Updated on 2025/08/22

写真a

 
KAMEKURA Ryuta
 
Organization
School of Medicine Department of Otolaryngology Lecturer
Title
Lecturer
External link

Degree

  • 医学博士 ( 札幌医科大学 )

Research Interests

  • epithelial cells

  • 鼻咽腔粘膜上皮バリア機能

  • タイト結合

  • epimmunome

Research Areas

  • Life Science / Otorhinolaryngology

  • Life Science / Immunology

Papers

  • Interleukin 9 mediates T follicular helper cell activation to promote antibody responses

    Taiki Sato, Ippei Ikegami, Masahiro Yanagi, Takeshi Ohyu, Taiki Sugaya, Shotaro Shirato, Masanobu Tanemoto, Shiori Kamiya, Kohei Kikuchi, Yuka Kamada, Takehito Nakata, Ryuta Kamekura, Akinori Sato, Ken-ichi Takano, Masahiro Miyajima, Atsushi Watanabe, Shingo Ichimiya

    Frontiers in Immunology   15   2024.9

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    Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

    Antigen-specific humoral responses are orchestrated through complex interactions among immune cells in lymphoid tissues, including the collaboration between B cells and T follicular helper (Tfh) cells. Accumulating evidence indicates a crucial role for interleukin-9 (IL-9) in the formation of germinal centers (GCs), enhancing the generation of class-switched high-affinity antibodies. However, the exact function of IL-9 in Tfh cell regulation remains unclear. In this study, we examined the humoral immune responses of CD4<sup>Cre/+</sup>Il9ra<sup>fl/fl</sup> mice, which lack an IL-9-specific receptor in Tfh cells. Upon intraperitoneal immunization with sheep red blood cells (SRBCs), CD4<sup>Cre/+</sup>Il9ra<sup>fl/fl</sup> mice displayed diminished levels of SRBC-specific IgG antibodies in their sera, along with reduced levels of GC B cells and plasma cells. Notably, Il9ra-deficient Tfh cells in the spleen exhibited decreased expression of their signature molecules such as B-cell lymphoma 6, C-X-C chemokine receptor 5, IL-4, and IL-21 compared to control mice. In models of allergic asthma induced by house dust mite (HDM) inhalation, CD4<sup>Cre/+</sup>Il9ra<sup>fl/fl</sup> mice failed to elevate serum levels of HDM-specific IgE and IgG. This was accompanied by reductions in Tfh cells, GC B cells, and plasma cells in mediastinal lymph nodes. Furthermore, group 2 innate lymphoid cells (ILC2s) were identified as producers of IL-9 under immunizing conditions, possibly induced by leukotrienes released by activated IgD<sup>+</sup> B cells around the T-B border. These observations may indicate the critical role of IL-9 receptor signaling in the activation of Tfh cells, with ILC2s potentially capable of supplying IL-9 in organized lymphoid tissues.

    DOI： 10.3389/fimmu.2024.1441407

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  • Bob1 maintains T follicular helper cells for long-term humoral immunity. International journal

    Masahiro Yanagi, Ippei Ikegami, Ryuta Kamekura, Tatsuya Sato, Taiki Sato, Shiori Kamiya, Kosuke Murayama, Sumito Jitsukawa, Fumie Ito, Akira Yorozu, Miho Kihara, Takaya Abe, Hiromi Takaki, Koji Kawata, Katsunori Shigehara, Satsuki Miyajima, Hirotaka Nishikiori, Akinori Sato, Noritsugu Tohse, Ken-Ichi Takano, Hirofumi Chiba, Shingo Ichimiya

    Communications biology   7 ( 1 )   185 - 185   2024.2

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    Language：English   Publishing type：Research paper (scientific journal)  

    Humoral immunity is vital for host protection, yet aberrant antibody responses can trigger harmful inflammation and immune-related disorders. T follicular helper (Tfh) cells, central to humoral immunity, have garnered significant attention for unraveling immune mechanisms. This study shows the role of B-cell Oct-binding protein 1 (Bob1), a transcriptional coactivator, in Tfh cell regulation. Our investigation, utilizing conditional Bob1-deficient mice, suggests that Bob1 plays a critical role in modulating inducible T-cell costimulator expression and cellular respiration in Tfh cells. This regulation maintains the long-term functionality of Tfh cells, enabling their reactivation from central memory T cells to produce antibodies during recall responses. In a bronchial asthma model induced by house dust mite (HDM) inhalation, Bob1 is observed to enhance HDM-specific antibodies, including IgE, highlighting its pivotal function in Tfh cell regulation. Further exploration of Bob1-dependent mechanisms in Tfh cells holds promise for governing protective immunity and addressing immune-related disorders.

    DOI： 10.1038/s42003-024-05827-0

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  • Circulating T follicular helper 2 cells, T follicular regulatory cells and regulatory B cells are effective biomarkers for predicting the response to house dust mite sublingual immunotherapy in patients with allergic respiratory diseases

    Katsunori Shigehara, Ryuta Kamekura, Ippei Ikegami, Hiroshi Sakamoto, Masahiro Yanagi, Shiori Kamiya, Kentaro Kodama, Yuichiro Asai, Satsuki Miyajima, Hirotaka Nishikiori, Eiji Uno, Keisuke Yamamoto, Kenichi Takano, Hirofumi Chiba, Hirofumi Ohnishi, Shingo Ichimiya

    Frontiers in Immunology   14   2023.11

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    Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

    The relationships between T follicular helper (Tfh) cells and antigen-specific immunoglobulins (sIgs) in patients with allergic respiratory diseases who are receiving antigen immunotherapy (AIT) have not been fully clarified. Therefore, we started to perform house dust mite sublingual immunotherapy (HDM-SLIT) for 20 patients with atopic asthma comorbid with allergic rhinitis (AA+AR) who were already receiving ordinary treatments including inhaled corticosteroid (ICS). We examined percentages of circulating T follicular helper (cTfh) and regulatory (cTfr) cells and percentages of circulating regulatory T (cTreg) and B (cBreg) cells by FACS and we examined levels of Der-p/f sIgs by ELISA. Based on the symptom score (asthma control questionnaire: ACQ) and medication score ((global initiative for asthma: GINA) treatment step score) in patients with AA, the patients were divided into responders and non-responders. The percentage of cTfh2 cells significantly decreased and the percentage of cTfh1 cells significantly increased within the first year. Der-p/f sIgEs decreased after a transient elevation at 3 months in both groups. Notably, the percentage of cTfh2 cells and the ratio of cTfh2/cBreg cells and Der-p/f sIgEs greatly decreased in responders from 6 months to 12 months. The percentages of cTfr and cTreg cells showed significant negative correlations with the percentage of cTfh2 cells. The percentage of IL-4<sup>+</sup> cTfh cells were significantly decreased and the percentage of IFN-γ<sup>+</sup> cTfh cells were increased before treatment to 24 months in 6 patients examined (4 responders and 2 non-responders). We performed multi plelogistic regression analysis based on these results, the ratios of cTfh2/cTfr cells and cTfh2/cBreg cells at the start of therapy were statistically effective biomarkers for predicting the response to HDM-SLIT in patients with AA+AR.

    DOI： 10.3389/fimmu.2023.1284205

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  • 免疫療法・薬物療法(臨床) 鼻炎合併喘息患者におけるダニ舌下免疫療法のICS減量効果 3年間の解析

    重原 克則, 亀倉 隆太, 宮島 さつき, 小玉 賢太郎, 錦織 博貴, 千葉 弘文

    アレルギー   72 ( 6-7 )   882 - 882   2023.8

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    Language：Japanese   Publisher：(一社)日本アレルギー学会  

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  • 通年性アレルギー性鼻炎・各種鼻炎:治療・管理・診断 ダニ舌下免疫療法の新しい効果発現のメカニズムの解明

    亀倉 隆太, 重原 克則, 山本 圭佑, 一宮 慎吾, 高野 賢一

    アレルギー   72 ( 6-7 )   872 - 872   2023.8

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  • IgG4-related disease administered dupilumab: case series and review of the literature. International journal

    Masatoshi Kanda, Ryuta Kamekura, Masanari Sugawara, Ken Nagahata, Chisako Suzuki, Kenichi Takano, Hiroki Takahashi

    RMD open   9 ( 1 )   2023.3

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    Dupilumab (DUP) is a monoclonal antibody that acts on the interleukin (IL)-4 receptor alpha, which inhibits IL-4 and IL-13 signalling and is approved for type 2 inflammatory diseases such as asthma, chronic rhinosinusitis with nasal polyposis and atopic dermatitis; however, the efficacy of DUP to IgG4-related disease (IgG4-RD) is under discussion due to the controversial outcomes based on the several case reports. Here, we reviewed the efficacy of DUP in four consecutive patients with IgG4-RD in our institute and the previous literature.All patients administered DUP fulfilled the 2019 ACR/EULAR classification criteria for IgG4-RD complicated with severe asthma and chronic rhinosinusitis with nasal polyposis. Two cases were administered DUP without systemic glucocorticoids (GCs), and in 6 months, the volume of swollen submandibular glands (SMGs) was reduced by approximately 70%. Two cases receiving GCs successfully reduced their daily dose of GCs (10 and 50% reduction, respectively) with dupilumab in 6 months. In all four cases, serum IgG4 concentration and IgG4-RD responder index decreased in 6 months.DUP reduced the volume of the swollen SMGs, serum IgG4 levels, responder index and the daily dose of GCs in patients with IgG4-RD with severe asthma or eosinophilic rhinosinusitis in 6 months.The efficacy of DUP to IgG4-RD is under discussion due to the limited case reports with controversial outcomes. Here, we demonstrated that two patients with IgG4-RD treated by DUP without systemic GCs, showed volume reduction of swollen SMGs and two cases showed GC-sparing effects by DUP. DUP can ameliorate the disease activity and be a steroid-sparing agent in patients with IgG4-RD.

    DOI： 10.1136/rmdopen-2023-003026

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  • 喘息 治療 アレルギー性鼻炎合併喘息の家塵ダニ舌下免疫療法における吸入ステロイド減量効果

    重原 克則, 亀倉 隆太, 宮島 さつき, 小玉 賢太郎, 柳 昌弘, 錦織 博貴, 千葉 弘文

    日本呼吸器学会誌   12 ( 増刊 )   185 - 185   2023.3

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  • Tubarial gland involvement in IgG4-related diseases. International journal

    Kenichi Takano, Makoto Kurose, Ryuta Kamekura, Masatoshi Kanda, Motohisa Yamamoto, Hiroki Takahashi

    Acta oto-laryngologica   1 - 4   2022.8

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    BACKGROUND: Tubarial glands (TGs) are a collection of unidentified salivary glands overlying the torus tubarius in the nasopharyngeal wall. Immunoglobulin G4-related disease (IgG4-RD) is a chronic fibroinflammatory state that often has multiple organ involvement. Involvement of the head and neck, especially the salivary glands, is common in IgG4-RD. AIMS/OBJECTIVES: This study aimed to elucidate the clinical significance of TGs in IgG4-RD. MATERIALS AND METHODS: We investigated the local findings of TGs in ten patients with IgG4-RD. RESULTS: Nasopharyngeal endoscopic examination revealed oedematous swelling of the nasopharyngeal wall surrounding the TGs, which improved after steroid treatment. Moreover, sonotubometry showed a stenotic pattern in three out of seven patients with IgG4-RD. CONCLUSIONS AND SIGNIFICANCE: TGs may be involved in IgG4-RD. The swollen TGs may be responsible for obstructive Eustachian tube dysfunction. Further studies are required to clarify the clinical significance and physiological roles of TGs in IgG4-RD.

    DOI： 10.1080/00016489.2022.2104368

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  • アレルゲン・抗原・免疫療法・検査法 ダニ舌下免疫療法における濾胞Tヘルパー細胞と特異的Igの2年間解析

    重原 克則, 亀倉 隆太, 柳 昌弘, 錦織 博貴, 一宮 慎吾

    アレルギー   71 ( 6-7 )   817 - 817   2022.8

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  • CD4+CD8+ T follicular helper cells regulate humoral immunity in chronic inflammatory lesions. International journal

    Kosuke Murayama, Ippei Ikegami, Ryuta Kamekura, Hiroshi Sakamoto, Masahiro Yanagi, Shiori Kamiya, Taiki Sato, Akinori Sato, Katsunori Shigehara, Motohisa Yamamoto, Hiroki Takahashi, Ken-Ichi Takano, Shingo Ichimiya

    Frontiers in immunology   13   941385 - 941385   2022

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    T follicular helper (Tfh) cells drive humoral immunity by facilitating B cell responses at the initial and recall phases. Recent studies have indicated the possible involvement of Tfh cells in the process of chronic inflammation. However, the functional role of Tfh cells in persistent immune settings remains unclear. Here, we report that CD4+CD8+ (double-positive, DP; CD3+CD4+CD8+CXCR5hiPD-1hi) Tfh cells, a subset of germinal-center-type Tfh cells, were abundantly present in the fibroinflammatory lesions of patients with immunoglobulin G4-related disease (IgG4-RD). Transcriptome analyses showed that these DP-Tfh cells in the lesions of IgG4-RD preferentially expressed signature genes characteristic of cytotoxic CD8+ T cells, such as Eomes, CRTAM, GPR56, and granzymes, in addition to CD70. Scatter diagram analyses to examine the relationships between tissue-resident lymphocytes and various clinical parameters revealed that the levels of DP-Tfh cells were inversely correlated to the levels of serum IgG4 and local IgG4-expressing (IgG4+) memory B cells (CD19+CD27+IgD-) in patients with IgG4-RD. Cell culture experiments using autologous tonsillar lymphocytes further suggested that DP-Tfh cells possess a poor B-cell helper function and instead regulate memory B cells. Since CD4+ (single positive, SP; CD3+CD4+CD8-CXCR5hiPD-1hi) Tfh cells differentiated into DP-Tfh cells under stimulation with IL-2 and IL-7 as assessed by in vitro experiments, these data imply that SP-Tfh cells are a possible origin of DP-Tfh cells under persistent inflammation. These findings highlight the potential feedback loop mechanism of Tfh cells in immune tolerance under chronic inflammatory conditions. Further studies on DP-Tfh cells may facilitate control of unresolved humoral responses in IgG4-RD pathological inflammation.

    DOI： 10.3389/fimmu.2022.941385

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  • 免疫療法 鼻炎合併喘息患者におけるダニ舌下免疫療法の濾胞ヘルパー及び濾胞制御性T細胞を中心とした解析

    重原 克則, 亀倉 隆太, 池上 一平, 柳 昌弘, 山本 圭佑, 一宮 慎吾

    アレルギー   70 ( 6-7 )   789 - 789   2021.8

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  • アレルギー性炎症疾患の病態形成における免疫系の役割 細胞傷害性Tph細胞のオリゴクローナルな増殖がIgG4関連疾患の病態形成に関与する

    亀倉 隆太, 村山 公介, 山本 圭佑, 重原 克則, 高野 賢一, 一宮 慎吾

    アレルギー   70 ( 6-7 )   817 - 817   2021.8

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  • Cytotoxic Tph-like cells are involved in persistent tissue damage in IgG4-related disease International journal

    Hayato Yabe, Ryuta Kamekura, Motohisa Yamamoto, Kosuke Murayama, Shiori Kamiya, Ippei Ikegami, Katsunori Shigehara, Hiromi Takaki, Hirofumi Chiba, Hiroki Takahashi, Kenichi Takano, Hiroki Takahashi, Shingo Ichimiya

    Modern Rheumatology   31 ( 1 )   249 - 260   2021.1

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

    OBJECTIVES: The aim of this study was to determine pathological features of T peripheral helper (Tph)-like (PD-1+CXCR5-CD4+ T) cells in IgG4-related disease (IgG4-RD). METHODS: Tph-like cells in the blood and submandibular glands (SMGs) from IgG4-RD patients were analyzed by flow cytometry. Correlations between level of a Tph-like cell subset and clinical parameters of IgG4-RD were investigated. The cytotoxic capacity of Tph-like cells was also examined. Expression profiles of a molecule related to a Tph-like cell subset in IgG4-RD SMGs were assessed by immunohistochemistry. RESULTS: Tph-like cells from IgG4-RD patients highly expressed a fractalkine receptor, CX3CR1. Percentages of circulating CX3CR1+ Tph-like cells were significantly correlated with clinical parameters including IgG4-RD Responder Index, number of involved organs, and serum level of soluble IL-2 receptor. CX3CR1+ Tph-like cells abundantly possessed cytotoxic T lymphocyte-related molecules such as granzyme A, perforin, and G protein-coupled receptor 56. Functional assays revealed their cytotoxic potential against vascular endothelial cells and ductal epithelial cells. Immunohistochemistry showed that fractalkine was markedly expressed in vascular endothelial cells and ductal epithelial cells in IgG4-RD SMGs. CONCLUSION: CX3CR1+ Tph-like cells are thought to contribute to persistent tissue injury in IgG4-RD and are a potential clinical marker and/or therapeutic target for inhibiting progression of IgG4-RD.

    DOI： 10.1080/14397595.2020.1719576

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  • ダニSLIT中のアレルギー性鼻炎合併喘息における末梢血濾胞ヘルパーT細胞の検討

    重原 克則, 亀倉 隆太, 矢部 隼人, 針生 寛之, 宇野 英二, 一宮 慎吾

    日本呼吸器学会誌   9 ( 増刊 )   324 - 324   2020.8

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  • Activated circulating T follicular helper cells and skewing of T follicular helper 2 cells are down-regulated by treatment including an inhaled corticosteroid in patients with allergic asthma. International journal

    Satsuki Miyajima, Katsunori Shigehara, Ryuta Kamekura, Hiromi Takaki, Hayato Yabe, Ippei Ikegami, Yuichiro Asai, Hirotaka Nishikiori, Hirohumi Chiba, Eiji Uno, Hiroki Takahashi, Shingo Ichimiya

    Allergology international : official journal of the Japanese Society of Allergology   69 ( 1 )   66 - 77   2020.1

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    BACKGROUND: CXCR5+ T follicular helper (TFH) cells primarily promote B cells to produce an antigen-specific antibody through germinal centers (GCs). TFH cells exist in circulation, and circulating(c) TFH2 cells, a subset of cTFH cells, are able to help naïve B cells produce IgE in healthy individuals. Conversely, IL-10-producing regulatory B (Breg) cells inhibit an accelerated immune response. METHODS: We investigated the roles of cTFH cells and cBreg cells based on a TH2 response in patients with atopic asthma (AA). Thirty-two patients with AA and 35 healthy volunteers (HV) were enrolled. We examined cTFH cells including their subsets, their expression of ICOS and PD-1, and cBreg cells by flow cytometry and their associations with clinical biomarkers. Plasma levels of CXCL13, which is a counterpart of CXCR5, were also measured using ELISA. RESULTS: In patients with AA, cTFH2 cells were increased and cTFH1 cells were decreased compared with those in HV. The expression levels of ICOS on cTFH and their subset cells were elevated and Breg cells were greatly decreased. The plasma levels of CXCL13 in patients with AA were significantly elevated and correlated well with the cTFH2/cBreg ratio. These cells were examined in 10 patients AA before and after inhaled corticosteroid (ICS) treatment. Interestingly, the percentages and numbers of TFH2 and ICOS+ cTFH cells declined after ICS treatment together with improvements in symptoms and clinical biomarkers. CONCLUSIONS: The percentages and numbers of cTFH2 and ICOS+ cTFH cells might be useful as biomarkers of TH2 typed airway inflammation in patients with AA.

    DOI： 10.1016/j.alit.2019.08.008

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  • IgG4 関連疾患の免疫病態と治療への展望.

    亀倉 隆太, 一宮 慎吾

    リウマチ科   64   559 - 566   2020

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    Other Link： https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18K09323/

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  • Aberrant populations of circulating T follicular helper cells and regulatory B cells underlying idiopathic pulmonary fibrosis. International journal

    Yuichiro Asai, Hirofumi Chiba, Hirotaka Nishikiori, Ryuta Kamekura, Hayato Yabe, Shun Kondo, Satsuki Miyajima, Katsunori Shigehara, Shingo Ichimiya, Hiroki Takahashi

    Respiratory research   20 ( 1 )   244 - 244   2019.11

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    BACKGROUND: T follicular helper (Tfh) cells have been identified as a new category of helper T cells, which express CXCR5 on their surface and induce the production of antigen-specific antibodies. Many investigations have found morbid proliferation and/or activation of Tfh cells in systemic autoimmune and allergic diseases. It is also known that Tfh cells are regulated by regulatory B (Breg) cells in the deteriorating such diseases. Recently, CXCL13, a ligand of CXCR5, has been reported to increase in the peripheral blood and lungs of patients with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the involvement of Tfh cells and Breg cells in IPF. METHODS: Peripheral blood samples were obtained from 18 patients with IPF. We isolated heparinized peripheral blood mononuclear cells and investigated the proportions of Breg cells, Tfh cells, PD-1+ICOS+ Tfh cells (activated form of Tfh cells), and the Tfh-cell subsets by flow cytometry. These cell profiles were compared with those of 21 healthy controls. Furthermore, we investigated the correlations between profiles of lymphocytes and lung physiology. RESULTS: The median proportions of Tfh cells per total CD4+ T cells and of PD-1+ICOS+ proportion of Tfh cells per total Tfh cells was significantly more in the IPF patients (20.4 and 5.2%, respectively) compared with healthy controls (15.4 and 2.1%, respectively; p = 0.042 and p = 0.004, respectively). The proportion of Tfh2 cells per total Tfh cells was significantly higher and the proportion of Tfh17 was smaller in the IPF patients than healthy controls. The percentage of Breg cells to total B cells was significantly decreased in the IPF patients (median, 8.5%) compared with that in the controls (median, 19.7%; p < 0.001). The proportion of Breg cells was positively correlated with the annual relative change in diffusing capacity of the lungs for carbon monoxide in the IPF patients (r = 0.583, p = 0.018). CONCLUSION: Proliferation and activation of Tfh cells and a decrease in Breg cells were observed in the peripheral blood of patients with IPF. The profile of the Tfh-cell subset also changed. Specific humoral immunity aberration would likely underlie complicated pathophysiology of IPF.

    DOI： 10.1186/s12931-019-1216-6

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  • Interleukin 5-producing ST2<sup>+</sup> memory Th2 cells in IgG4-related dacryoadenitis and sialadenitis. Reviewed

    Yamamoto M, Takano KI, Kamekura R, Aochi S, Suzuki C, Ichimiya S, Nakase H, Himi T, Takahashi H

    Modern rheumatology   29 ( 5 )   856 - 860   2019.9

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    DOI： 10.1080/14397595.2018.1526357

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  • Bob1 enhances RORγt-mediated IL-17A expression in Th17 cells through interaction with RORγt. Reviewed

    Ikegami I, Takaki H, Kamiya S, Kamekura R, Ichimiya S

    Biochemical and biophysical research communications   514 ( 4 )   1167 - 1171   2019.7

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    DOI： 10.1016/j.bbrc.2019.05.057

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  • 舌下免疫療法 ダニ舌下免疫療法中の喘息合併アレルギー性鼻炎患者における濾胞ヘルパーT細胞を中心とした検討

    重原 克則, 亀倉 隆太, 矢部 勇人, 高木 宏美, 宇野 英二, 一宮 慎吾

    アレルギー   68 ( 4-5 )   503 - 503   2019.5

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  • 生体バリア機構とアレルギー疾患 アレルギー性鼻炎に関連するエピイムノームの新機能

    亀倉 隆太, 矢部 勇人, 重原 克則, 高野 賢一, 一宮 慎吾

    アレルギー   68 ( 4-5 )   320 - 320   2019.5

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  • Potential utility of core needle biopsy in the diagnosis of IgG4-related dacryoadenitis and sialadenitis

    Kenichi Takano, Tsuyoshi Okuni, Keisuke Yamamoto, Ryuta Kamekura, Ryoto Yajima, Motohisa Yamamoto, Hiroki Takahashi, Tetsuo Himi

    Modern Rheumatology   29 ( 2 )   393 - 396   2019.3

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Taylor and Francis Ltd  

    DOI： 10.1080/14397595.2018.1465665

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  • IL-10<sup>+</sup> T follicular regulatory cells are associated with the pathogenesis of IgG4-related disease. Reviewed International journal

    Ito F, Kamekura R, Yamamoto M, Takano K, Takaki H, Yabe H, Ikegami I, Shigehara K, Himi T, Takahashi H, Ichimiya S

    Immunology letters   207   56 - 63   2019.3

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    DOI： 10.1016/j.imlet.2019.01.008

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  • 鼻炎合併アトピー型喘息患者のダニ抗原SLIT施行における濾胞ヘルパー細胞と濾胞制御性T細胞の検討

    重原 克則, 亀倉 隆太, 矢部 隼人, 宇野 英二, 一宮 慎吾

    日本呼吸器学会誌   8 ( 増刊 )   250 - 250   2019.3

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  • A unique subset of PD-1(+)CXCR5(-)CD4(+) T cells is involved in immunological mechanisms of IgG4-related disease Reviewed

    Kamekura Ryuta, Yamamoto Motohisa, Yabe Hayato, Takaki Hiromi, Takano Kenichi, Takahashi Hiroki, Takahashi Hiroki, Himi Tetsuo, Ichimiya Shingo

    JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY   143 ( 2 )   AB231   2019.2

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  • Analysis of allergic reaction in IgG4-related disease. Reviewed International journal

    Yamamoto M, Takano KI, Kamekura R, Aochi S, Suzuki C, Ichimiya S, Takahashi H

    Modern rheumatology   29 ( 6 )   1 - 3   2019.1

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    DOI： 10.1080/14397595.2019.1572488

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  • New insights into IgG4-related disease: emerging new CD4+ T-cell subsets. Reviewed International journal

    Kamekura R, Takahashi H, Ichimiya S

    Current opinion in rheumatology   31 ( 1 )   9 - 15   2019.1

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    DOI： 10.1097/BOR.0000000000000558

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  • Stage classification of IgG4-related dacryoadenitis and sialadenitis by the serum cytokine environment. Reviewed International journal

    Motohisa Yamamoto, Kenichi Takano, Ryuta Kamekura, Chisako Suzuki, Shingo Ichimiya, Tetsuo Himi, Hiroshi Nakase, Hiroki Takahashi

    Modern rheumatology   28 ( 6 )   1004 - 1008   2018.11

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    OBJECTIVES: Patients with immunoglobulin-G4 related disease (IgG4-RD) diagnosed according to the comprehensive diagnostic criteria (CDC) show varied therapeutic responses and prognoses. We assumed that there are clinical stages in IgG4-RD and have verified it using serum cytokine levels in the groups classified by lesion distribution. METHODS: Definite IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) cases were divided according to the CDC for IgG4-RD into 11 cases with focal type and 30 cases with systemic type. The levels of serum interleukin (IL)-4, IL-5, IL-6, IL-10, IL-13, IL-15, IL-21, interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, and monocyte chemotactic protein (MCP)-1 were measured in healthy controls, allergic patients, probable IgG4-RD cases, and focal and systemic type cases. The cytokine environment was analyzed in each group. The 52 definite IgG4-RD cases were next classified into four groups with cluster analysis in terms of therapeutic responses and prognosis. The relationships between each cytokine level and therapeutic responses were also analyzed. RESULTS: Both serum IL-5 and IFN-α concentrations were very low in healthy controls, but they increased in the allergic cases, probable cases, and focal and systemic type cases. The level of serum IL-5 was significantly higher in definite cases than in healthy controls. The serum IL-5 level was also significantly increased in the groups with a poor prognosis than in the good prognosis group. CONCLUSION: These results suggest that there are clinical stages in IgG4-RD, and serum IL-5 play roles in the pathogenesis of IgG4-RD.

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  • ダニ舌下免疫療法における血液機能性リンパ球サブセットの経時的変化

    亀倉 隆太, 重原 克則, 伊藤 史恵, 高野 賢一, 氷見 徹夫, 一宮 慎吾

    アレルギー   67 ( 4-5 )   598 - 598   2018.5

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  • Predicting therapeutic response in IgG4-related disease based on cluster analysis. Reviewed

    Yamamoto M, Takano KI, Kamekura R, Suzuki C, Tabeya T, Murakami R, Honda S, Mukai M, Nojima M, Ichimiya S, Himi T, Nakase H, Takahashi H

    Immunological medicine   41 ( 1 )   30 - 33   2018.3

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  • COPD患者における喘息患者との対比を含めた末梢血濾胞ヘルパーT細胞と制御性B細胞の検討

    重原 克則, 亀倉 隆太, 川田 耕司, 宮島 さつき, 矢部 勇人, 高橋 弘毅, 一宮 慎吾

    日本呼吸器学会誌   7 ( 増刊 )   219 - 219   2018.3

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  • Unique profiles of lesional T follicular helper cells in the pathogenesis of IgG4-related disease Reviewed

    Kamekura Ryuta, Yabe Hayato, Takano Kenichi, Yamamoto Motohisa, Ikegami Ippei, Ito Fumie, Takahashi Hiroki, Himi Tetsuo, Ichimiya Shingo

    JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY   141 ( 2 )   AB284   2018.2

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  • Circulating PD-1<sup>+</sup>CXCR5<sup>-</sup>CD4<sup>+</sup> T cells underlying the immunological mechanisms of IgG4-related disease. Reviewed

    Kamekura R, Yamamoto M, Takano K, Yabe H, Ito F, Ikegami I, Takaki H, Shigehara K, Suzuki C, Himi T, Takahashi H, Ichimiya S

    Rheumatology advances in practice   2 ( 2 )   rky043   2018

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    DOI： 10.1093/rap/rky043

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  • Keratinocytes in atopic dermatitis express abundant Delta Np73 regulating thymic stromal lymphopoietin production via NF-kappa B Reviewed

    Ayako Kumagai, Terufumi Kubo, Koji Kawata, Ryuta Kamekura, Keiji Yamashita, Sumito Jitsukawa, Tomonori Nagaya, Yasuyuki Sumikawa, Tetsuo Himi, Toshiharu Yamashita, Shingo Ichimiya

    JOURNAL OF DERMATOLOGICAL SCIENCE   88 ( 2 )   175 - 183   2017.11

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    DOI： 10.1016/j.jdermsci.2017.06.017

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  • Loss of sorting nexin 5 stabilizes internalized growth factor receptors to promote thyroid cancer progression Reviewed

    Sumito Jitsukawa, Ryuta Kamekura, Koji Kawata, Fumie Ito, Akinori Sato, Hiroshi Matsumiya, Tomonori Nagaya, Keiji Yamashita, Terufumi Kubo, Tomoki Kikuchi, Noriyuki Sato, Tadashi Hasegawa, Hiroshi Kiyonari, Yoshiko Mukumoto, Ken-ichi Takano, Tetsuo Himi, Shingo Ichimiya

    JOURNAL OF PATHOLOGY   243 ( 3 )   342 - 353   2017.11

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  • High frequency of Bob1(1o) T follicular helper cells in florid reactive follicular hyperplasia Reviewed

    Hiroshi Matsumiya, Koji Kawata, Ryuta Kamekura, Chieko Tsubomatsu, Sumito Jitsukawa, Takamasa Asai, Syunsuke Akasaka, Motonari Kamei, Keiji Yamashita, Fumie Ito, Terufumi Kubo, Noriyuki Sato, Ken-ichi Takano, Tetsuo Himi, Shingo Ichimiya

    IMMUNOLOGY LETTERS   191   23 - 30   2017.11

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    DOI： 10.1016/j.imlet.2017.07.012

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  • Cutting Edge: A Critical Role of Lesional T Follicular Helper Cells in the Pathogenesis of IgG4-Related Disease Reviewed

    Ryuta Kamekura, Kenichi Takano, Motohisa Yamamoto, Koji Kawata, Katsunori Shigehara, Sumito Jitsukawa, Tomonori Nagaya, Fumie Ito, Akinori Sato, Noriko Ogasawara, Chieko Tsubomatsu, Hiroki Takahashi, Hiroshi Nakase, Tetsuo Himi, Shingo Ichimiya

    JOURNAL OF IMMUNOLOGY   199 ( 8 )   2624 - 2629   2017.10

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    DOI： 10.4049/jimmunol.1601507

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  • Deterioration of regulatory B cells and activation of follicular helper T cells in idiopathic interstitial pneumonias patients Reviewed

    Asai Yuichiro, Chiba Hirofumi, Kondoh Syun, Nishikiori Hirotaka, Takahashi Mamoru, Kuronuma Koji, Otsuka Mitsuo, Yamada Gen, Kamekura Ryuta, Ichimiya Shingo, Takahashi Hiroki

    EUROPEAN RESPIRATORY JOURNAL   50   2017.9

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  • Lipid mediators foster the differentiation of T follicular helper cells Reviewed

    Tomonori Nagaya, Koji Kawata, Ryuta Kamekura, Sumito Jitsukawa, Terufumi Kubo, Motonari Kamei, Noriko Ogasawara, Ken-ichi Takano, Tetsuo Himi, Shingo Ichimiya

    IMMUNOLOGY LETTERS   181   51 - 57   2017.1

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    DOI： 10.1016/j.imlet.2016.11.006

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  • Functional RNAs control T follicular helper cells Reviewed

    Shingo Ichimiya, Ryuta Kamekura, Koji Kawata, Motonari Kamei, Tetsuo Himi

    JOURNAL OF HUMAN GENETICS   62 ( 1 )   81 - 86   2017.1

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  • KS-2 IgG4関連涙腺・唾液腺炎の病態形成における濾胞ヘルパーT細胞の機能的役割

    亀倉 隆太, 高野 賢一, 山本 元久, 伊藤 史恵, 矢部 勇人, 川田 耕司, 高橋 裕樹, 氷見 徹夫, 一宮 慎吾

    日本臨床免疫学会会誌   40 ( 4 )   292b - 292b   2017

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    <p>【目的】IgG4関連涙腺・唾液腺炎（IgG4-DS）は，涙腺・唾液腺の持続性腫脹と高IgG4血症，局所でのIgG4陽性形質細胞の浸潤を特徴とする疾患である．近年，IgG4産生に関連して，濾胞ヘルパーT（Tfh）細胞と本疾患との関連を示唆する報告が散見されるが，病変部位でのTfh細胞の機能的役割は不明である．【方法】IgG4-DS患者の顎下腺組織からTfh細胞（CD3<sup>+</sup>CD4<sup>+</sup>CXCR5<sup>+</sup>PD-1<sup>hi</sup>）を分離し，DNAマイクロアレイやリアルタイムPCRによる遺伝子発現解析に加え，B細胞との共培養の系でIgG4産生について検討した．比較対照としてヒト口蓋扁桃由来のTfh細胞を用いた．【結果】IgG4-DSの顎下腺組織中に存在するCD4陽性T細胞の多くはCXCR5陽性，PD-1強陽性のTfh細胞であり，口蓋扁桃由来のTfh細胞と比較して，Tfh細胞関連分子（BCL6, CXCL13, IL-10）の発現上昇を認めた．また，IgG4-DSの顎下腺由来Tfh細胞とB細胞との共培養で，口蓋扁桃由来のTfh細胞とB細胞との共培養と比較して，より効率的にIgG4の産生が誘導された．さらにDNAマイクロアレイによる解析でIgG4-DSの顎下腺由来のTfh細胞ではCD8A, Granzyme Kといった細胞障害性T細胞関連遺伝子の発現上昇を認めた．【結論】今回の結果から，IgG4-DSの病態形成に強力な抗体産生誘導能と細胞障害能を併せ持つ特殊なTfh細胞が関与している可能性が考えられた．病変部位におけるTfh細胞が，IgG4-DSの新規治療法を開発する上での治療標的となる可能性が示唆された．</p>

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  • Importance of "epimmunome" as a new therapeutic target for allergic rhinitis Reviewed

    Ryuta Kamekura, Shingo Ichimiya, Tetsuo Himi

    Japanese Journal of Allergology   66 ( 2 )   91 - 96   2017

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    DOI： 10.15036/arerugi.66.91

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  • Bob1 limits cellular frequency of T-follicular helper cells (vol 46, pg 1361, 2016) Reviewed

    Yamashita Keiji, Kawata Koji, Matsumiya Hiroshi, Kamekura Ryuta, Jitsukawa Sumito, Nagaya Tomonori, Ogasawara Noriko, Takano Ken-ichi, Kubo Terufumi, Kimura Sachiko, Shigehara Katsunori, Himi Tetsuo, Ichimiya Shingo

    EUROPEAN JOURNAL OF IMMUNOLOGY   46 ( 8 )   2054   2016.8

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  • Novel Mechanisms of Compromised Lymphatic Endothelial Cell Homeostasis in Obesity: The Role of Leptin in Lymphatic Endothelial Cell Tube Formation and Proliferation Reviewed

    Akinori Sato, Ryuta Kamekura, Koji Kawata, Masaya Kawada, Sumito Jitsukawa, Keiji Yamashita, Noriyuki Sato, Tetsuo Himi, Shingo Ichimiya

    PLOS ONE   11 ( 7 )   e0158408   2016.7

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  • Clinicopathological analysis of salivary gland tissue from patients with IgG4-related disease Reviewed

    Kenichi Takano, Kazuaki Nomura, Ayumi Abe, Ryuta Kamekura, Motohisa Yamamoto, Shingo Ichimiya, Hiroki Takahashi, Tetsuo Himi

    ACTA OTO-LARYNGOLOGICA   136 ( 7 )   717 - 721   2016.7

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    DOI： 10.3109/00016489.2016.1154605

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  • Bob1 limits cellular frequency of T-follicular helper cells Reviewed

    Keiji Yamashita, Koji Kawata, Hiroshi Matsumiya, Ryuta Kamekura, Sumito Jitsukawa, Tomonori Nagaya, Noriko Ogasawara, Ken-ichi Takano, Terufumi Kubo, Sachiko Kimura, Katsunori Shigehara, Tetsuo Himi, Shingo Ichimiya

    EUROPEAN JOURNAL OF IMMUNOLOGY   46 ( 6 )   1361 - 1370   2016.6

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    DOI： 10.1002/eji.201545499

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  • Studies of tonsils in basic and clinical perspectives: From the past to the future Reviewed

    Keiji Yamashita, Shingo Ichimiya, Ryuta Kamekura, Tomonori Nagaya, Sumito Jitsukawa, Hiroshi Matsumiya, Kenichi Takano, Tetsuo Himi

    Advances in Oto-Rhino-Laryngology   77   119 - 124   2016

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    DOI： 10.1159/000441902

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  • Role of Crosstalk between Epithelial and Immune Cells, the Epimmunome, in Allergic Rhinitis Pathogenesis. Reviewed

    Kamekura R, Yamashita K, Jitsukawa S, Nagaya T, Ito F, Ichimiya S, Himi T

    Advances in oto-rhino-laryngology   77   75 - 82   2016

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  • Clarithromycin prevents human respiratory syncytial virus-induced airway epithelial responses by modulating activation of interferon regulatory factor-3 Reviewed

    Yamamoto K, Yamamoto S, Ogasawara N, Takano K, Shiraishi T, Sato T, Miyata R, Kakui T, Kamekura R, Kojima T, Tsutsumi H, Himi T, Yokota S

    Pharmacological Research   111   804 - 814   2016

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    DOI： 10.1016/j.phrs.2016.07.033

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  • Alteration of circulating type 2 follicular helper T cells and regulatory B cells underlies the comorbid association of allergic rhinitis with bronchial asthma. Reviewed

    Kamekura R, Shigehara K, Miyajima S, Jitsukawa S, Kawata K, Yamashita K, Nagaya T, Kumagai A, Sato A, Matsumiya H, Ogasawara N, Seki N, Takano K, Kokai Y, Takahashi H, Himi T, Ichimiya S

    Clinical immunology (Orlando, Fla.)   158 ( 2 )   204 - 211   2015.6

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  • Alteration of human blood type 2 follicular helper T cells and regulatory B cells underlies comorbid association of allergic rhinitis with bronchial asthma Reviewed

    Kamekura Ryuta, Shigehara Katsunori, Jitsukawa Sumito, Kawata Koji, Himi Tetsuo, Ichimiya Shingo

    JOURNAL OF IMMUNOLOGY   194   2015.5

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  • アレルギー性気道疾患の病態形成における濾胞ヘルパーT細胞と制御性B細胞の役割

    亀倉 隆太, 重原 克則, 實川 純人, 小笠原 徳子, 高野 賢一, 氷見 徹夫, 一宮 慎吾

    アレルギー   64 ( 3-4 )   570 - 570   2015.4

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  • アレルギー性鼻炎の病態形成におけるエピイムノームの役割. 特集 アレルギー疾患ガイドラインダイジェストに寄せる

    亀倉 隆太, 氷見 徹夫, 一宮 慎吾

    アレルギーの臨床   35   57 - 63   2015

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  • Delta Np63 Controls a TLR3-Mediated Mechanism That Abundantly Provides Thymic Stromal Lymphopoietin in Atopic Dermatitis Reviewed

    Terufumi Kubo, Ryuta Kamekura, Ayako Kumagai, Koji Kawata, Keiji Yamashita, Yukari Mitsuhashi, Takashi Kojima, Kotaro Sugimoto, Akihiro Yoneta, Yasuyuki Sumikawa, Toshiharu Yamashita, Noriyuki Sato, Tetsuo Himi, Shingo Ichimiya

    PLOS ONE   9 ( 8 )   e105498   2014.8

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  • Regulation of Tight Junctions in Upper Airway Epithelium Reviewed

    Takashi Kojima, Mitsuru Go, Ken-ichi Takano, Makoto Kurose, Tsuyoshi Ohkuni, Jun-ichi Koizumi, Ryuta Kamekura, Noriko Ogasawara, Tomoyuki Masaki, Jun Fuchimoto, Kazufumi Obata, Satoshi Hirakawa, Kazuaki Nomura, Takashi Keira, Ryou Miyata, Nobuhiro Fujii, Hiroyuki Tsutsumi, Tetsuo Himi, Norimasa Sawada

    BIOMED RESEARCH INTERNATIONAL   2013   947072   2013

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  • Altered expression of claudin-1, claudin-7, and tricellulin regardless of human papilloma virus infection in human tonsillar squamous cell carcinoma Reviewed

    Atsushi Kondoh, Ken-Ichi Takano, Takashi Kojima, Tsuyoshi Ohkuni, Ryuta Kamekura, Noriko Ogasawara, Mitsuru Go, Norimasa Sawada, Tetsuo Himi

    ACTA OTO-LARYNGOLOGICA   131 ( 8 )   861 - 868   2011.8

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    DOI： 10.3109/00016489.2011.562537

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  • Epithelial barrier and antigen uptake in lymphoepithelium of human adenoids Reviewed

    Noriko Ogasawara, Takashi Kojima, Mitsuru Go, Ken-Ichi Takano, Ryuta Kamekura, Tsuyoshi Ohkuni, Jun-Ichi Koizumi, Tomoyuki Masaki, Jun Fuchimoto, Kazufumi Obata, Makoto Kurose, Tomoko Shintani, Norimasa Sawada, Tetsuo Himi

    ACTA OTO-LARYNGOLOGICA   131 ( 2 )   116 - 123   2011.2

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  • Poly(I:C) reduces expression of JAM-A and induces secretion of IL-8 and TNF-alpha via distinct NF-kappa B pathways in human nasal epithelial cells Reviewed

    Tsuyoshi Ohkuni, Takashi Kojima, Noriko Ogasawara, Tomoyuki Masaki, Jun Fuchimoto, Ryuta Kamekura, Jun-ichi Koizumi, Shingo Ichimiya, Masaki Murata, Satoshi Tanaka, Tetsuo Himi, Norimasa Sawada

    TOXICOLOGY AND APPLIED PHARMACOLOGY   250 ( 1 )   29 - 38   2011.1

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    DOI： 10.1016/j.taap.2010.09.023

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  • Mucosal Immune Barrier and Antigen-Presenting System in Human Nasal Epithelial Cells Reviewed

    Tetsuo Himi, Ken-ichi Takano, Noriko Ogasawara, Mitsuru Go, Makoto Kurose, Jun-ichi Koizumi, Ryuta Kamekura, Atsushi Kondo, Tsuyoshi Ohkuni, Tomoyuki Masaki, Takashi Kojima, Norimasa Sawada, Hiroyuki Tsutsumi

    RECENT ADVANCES IN TONSILS AND MUCOSAL BARRIERS OF THE UPPER AIRWAYS   72   28 - +   2011

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  • PPAR gamma agonists upregulate the barrier function of tight junctions via a PKC pathway in human nasal epithelial cells Reviewed

    Noriko Ogasawara, Takashi Kojima, Mitsuru Go, Tsuyoshi Ohkuni, Jun-ichi Koizumi, Ryuta Kamekura, Tomoyuki Masaki, Masaki Murata, Satoshi Tanaka, Jun Fuchimoto, Tetsuo Himi, Norimasa Sawada

    PHARMACOLOGICAL RESEARCH   61 ( 6 )   489 - 498   2010.6

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    DOI： 10.1016/j.phrs.2010.03.002

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  • Thymic stromal lymphopoietin induces tight junction protein claudin-7 via NF-kappa B in dendritic cells Reviewed

    Ryuta Kamekura, Takashi Kojima, Akira Takashima, Jun-ichi Koizumi, Noriko Ogasawara, Mitsuru Go, Ken-ichi Takano, Masaki Murata, Satoshi Tanaka, Shingo Ichimiya, Tetsuo Himi, Norimasa Sawada

    HISTOCHEMISTRY AND CELL BIOLOGY   133 ( 3 )   339 - 348   2010.3

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    DOI： 10.1007/s00418-009-0674-1

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  • Induction of JAM-A during differentiation of human THP-1 dendritic cells Reviewed

    Noriko Ogasawara, Takashi Kojima, Mitsuru Go, Jun Fuchimoto, Ryuta Kamekura, Jun-ichi Koizumi, Tsuyoshi Ohkuni, Tomoyuki Masaki, Masaki Murata, Satoshi Tanaka, Shingo Ichimiya, Tetsuo Himi, Norimasa Sawada

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   389 ( 3 )   543 - 549   2009.11

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    DOI： 10.1016/j.bbrc.2009.09.024

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  • Thymic stromal lymphopoietin enhances tight-junction barrier function of human nasal epithelial cells Reviewed

    Ryuta Kamekura, Takashi Kojima, Jun-ichi Koizumi, Noriko Ogasawara, Makoto Kurose, Mitsuru Go, Atsushi Harimaya, Masaki Murata, Satoshi Tanaka, Hideki Chiba, Tetsuo Himi, Norimasa Sawada

    CELL AND TISSUE RESEARCH   338 ( 2 )   283 - 293   2009.11

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  • ヒト鼻粘膜上皮細胞と樹状細胞のタイト結合蛋白はthymic stromal lymphopoietin(TSLP)によって誘導される

    亀倉 隆太, 小島 隆, 小笠原 徳子, 大國 毅, 高野 賢一, 郷 充, 澤田 典均, 氷見 徹夫

    日本耳鼻咽喉科学会会報   112 ( 4 )   376 - 376   2009.4

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  • Protein kinase C enhances tight junction barrier function of human nasal epithelial cells in primary culture by transcriptional regulation Reviewed

    Jun-ichi Koizumi, Takashi Kojima, Noriko Ogasawara, Ryuta Kamekura, Makoto Kurose, Mitsuru Go, Atsushi Harimaya, Masaki Murata, Makoto Osanai, Hideki Chiba, Tetsuo Himi, Norimasa Sawada

    MOLECULAR PHARMACOLOGY   74 ( 2 )   432 - 442   2008.8

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  • Expression of tight junction proteins in epithelium including Ck20-positive M-like cells of human adenoids in vivo and in vitro Reviewed

    Ken-ichi Takano, Takashi Kojima, Noriko Ogasawara, Mitsuru Go, Shin Kikuchi, Takafumi Ninomiya, Makoto Kurose, Jun-ichi Koizumi, Ryuta Kamekura, Masaki Murata, Satoshi Tanaka, Hideki Chiba, Tetsuo Himi, Norimasa Sawada

    JOURNAL OF MOLECULAR HISTOLOGY   39 ( 3 )   265 - 273   2008.6

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  • Expression of thymic stromal lymphopoietin (TSLP) in allergic rhinitis : Induction of tight junction proteins in human nasal epithelial cells and dendritic cells by epithelial-derived TSLP

    KAMEKURA Ryuta, KOJIMA Takashi, KOIZUMI Jun-ichi, OGASAWARA Noriko, KUROSE Makoto, TAKANO Ken-ichi, GO Mitsuru, HIMI Tetsuo, SAWADA Norimasa

    Inflammation and Regeneration   28 ( 3 )   160 - 165   2008.5

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    Thymic stromal lymphopoietin (TSLP) is an interleukin 7-like cytokine that triggers dendritic cell (DC)-mediated T helper 2-type inflammatory responses and is considered to be a master switch for allergic inflammation such as that in asthma and atopic dermatitis. Furthermore, proinflammatory cytokines and Toll-like receptor ligands can induce TSLP production in human bronchial epithelial cells and human keratinocytes. We first found high expression of endogenous TSLP in the epithelium of allergic rhinitis with recruitment and infiltration of DCs. In culture, the TSLP production in human nasal epithelial cells was markedly and significantly increased by treatment with the proinflammatory cytokines interleukin 1β/tumor necrosis factor-α and a Toll-like receptor 2 ligand, P<SUB>3</SUB>CSK<SUB>4</SUB>. Since it is also thought that TSLP expression not only activates DCs but also affects the epithelial barrier in allergic rhinitis, we investigated the effects of TSLP on tight junctions of human nasal epithelial cells and DCs <I>in vitro</I>. Treatment with TSLP enhanced the barrier function of human nasal epithelial cells <I>in vitro</I> together with an increase of the tight junction proteins claudin-1,-4,-7, and occludin. Furthermore, TSLP could exclusively induce claudin-7 expression in mouse DC line XS52, which expressed tight junction molecules claudin-1,-3,-4,-6,-7,-8, occludin and tricellulin.<BR>These findings suggest that nasal epithelial-derived TSLP plays an important role in allergic rhinitis as well as asthma and atopic dermatitis and may control tight junctions of epithelial cells and DCs to preserve the epithelial barrier and promote direct sampling of antigens by DCs.

    Other Link： https://jlc.jst.go.jp/DN/JALC/00314785334?from=CiNii

    DOI： 10.2492/inflammregen.28.160

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  • アレルギー性鼻炎における鼻粘膜上皮バリアと免疫調節機構

    氷見 徹夫, 郷 充, 高野 賢一, 黒瀬 誠, 小泉 純一, 亀倉 隆太, 小笠原 徳子, 小島 隆, 澤田 典均

    アレルギーの臨床   27 ( 13 )   1038 - 1043   2007.12

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  • Induction of claudins in passaged hTERT-transfected human nasal epithelial cells with an extended life span Reviewed

    Makoto Kurose, Takashi Kojima, Jun-Ichi Koizumi, Ryuta Kamekura, Takafumi Ninomiya, Masaki Murata, Shingo Ichimiya, Makoto Osanai, Hideki Chiba, Tetsuo Himi, Norimasa Sawada

    CELL AND TISSUE RESEARCH   330 ( 1 )   63 - 74   2007.10

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    DOI： 10.1007/s00441-007-0453-z

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  • テロメラーゼ遺伝子導入培養ヒト鼻粘膜上皮細胞のタイト結合の発現と機能

    小島 隆, 黒瀬 誠, 亀倉 隆太, 小泉 純一, 小笠原 徳子, 氷見 徹夫, 澤田 典均

    Inflammation and Regeneration   27 ( 4 )   439 - 439   2007.7

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    Ichushi

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  • Connexin 26 expression prevents down-regulation of barrier and fence functions of tight junctions by Na+/K+-ATPase inhibitor ouabain in human airway epithelial cell line Calu-3. Reviewed

    Go M, Kojima T, Takano K, Murata M, Koizumi J, Kurose M, Kamekura R, Osanai M, Chiba H, Spray DC, Himi T, Sawada N

    Experimental cell research   312   3847 - 3856   2006.11

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  • in vivoおよびin vitroにおけるヒト鼻粘膜上皮細胞のM様細胞とタイト結合

    小泉 純一, 小島 隆, 黒瀬 誠, 高野 賢一, 亀倉 隆太, 澤田 典均, 氷見 徹夫

    耳鼻咽喉科免疫アレルギー   24 ( 2 )   179 - 179   2006.9

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    Ichushi

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MISC

  • 頭頸部がん組織におけるHLA提示ペプチドの網羅的解析

    黒瀬 誠, 亀倉 隆太, 小笠原 徳子, 高野 賢一

    耳鼻咽喉科免疫アレルギー   38 ( 4 )   170 - 170   2020.12

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    Ichushi

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  • 頭頸部がん組織におけるHLA提示ペプチドの網羅的解析

    黒瀬 誠, 亀倉 隆太, 小笠原 徳子, 高野 賢一

    耳鼻咽喉科免疫アレルギー   38 ( 4 )   170 - 170   2020.12

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    Ichushi

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  • アトピー型喘息における治療前後の末梢血濾胞ヘルパーT細胞および制御性B細胞の変化

    重原 克則, 宮島 さつき, 亀倉 隆太, 矢部 隼人, 高橋 弘毅, 一宮 慎吾

    アレルギー   67 ( 4-5 )   637 - 637   2018.5

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    Ichushi

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  • COPD患者における喘息患者との対比を含めた末梢血濾胞ヘルパーT細胞と制御性B細胞の検討

    重原 克則, 亀倉 隆太, 宮島 さつき, 矢部 勇人, 高橋 弘毅, 一宮 慎吾

    日本内科学会雑誌   107 ( Suppl. )   215 - 215   2018.2

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  • 免疫学の進歩と神経免疫学への応用 濾胞ヘルパーT細胞の機能異常と免疫関連疾患

    一宮 慎吾, 亀倉 隆太

    神経免疫学   22 ( 1 )   66 - 66   2017.10

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  • アトピー性皮膚炎表皮におけるNF-κBを介したΔNp73によるTSLPの産生制御

    熊谷 綾子, 川田 耕司, 亀倉 隆太, 澄川 靖之, 一宮 慎吾, 山下 利春

    日本皮膚科学会雑誌   127 ( 5 )   1175 - 1175   2017.5

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    Ichushi

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  • 血管炎・その他の免疫疾患 IgG4関連涙腺唾液腺炎の病変部位とリンパ組織に存在する濾胞ヘルパーT細胞の機能的差異

    亀倉 隆太, 高野 賢一, 山本 元久, 伊藤 史恵, 川田 耕司, 重原 克則, 高橋 裕樹, 氷見 徹夫, 一宮 慎吾

    アレルギー   66 ( 4-5 )   622 - 622   2017.5

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  • 好酸球、T細胞、抗原提示細胞 間質性肺炎患者における濾胞性ヘルパーT細胞サブセットについての前向き観察研究

    浅井 悠一郎, 近藤 瞬, 角 俊行, 田中 悠祐, 錦織 博貴, 宮島 さつき, 千葉 弘文, 高橋 弘彦, 亀倉 隆太, 川田 耕司, 一宮 慎吾, 重原 克則

    アレルギー   66 ( 4-5 )   595 - 595   2017.5

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  • 成人喘息 病態 アトピー型喘息における末梢血濾胞ヘルパーT細胞の活性化と治療における変化の検討

    重原 克則, 宮島 さつき, 亀倉 隆太, 川田 耕司, 高橋 弘毅, 一宮 慎吾

    アレルギー   66 ( 4-5 )   574 - 574   2017.5

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    Ichushi

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  • クラリスロマイシンは気道上皮でRSVによって誘導されるインターフェロンIRF-3を介して調整する

    山本 圭佑, 小笠原 徳子, 高野 賢一, 宮田 遼, 角木 拓也, 亀倉 隆太, 氷見 徹夫

    日本耳鼻咽喉科学会会報   120 ( 4 )   601 - 601   2017.4

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    Ichushi

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  • IgG4関連涙腺・唾液腺の病変部位におけるIgG4産生機構の解明

    伊藤 史恵, 亀倉 隆太, 川田 耕司, 高野 賢一, 氷見 徹夫, 一宮 慎吾

    日本病理学会会誌   106 ( 1 )   324 - 324   2017.3

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    Ichushi

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  • Role of Lesional BCL6hiPD-1hi T Follicular Helper Cells As a Cardinal B-Cell Helper to Produce IgG4 in IgG4-Related Disease

    Ryuta Kamekura, Kenichi Takano, Motohisa Yamamoto, Koji Kawata, Sumito Jitsukawa, Tomonori Nagaya, Fumie Ito, Chieko Tsubomatsu, Hiroki Takahashi, Tetsuo Himi, Shingo Ichimiya

    JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY   139 ( 2 )   AB13 - AB13   2017.2

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  • シラカバ花粉症の病態形成における血液濾胞ヘルパーT細胞の役割

    亀倉 隆太, 實川 純人, 長屋 朋典, 川田 耕司, 重原 克則, 一宮 慎吾, 氷見 徹夫

    耳鼻咽喉科免疫アレルギー   34 ( 2 )   48 - 49   2016.6

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    Ichushi

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  • アトピー性皮膚炎表皮におけるTSLPの発現はΔNp73に依存する

    熊谷 綾子, 山下 利春, 川田 耕司, 亀倉 隆太, 一宮 慎吾

    日本皮膚科学会雑誌   126 ( 7 )   1325 - 1325   2016.6

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    Ichushi

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  • 咳喘息患者における末梢血濾胞ヘルパーT細胞と制御性B細胞の検討

    重原 克則, 亀倉 隆太, 川田 耕司, 一宮 慎吾

    アレルギー   65 ( 4-5 )   629 - 629   2016.5

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    Ichushi

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  • 濾胞ヘルパーT細胞の分化と機能における脂質メディエーターの役割

    長屋 朋典, 亀倉 隆太, 山下 恵司, 實川 純人, 川田 耕司, 一宮 慎吾, 氷見 徹夫

    日本耳鼻咽喉科学会会報   119 ( 4 )   639 - 639   2016.4

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  • 咳喘息患者における末梢血濾胞ヘルパーT細胞と抑制性B細胞の検討

    重原 克則, 亀倉 隆太, 宮島 さつき, 川田 耕司, 高橋 弘毅, 一宮 慎吾

    日本呼吸器学会誌   5 ( 増刊 )   291 - 291   2016.3

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    Ichushi

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  • Role of Circulating ICOS plus Follicular Helper T Cells in the Pathogenesis of Birch Pollen Allergy

    Ryuta Kamekura, Koji Kawata, Sumito Jitsukawa, Tomonori Nagaya, Keiji Yamashita, Fumie Ito, Kenichi Takano, Katsunori Shigehara, Tetsuo Himi, Shingo Ichimiya

    JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY   137 ( 2 )   AB393 - AB393   2016.2

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    DOI： 10.1016/j.jaci.2015.12.1219

    Web of Science

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  • ヒト口蓋扁桃に存在する濾胞ヘルパーT細胞の機能制御機構の解明

    山下 恵司, 川田 耕司, 實川 純人, 長屋 朋典, 松宮 弘, 亀倉 隆太, 一宮 慎吾, 氷見 徹夫

    日本耳鼻咽喉科学会会報   118 ( 4 )   508 - 508   2015.4

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    DOI： 10.3950/jibiinkoka.118.508

    Ichushi

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  • 2型濾胞ヘルパーT細胞と制御性B細胞はアレルギー性鼻炎から気管支喘息への移行に関与している

    亀倉 隆太, 重原 克則, 實川 純人, 川田 耕司, 氷見 徹夫, 一宮 慎吾

    日本病理学会会誌   104 ( 1 )   452 - 452   2015.3

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  • アトピー型気管支喘息における末梢血濾胞ヘルパーT細胞の解析

    重原 克則, 亀倉 隆太, 宮島 さつき, 高橋 弘毅, 伊藤 進, 一宮 慎吾

    日本呼吸器学会誌   4 ( 増刊 )   244 - 244   2015.3

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  • リンパ管内皮細胞のリンパ管管腔形成におけるレプチンの役割

    佐藤 明紀, 亀倉 隆太, 川田 耕司, 川田 将也, 山下 恵司, 實川 純人, 熊谷 綾子, 佐藤 昇志, 一宮 慎吾

    日本病理学会会誌   104 ( 1 )   381 - 381   2015.3

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  • Role of follicular helper T cell subsets in development of human diseases

    63 ( 3 )   214 - 217   2015.3

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  • 甲状腺癌発生におけるソーティングネキシン5の機能的意義

    實川 純人, 亀倉 隆太, 川田 耕司, 熊谷 綾子, 佐藤 明紀, 長屋 朋典, 山下 恵司, 氷見 徹夫, 一宮 慎吾

    日本病理学会会誌   104 ( 1 )   391 - 391   2015.3

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  • 濾胞ヘルパーT細胞の分化誘導機構と疾患関連性の検討

    長屋 朋典, 亀倉 隆太, 山下 恵司, 實川 純人, 関 伸彦, 川田 耕司, 一宮 慎吾, 氷見 徹夫

    口腔・咽頭科   27 ( 3 )   344 - 344   2014.8

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  • POU2AF1 arranges systemic distribution of follicular helper T cells

    Keiji Yamashita, Yukari Mitsuhashi, Tomonori Nagaya, Sumito Jistukawa, Ryuta Kamekura, Nobuhiko Seki, Ayako Kumagai, Koji Kawata, Tetsuo Himi, Singo Ichimiya

    JOURNAL OF IMMUNOLOGY   192   2014.5

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  • S22-4 鼻粘膜上皮のバリア機能と免疫調節機構としての位置づけ(S22 chronic rhinosinusitisの免疫,シンポジウム,第61回日本アレルギー学会秋季学術大会)

    氷見 徹夫, 高野 賢一, 郷 充, 大國 毅, 亀倉 隆太, 小幡 和史, 計良 宗, 小島 隆, 澤田 典均

    アレルギー   60 ( 9 )   2011.10

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  • M-Like Cells of Human Adenoids in vivo and in vitro

    Ken-ichi Takano, Takashi Kojima, Noriko Ogasawara, Mitsuru Go, Shin Kikuchi, Takafumi Ninomiya, Makoto Kurose, Jun-ichi Koizumi, Ryuta Kamekura, Norimasa Sawda, Tetsuo Himi

    RECENT ADVANCES IN TONSILS AND MUCOSAL BARRIERS OF THE UPPER AIRWAYS   72   185 - 185   2011

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  • Expression and Function of Tight Junctions in the Crypt Epithelium of Human Palatine Tonsils

    Mitsuru Go, Takashi Kojima, Ken-ichi Takano, Makoto Kurose, Tsuyoshi Ohkuni, Tomoyuki Masaki, Ryuta Kamekura, Atsushi Kondo, Noriko Ogasawara, Tetsuo Himi, Norimasa Sawada

    RECENT ADVANCES IN TONSILS AND MUCOSAL BARRIERS OF THE UPPER AIRWAYS   72   185 - 186   2011

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  • The role of PPAR γ on tight junction proteins of human nasal epithelial cells and dendritic cells

    OGASAWARA N, KOJIMA T, GO M, KAMEKURA R, TAKANO K, OKUNI T, MASAKI T, SAWADA N, HIMI T

    27 ( 2 )   82 - 83   2009.2

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  • MS3-2 核内受容体PPAR-gammaを介したヒト鼻粘膜上皮細胞および樹状細胞のタイト結合の発現調節機構(抗原提示細胞,第58回日本アレルギー学会秋季学術大会)

    小笠原 徳子, 小島 隆, 郷 充, 亀倉 隆太, 高野 賢一, 大國 毅, 澤田 典均, 氷見 徹夫

    アレルギー   57 ( 9 )   2008.10

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  • EVS9-1 アレルギー性鼻炎における鼻粘膜上皮バリアと抗原認識・提示機構(イブニングシンポジウム9 鼻アレルギー-病態解明と治療の進歩-,第56回日本アレルギー学会秋季学術大会)

    氷見 徹夫, 高野 賢一, 黒瀬 誠, 小泉 純一, 亀倉 隆太, 小島 隆, 澤田 典均

    アレルギー   55 ( 8 )   2006.9

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Research Projects

  • IgG4関連疾患の解析に基づいたヒトIgEのクラススイッチの制御機構の解明

    Grant number：24K12651  2024.4 - 2027.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    大國 毅, 亀倉 隆太, 一宮 慎吾, 高野 賢一

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

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  • T 細胞疲弊を標的としたアレルギー性鼻炎の新規治療戦略

    Grant number：22K09670  2022.4 - 2026.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    山本 圭佑, 一宮 慎吾, 高野 賢一, 亀倉 隆太

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    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

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  • 唾液腺免疫性疾患における腺機能障害に対する基礎的研究

    Grant number：21K09610  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    高野 賢一, 小島 隆, 一宮 慎吾, 亀倉 隆太

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    Grant amount：\4030000 （ Direct Cost: \3100000 、 Indirect Cost：\930000 ）

    すでに確立しているヒト唾液腺腺管上皮細胞の培養系を用いて、タイト結合分子の中でも特にcutokinesisにおけるlipolysis-stimulated lipoprotein receptor (LSR)およびtricellulinに着目した。現在のところ、
    2細胞間タイト結合分子であるoccludin, claudin-7, zonula occludens-1 cingulinや極性に関与するPAR3が、cytokinesisにおいて発現増強し、上皮バリア機能も保たれ、LSRやtricellulin がアセチル化チューブリン陽性中央体やガンマチューブリン陽性中心体にHook2とともに認められた。Hook2をノックダウンすると上皮バリア機能低下や関連分子の発現が中心体から消失した。LSRの多様な機能が示唆されている。

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  • T 細胞老化に関連した慢性炎症性疾患の発症メカニズムの解明

    Grant number：21K09658  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    亀倉 隆太, 一宮 慎吾, 高野 賢一

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    Grant amount：\4030000 （ Direct Cost: \3100000 、 Indirect Cost：\930000 ）

    IgG4関連疾患(IgG4-RD)の病因としてIgG4産生に関わる適応免疫系の機能異常が存在すると考えられているが、未だ病態の全容解明には至っていない。IgG4-RDの病変部位には多数のCD4陽性T細胞の浸潤が認められ、また一方で難治性免疫関連疾患の病態背景にエフェクターヘルパーCD4陽性T細胞が関与することから、我々はCD4陽性T細胞サブセットの一つである末梢ヘルパーT(Tph)細胞に注目してIgG4-RDの病態解析を行っている。CXCR5などのケモカインレセプターの発現パターンからTph細胞は病変部位(リンパ濾胞外)で機能を発揮すると考えられており、特定のB細胞サブセットとの相互作用が推察される。今回我々はTph細胞の制御機構を明らかにするために、濾胞外B細胞(CD19+CD11c+CD21-)に着目して、IgG4-RDにおける濾胞外B細胞の機能的役割やTph細胞との相互作用について検討した。結果、IgG4-RD患者では健常者と比較して血液濾胞外B細胞の割合が増加していた。また血液Tph細胞の割合と濾胞外B細胞の割合との間に有意な正の相関関係を認めた。一方血液濾胞ヘルパーT(Tfh)細胞の割合と濾胞外B細胞の割合との間には相関関係を認めなかった。この結果から、Toll-like receptorを発現する濾胞外B細胞が抗原提示細胞としてTph細胞の分化・増殖に関与している一方で、Tph細胞が抗体産生などの濾胞外B細胞の機能を制御している可能性が考えられた。このTph細胞と濾胞外B細胞との関係は適応免疫と自然免疫のクロストークの一例といえる。Tph細胞はIgG4-RDにとどまらず、他の慢性炎症性疾患の病態形成に関与している可能性があることから、今後も検討を進めていきたい。

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  • The analysis of T follicular helper and regulatory cells of patients with atopic asthma comorbid with allergic rhinitis by treated with HDM-SLIT

    Grant number：21K08441  2021.4 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

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  • 抗PD-1抗体投与による濾胞性ヘルパーT細胞とCD4+T細胞の変動の意義

    Grant number：19K08779  2019.4 - 2023.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    加藤 潤史, 亀倉 隆太

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    Grant amount：\2990000 （ Direct Cost: \2300000 、 Indirect Cost：\690000 ）

    研究の目的は抗PD-1抗体とCD4+細胞サブセット、特に濾胞性ヘルパーT細胞にどのような影響を与えているのかを明らかにすることである。抗PD-1抗体投与による濾胞性ヘルパーT細胞の活性化が観察されている。濾胞性ヘルパーT細胞の活性化が強く観察されているのは奏効症例もしくは副作用症例で比較的多い傾向にある。濾胞性ヘルパーT細胞の活性化が治療効果予測のバイオマーカーとなる可能性が示唆される。症例数を増やすことを目標としつつ、施行した症例に対してさらなる解析を進める。

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  • New therapeutic strategy targeting cytotoxic Tfh cells for IgG4-related disease

    Grant number：18K09323  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Kamekura Ryuta

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    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    We analyzed CD4+CD8+ Tfh cells and B cell subsets from submandibular glands (SMGs) of patients with IgG4-RD by flow cytometry. The percentage of CD4+CD8+ Tfh cells in IgG4-RD SMGs was increased compared with that in tonsils and was negatively correlated with the percentage of memory B cells in IgG4-RD SMGs. In a coculture experiment with CD4+CD8+ Tfh cells and memory B cells from IgG4-RD SMGs, the amount of IgG produced by memory B cells in the culture supernatant was reduced. In vitro experiments also revealed that CD4+CD8+ Tfh cells have a functional capacity for production of a large amount of granzyme. The results suggest that the number of CD4+CD8+ Tfh cells was increased under the condition of chronic inflammation and that the cells exerted cytotoxity to memory B cells. Therefore, CD4+CD8+ Tfh cells inhibit the production of IgG from memory B cells and regulate immune responses in lesions of IgG4-RD.

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  • The mechanisms of salivary gland fibrosis in IgG4-related disease

    Grant number：18K09324  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Takano Kenichi

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    The aim of this study was to investigate the mechanisms driving fibrosis in the submandibular glands (SMG) of patients with IgG4-related disease (IgG4-RD). Our results suggest fibrosis in the SMG of affected patients is closely linked to the proliferation of fibroblasts following induction of IL-6 and WISP1 by inflammatory cytokines. The Th2 cytokines TSLP and IL-33 are also upregulated in affected SMG, and thus may cause chronic inflammation and IgG4 accumulation.

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  • Analysis of T follicular helper cells and B regulatory cells in patients with asthma comorbid with rhinitis by HDM-mites SLIT

    Grant number：18K08391  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Shigehara Katsunori

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    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    We examined T follicular helper(Tfh) cells and B regulatory(Breg) cells in patients with atopic asthma comorbid with allergic rhinitis treated with house dust mite(HDM)-sublingual immunotherapy(SLIT). Eleven patients of 18 patients showed good response. Tfh2 cells gradually decreased after 3 month therapy, conversely, Tfh1 cells gradually increased. HDM-specific IgE was transiently elevated at 3 month therapy, however, after 3 month therapy gradually decreased, HDM-specific IgG4 gradually increased for 12 months.
    Tfh2 cells showed significantly negative correlation with T follicular regulatory(Tfr) cells and T regulatory (Treg) cells after 6 month therapy in responder patients.Inhibition against Tfh2 cell by Tfr and Treg cells lead to reduced production of HDM-specific IgE, and consequently improve Th2 reaction in responder patients.

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  • Usefulness of disease-specific microRNA for respiratory syncytial virus induced lower respiratory tract inflammation

    Grant number：16K20266  2016.4 - 2018.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    Yamamoto Keisuke, HIMI Tetsuo, YOKOTA Shin-ichi, Takano Kenichi, KUROSE Makoto, KAMEKURA Ryuta, OHKUNI Tsuyoshi, OGASAWARA Noriko, YAMAMOTO Soh

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    Grant amount：\3900000 （ Direct Cost: \3000000 、 Indirect Cost：\900000 ）

    (1)Clarithromycin (CAM) as a treatment of RSV infection and (2)disease-specific microRNA as an index of disease evaluation were examined.CAM treatment led to a significant reduction in RSV-mediated IL-8, CCL5, IFN-βand -λ production.Furthermore,IFN-β promoter activity (activated by poly I:C and RSV infection) was significantly reduced after treatment with CAM.CAM also inhibited IRF-3 dimerization and subsequent translocation to the nucleus.
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    RSV infection-specific secreted miRNAs were identified. Housekeeping gene of nasal secreted miRNA was identified.

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  • New treatment strategy for allergic diseases by targeting blood type 2 follicular helper T cells and regulatory B cells

    Grant number：15K10787  2015.4 - 2018.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Kamekura Ryuta, ICHIMIYA Shingo, HIMI Tetsuo

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    Grant amount：\4810000 （ Direct Cost: \3700000 、 Indirect Cost：\1110000 ）

    We analyzed lymphocytes in blood from patients with birch pollen allergy. The percentage of circulating Tfh2 cells in blood from patients with birch pollen allergy during the non-pollen season was increased compared with that in blood from healthy volunteers. We also found that the percentage of ICOS+ Tfh cells in blood from patients with birch pollen allergy increased during the pollen season and decreased during the non-pollen season. The percentage of circulating ICOS+ Tfh cells in blood from patients with birch pollen allergy was positively correlated with total symptom scores and level of birch-specific serum IgE. In addition, an increase in Bet v1-specific MHC class 2 tetramer-positive and ICOS+ Tfh cells was seen in patients with birch pollen allergy during the pollen season. The results suggest that elevated circulating Tfh2 cells reflect an allergic predisposition and that birch-specific and ICOS+ Tfh cells play an important role in the pathogenesis of birch pollen allergy.

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  • The relationship between follicular helper T cells and pathogenesis of tonsillar hypertrophy in patients with child OSAS

    Grant number：15K20213  2015.4 - 2017.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    Tsubomatsu Chieko, HIMI Tetsuo, ICHIMIYA Shingo, KAMEKURA Ryuta, NAGAYA Tomonori, YAMASHITA Keiji, SHINTANI Tomoko, Ito Fumie

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    Grant amount：\3900000 （ Direct Cost: \3000000 、 Indirect Cost：\900000 ）

    Obstructive sleep apnea syndrome (OSAS) in childhood is caused by adeno-tonsillar hypertrophy, and adeno-tonsillectomy is commonly performed as a treatment.Histologically, tonsillar hypertrophy is characterized by prominent germinal centers (GCs). Antigen specific humoral immune responses are established by the active interactions of B and Tfh cells (follicular helper T cells) in GCs. Therefore, we focused on the potential of these cells to induce lymphoid hyperplasia promoted in OSAS pathogenesis. The results revealed that the tonsils of OSAS were considerably different from those of RT tonsils in terms of Tfh cells. Moreover, lipoxin A4 and leukotriene B4 have the capacity to differentiate naive CD4+ T cells into Tfh cells. The results suggest that such lipid mediators have a potential role in the development of lymphoid follicles through the regulation of Tfh cell differentiation and regulation of these mediators should be considered as a candidate of conservative treatment.

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  • アレルギー性鼻炎の病態形成におけるエピイムノーム機構の解明

    Grant number：26893213  2014.8 - 2015.3

    日本学術振興会  科学研究費助成事業 研究活動スタート支援  研究活動スタート支援

    亀倉 隆太

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    Grant amount：\1430000 （ Direct Cost: \1100000 、 Indirect Cost：\330000 ）

    アレルギー性鼻炎の罹患率は近年増加の一途を辿っており、その予防・治療法の開発は解決すべき喫緊の課題である。アレルギー性鼻炎に代表されるアレルギー疾患では 2 型ヘルパー T (Th2) 細胞が病態形成に関与するとされるが、抗原特異的 IgE の産生機構の本体など未だ不明な点が多く残されている。近年、液性免疫を制御するヘルパー T 細胞サブセットの 1 つである濾胞ヘルパー T (Tfh) 細胞と免疫調節機能をもつ B 細胞サブセットである制御性 B (Breg) 細胞の異常がアレルギー疾患の発症に関与しているという報告が散見され、Tfh 細胞と Breg 細胞の不均衡がアレルギー疾患の病態形成の原因となっていることが推察される。そこで今回我々は、これら2つの細胞群に焦点を当て、鼻粘膜のアレルギー炎症の発症や増悪因子としての役割について検討した。
    健常者群 (24 例)、アレルギー性鼻炎単独 (AR) 群 (23 例)、気管支喘息合併アレルギー性鼻炎 (AR + Asthma) 群 (19 例) の末梢血リンパ球中の Tfh 細胞サブセット (Tfh1, Tfh2, Tfh17細胞) とBreg 細胞の割合をフローサイトメーターで解析したところ、AR 群と AR + Asthma 群で健常者群と比較して全 Tfh 細胞に占める Tfh2 細胞の割合が増加していた。一方、Breg 細胞の全 B 細胞に占める割合は AR 群と AR + Asthma 群で健常者群と比較して減少しており、さらに AR + Asthma 群では AR 群よりも有意に Breg 細胞の割合が減少していた。
    今回の結果から、Tfh2/Breg バランスの破綻がアレルギー性鼻炎の発症、重症化にとって重要であると考えられた。

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  • Development of immunopathologic diagnosis with a new transition marker of follicular helper T cells

    Grant number：26670178  2014.4 - 2016.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research  Grant-in-Aid for Challenging Exploratory Research

    Ichimiya Shingo, HIMI Tetsuo, SATO Noriyuki, KAWATA Koji, KAMEKURA Rhyuta

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    Grant amount：\3770000 （ Direct Cost: \2900000 、 Indirect Cost：\870000 ）

    In this study, we performed functional analysis of T follicular helper (Tfh) cells and their transitional cell subsets to apply novel findings for histopathological examinations of immune-related disorders. As a result, we found high expression of a Bob1 transcription factor in Tfh cells and the involvement of Bob1 in the regulation of cell numbers of Tfh cells (Eur J Immunol. 2016). Further, we revealed that Tfh2-cell polarization preferentially occurred in the patients with allergic asthma and allergic rhinitis, as seen as Th2-cell polarization in the patients（Clin Immunol. 2015）. This implies the common mechanism underlying Tfh2-cell and Th2-cell polarization, suggesting that a manner of skewing of Tfh-cell subset would reflect a disease-specific feature of helper CD4(+) T cells. By virtue of a characteristic molecule(s) in Tfh cells and Tfh-cell subsets, further studies might lead to a new modality for histopathological diagnosis of immune-related disorders.

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  • アレルギー性鼻炎における上皮産生サイトカインの役割とその調節機構の解明

    Grant number：22791616  2010 - 2011

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    亀倉 隆太

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    Grant amount：\4030000 （ Direct Cost: \3100000 、 Indirect Cost：\930000 ）

    近年,アレルギー疾患発症の起点や増悪因子としてThymic stromal lymphopoietinやIL-25,IL-33といった,上皮細胞が産生するサイトカインが注目されている.なかでもIL-1ファミリーサイトカインのIL-33は,Th2型のアレルギー疾患への関与が指摘されており,これまで,気管支喘息やアトピー性皮膚炎での役割について数多くの報告がある.
    我々は今回、IL-33とその特異的レセプターであるST2に着目し、鼻粘膜上皮におけるIL-33とST2の役割について検討した。結果,鼻粘膜上皮はIL-33とST2遺伝子の発現を認めており,アレルギー性鼻炎の鼻粘膜においてそれらの発現が増加していた.また,アレルギー性鼻炎患者の血清IL-33値は正常コントロールと比較して有意に増加していた.次にIL-33が鼻粘膜上皮細胞に作用し、上皮産生サイトカインの発現誘導に関与しているという仮説をたて,IL-33を鼻粘膜上皮細胞に処理し,検討を行った.結果,IL-33処理により鼻粘膜上皮細胞からIL-8,GM-CSFの産生が有意に増加した.
    以上の結果から,IL-33とそのレセプターのST2はアレルギー性鼻炎の病態形成に関与している可能性が示唆された.また,アレルギー性鼻炎患者の鼻粘膜上皮では正常コントロールと比較して,IL-33由来の炎症反応が起こりやすい状態にあることが示唆された,今回の知見はIL-33/ST2経路が粘膜上皮細胞由来の炎症反応を制御するためのターゲットとなり得ること示している.

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  • The role of tight junction proteins in human pharyngeal carcinoma

    Grant number：20791208  2008 - 2009

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    KONDOH Atsushi, HIMI Tetsuo, SAWADA Norimasa, KAMEKURA Ryuta

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    In human tonsillar squamous cell carcinoma, the expression of claudin-7 and tricellulin was weak or absent, whereas claudin-1 was observed strong expression. At the invasive front, claudin-1 was stronger expression. There were not significant relationships between the tight junction expressions and HPV status.

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  • The role of dendritic cell-activating factor TSLP in allergic rhinitis

    Grant number：20791207  2008 - 2009

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    KAMEKURA Ryuta, HIMI Tetsuo, GO Mitsuru, TAKANO Kenichi, SAWADA Norimasa, KOJIMA Takashi

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine that triggers dendritic cell (DC)-mediated T helper 2-type inflammatory responses. TSLP is a master molecule for allergic inflammation such as that in asthma and atopic dermatitis. In the present study, we first found high expression of TSLP in the epithelium of allergic rhinitis with recruitment and infiltration of DCs. In human nasal epithelial cells in vitro TSLP was significantly induced by treatment with the proinflammatory cytokines and a Toll-like receptor ligand. Treatment with TSLP also enhanced the barrier function of tight junctions of human nasal epithelial cells in vitro and mouse DC line XS52 together with an increase of tight junction proteins.

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  • M細胞機能の測定

    2006 - 2008

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    Grant type：Competitive

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