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  星薬科大学   薬学部   薬学科  

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• ライフサイエンス   免疫学  

• ライフサイエンス   実験病理学  

• ライフサイエンス   病態医化学  

• ライフサイエンス   実験動物学  

• ライフサイエンス   分子生物学  

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• 札幌医科大学医学部フロンティア医学研究所   免疫制御医学部門   助教  

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• 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 ( Frontiers Media SA )  15   1441407  2024年09月  [査読有り]

  担当区分：   筆頭著者

  　概要を見る

  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^Cre/+Il9ra^fl/fl mice, which lack an IL-9-specific receptor in Tfh cells. Upon intraperitoneal immunization with sheep red blood cells (SRBCs), CD4^Cre/+Il9ra^fl/fl 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^Cre/+Il9ra^fl/fl 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⁺ 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

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

  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年02月  [査読有り]  [国際誌]

  担当区分：   筆頭著者

  　概要を見る

  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 PubMed

• 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 ( Frontiers Media SA )  14  2023年11月  [査読有り]

  　概要を見る

  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⁺ cTfh cells were significantly decreased and the percentage of IFN-γ⁺ 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

• 原発性肺癌浸潤CD4陽性T細胞組成と浸潤メカニズムの解析

  佐藤 太軌, 石井 大智, 大湯 岳, 千葉 慶宜, 鶴田 航大, 高橋 有毅, 槙 龍之輔, 高瀬 貴章, 宮島 正博, 渡辺 敦, 池上 一平, 一宮 慎吾

  肺癌 ( (NPO)日本肺癌学会 )  63 ( 2 ) 130 - 130  2023年04月  [査読有り]

• Functional Interplay between IL-9 and Peptide YY Contributes to Chronic Skin Inflammation.

  Shiori Kamiya, Ippei Ikegami, Masahiro Yanagi, Hiromi Takaki, Ryuta Kamekura, Taiki Sato, Keiju Kobayashi, Takafumi Kamiya, Yuka Kamada, Takaya Abe, Ken-Ichi Inoue, Tokimasa Hida, Hisashi Uhara, Shingo Ichimiya

  The Journal of investigative dermatology   142 ( 12 ) 3222 - 3231  2022年12月  [査読有り]  [国際誌]

  担当区分：   筆頭著者

  　概要を見る

  Complex interactions between keratinocytes and various cell types, such as inflammatory cells and stromal cells, contribute to the pathogenesis of chronic inflammatory skin lesions. In proinflammatory cytokine‒mediated disease settings, IL-9 plays a pathological role in inflammatory dermatitis. However, IL-9‒related mechanisms remain incompletely understood. In this study, we established tamoxifen-induced keratinocyte-specific IL-9RA-deficient mice (K14CRE/ERTIl9raΔ/Δ mice) to examine the role of IL-9 in multicellular interactions under chronic skin inflammatory conditions. Studies using an imiquimod-induced psoriasis-like model showed that K14CRE/ERTIl9raΔ/Δ mice exhibited a significantly reduced severity of dermatitis and mast cell infiltration compared with control K14WTIl9rafl/fl mice. Transcriptome analyses of psoriasis-like lesions showed that the level of peptide Y-Y (Pyy), a member of the neuropeptide Y family, was markedly downregulated in K14CRE/ERTIl9raΔ/Δ epidermis. Pyy blockade suppressed epidermal thickening and mast cell numbers in imiquimod-treated wild-type mice. Together with in vitro studies indicating that Pyy induced IL-9 production and chemotactic activity in bone marrow‒derived mast cells, these findings suggest that Pyy-mediated interplay between keratinocytes and mast cells contributes to psoriasiform inflammation. Further investigation focusing on the IL-9‒Pyy axis may provide valuable information for the development of new treatment modalities for inflammatory dermatitis.

  DOI PubMed

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• インターロイキン9による濾胞ヘルパーT細胞の病態制御機構の解明

  若手研究

  研究期間:

  2022年04月

  -

  2025年03月

   

  池上 一平

• 転写共役因子Bob1による濾胞ヘルパーT細胞の免疫記憶制御機構の解明

  研究活動スタート支援

  研究期間:

  2021年08月

  -

  2023年03月

   

  池上 一平

  　研究概要を見る

  自己免疫疾患やアレルギー疾患などの免疫難病の病態背景として抗原特異的抗体の産生異常があるため、病態解明に向けてこの機構に着目した研究が多角的に行われている。研究代表者（池上）の所属する研究室はこれまでにBob1転写共役因子がCD4陽性エフェクターヘルパーT(CD4+T)細胞群の中で、抗原特異的抗体の産生機能を司る濾胞ヘルパーT(Tfh)細胞に高発現していることを同定し(Yamashita K. et al, Eur. J. Immunol., 2016)、Bob1の機能的意義に着目して研究を行っている。Bob1は、Tfh細胞の他に抗原特異的抗体の産生に寄与するB2細胞に発現していることから、本研究ではCD4+T細胞特異的Bob1欠損(Bob1 CD4KO)マウスを新たに作出した。2021年度はこのBob1 CD4KOマウスを用いて、Tfh細胞の抗体産生誘導機能と免疫記憶機能におけるBob1の役割を検討した。液性免疫応答について解析した結果、Bob1 CD4KOマウスでは抗原特異的な血清抗体価が有意に低下していた。さらにBob1が、Tfh細胞の数的制御ならびに免疫チェックポイント分子発現制御に関与している事実が明らかとなった。これらの結果をまとめ、Tfh細胞の抗体産生制御機構におけるBob1の機能的役割を学会報告した(The 50th Annual Meeting of The Japanese Society for Immunology, 2021年12月)。2021年度の各種検討より外来抗原の再投与時期に液性免疫応答の変化が顕著だったことから、2022年度はこの時点に焦点を絞り、Tfh細胞における免疫記憶機構とBob1との関連を解明していく。