitory cytokine interleukin-10 (IL-10) have been identified. Although rare, B10 cells are potent negative regulators of antigen-specific inflammation and T-cell-dependent autoimmune diseases in mice. How B10-cell IL-10 production and regulation of antigen-specific immune responses are controlled in vivo without inducing systemic immunosuppression is unknown. Using a mouse model for multiple sclerosis, here we show that B10-cell maturation into functional IL-10-secreting effector cells that inhibit in vivo autoimmune disease requires IL-21 and CD40-dependent cognate interactions with T cells. Moreover, the ex vivo provision of CD40 and IL-21 receptor signals can drive B10-cell development and expansion by four-million-fold, and generate B10 effector cells producing IL-10 that markedly inhibit disease symptoms when transferred into mice with established autoimmune disease. The ex vivo expansion and reinfusion of autologous B10 cells may provide a novel and effective in vivo treatment for severe autoimmune diseases that are resistant to current therapies.
    Nature 10/2012; · 38.60 Impact Factor
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    ABSTRACT: Many patients with cutaneous T-cell lymphoma (CTCL) experience severe pruritus. This study evaluated serum levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in patients with CTCL. Although serum NGF and BDNF levels in patients with CTCL were not significantly higher than in healthy controls, serum NGF levels in patients with Sézary syndrome were higher than in those with mycosis fungoides and in healthy controls. Enhanced NGF expression by keratinocytes and increased dermal nerve fibres were detected in lesional skin of subjects with Sézary syndrome. Correlations between pruritus in CTCL and serum levels of NGF, BDNF, chemokine (C-C motif) ligand 1 (CCL1), CCL17, CCL26, CCL27, lactate dehydrogenase (LDH), IgE, and soluble interleukin-2 receptor were analysed. Serum CCL1, CCL26, LDH, and IgE levels correlated with pruritus in patients with CTCL. NGF may be associated with increased dermal nerve fibres and pruritus in Sézary syndrome, and CCL1, CCL26, and IgE may be associated with pruritus in CTCL.
    Acta Dermato-Venereologica 09/2012;
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    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract is missing (Letter).
    Acta Dermato-Venereologica 08/2012;
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    ABSTRACT: Classically activated macrophages produce IL-12, IL-23, and TNF-α, whereas alternatively activated macrophages (M2 cells) produce IL-10 and express several receptors such as mannose receptor and CD163. Tumor-associated macrophages exhibit M2 phenotype, whose presence has been associated with poor prognosis in various tumors. To investigate distribution of CD163(+) cells in lesional skin and serum levels of soluble CD163 (sCD163) in patients with cutaneous T cell lymphoma (CTCL), atopic dermatitis (AD), or psoriasis. The numbers of CD163(+) and CD68(+) cells in lesional skin of CTCL, AD, or psoriasis, and in normal skin were examined by immunohistochemistry. Serum soluble CD163 (sCD163) levels were quantified by enzyme-linked immunosorbent assay. The numbers of CD163(+) cells in lesional skin of CTCL, AD, or psoriasis were significantly larger than in normal skin. In CTCL, the numbers of CD163(+) or CD68(+) cells increased as more tumor cells infiltrated and they decreased after treatment with topical steroid and ultraviolet light. Moreover, CTCL patients with an increased number of CD163(+) cells showed worse prognosis. Serum sCD163 levels in patients with CTCL, AD, or psoriasis were significantly higher than those in normal controls. In CTCL patients, serum sCD163 levels significantly correlated with serum soluble interleukin-2 receptor and CCL17 levels. In AD patients, serum sCD163 levels correlated with serum IgE levels. The numbers of CD163(+) cells in lesional skin and serum sCD163 levels were associated with disease progression of CTCL. Further study focusing on CD163(+) cells in CTCL lesional skin would be an interesting research field.
    Journal of dermatological science 07/2012; 68(1):45-51. · 3.71 Impact Factor

Publication Stats

203 Citations
179.48 Total Impact Points

Institutions

  • 2008–2014
    • The University of Tokyo
      • • Department of Dermatology and Photolaser Medicine
      • • Department of Surgical Sciences
      Edo, Tōkyō, Japan
  • 2012
    • National Center for Global Health and Medicine in Japan
      • Dermatology Division
      Edo, Tōkyō, Japan