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

• Project/Area Number: 15K10787
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: Sapporo Medical University
• Principal Investigator: Kamekura Ryuta 札幌医科大学, 医学部, 講師 (70404697)
• Co-Investigator(Renkei-kenkyūsha): ICHIMIYA Shingo 札幌医科大学, 医学部附属フロンティア医学研究所・免疫制御医学部門, 教授 (30305221) ; HIMI Tetsuo 札幌医科大学, 耳鼻咽喉科, 教授 (90181114)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 濾胞ヘルパーT細胞 / Tfh2細胞 / シラカバ花粉症 / アレルギー性鼻炎 / ICOS / Tfh細胞 / 制御性B細胞 / Tfh 細胞 / Tfh2 細胞

Outline of Final Research Achievements

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.

Research Products

• [Journal Article] Stage classification of IgG4-related dacryoadenitis and sialadenitis by the serum cytokine environment (2018)
  • Author(s): Motohisa Yamamoto, Kenichi Takano, Ryuta Kamekura, Chisako Suzuki, Shingo Ichimiya, Tetsuo Himi, Hiroshi Nakase & Hiroki Takahashi
  • Journal Title: Modern Rheumatology Volume: 印刷中 Issue: 6 Pages: 1-5
  • DOI: 10.1080/14397595.2018.1436029
  • Peer Reviewed
• [Journal Article] Potential utility of core needle biopsy in the diagnosis of IgG4-related dacryoadenitis and sialadenitis (2018)
  • Author(s): Takano Kenichi、Okuni Tsuyoshi、Yamamoto Keisuke、Kamekura Ryuta、Yajima Ryoto、Yamamoto Motohisa、Takahashi Hiroki、Himi Tetsuo
  • Journal Title: Modern Rheumatology Volume: in press Issue: 2 Pages: 1-11
  • DOI: 10.1080/14397595.2018.1465665
  • Peer Reviewed
• [Journal Article] Keratinocytes in atopic dermatitis express abundant ΔNp73 regulating thymic stromal lymphopoietin production via NF-κB (2017)
  • Author(s): Kumagai Ayako、Kubo Terufumi、Kawata Koji、Kamekura Ryuta、Yamashita Keiji、Jitsukawa Sumito、Nagaya Tomonori、Sumikawa Yasuyuki、Himi Tetsuo、Yamashita Toshiharu、Ichimiya Shingo
  • Journal Title: Journal of Dermatological Science Volume: 88 Issue: 2 Pages: 175-183
  • DOI: 10.1016/j.jdermsci.2017.06.017
  • Peer Reviewed
• [Journal Article] High frequency of Bob1 lo T follicular helper cells in florid reactive follicular hyperplasia (2017)
  • Author(s): Matsumiya Hiroshi、Kawata Koji、Kamekura Ryuta、Tsubomatsu Chieko、Jitsukawa Sumito、Asai Takamasa、Akasaka Syunsuke、Kamei Motonari、Yamashita Keiji、Ito Fumie、Kubo Terufumi、Sato Noriyuki、Takano Ken-ichi、Himi Tetsuo、Ichimiya Shingo
  • Journal Title: Immunology Letters Volume: 191 Pages: 23-30
  • DOI: 10.1016/j.imlet.2017.07.012
  • Peer Reviewed
• [Journal Article] Loss of sorting nexin 5 stabilizes internalized growth factor receptors to promote thyroid cancer progression (2017)
  • Author(s): Jitsukawa Sumito、Kamekura Ryuta、Kawata Koji、Ito Fumie、Sato Akinori、Matsumiya Hiroshi、Nagaya Tomonori、Yamashita Keiji、Kubo Terufumi、Kikuchi Tomoki、Sato Noriyuki、Hasegawa Tadashi、Kiyonari Hiroshi、Mukumoto Yoshiko、Takano Ken-ichi、Himi Tetsuo、Ichimiya Shingo
  • Journal Title: The Journal of Pathology Volume: 243 Issue: 3 Pages: 342-353
  • DOI: 10.1002/path.4951
  • Peer Reviewed / Open Access
• [Journal Article] Cutting Edge: A Critical Role of Lesional T Follicular Helper Cells in the Pathogenesis of IgG4-Related Disease (2017)
  • Author(s): Kamekura Ryuta、Takano Kenichi、Yamamoto Motohisa、Kawata Koji、Shigehara Katsunori、Jitsukawa Sumito、Nagaya Tomonori、Ito Fumie、Sato Akinori、Ogasawara Noriko、Tsubomatsu Chieko、Takahashi Hiroki、Nakase Hiroshi、Himi Tetsuo、Ichimiya Shingo
  • Journal Title: The Journal of Immunology Volume: 199 Issue: 8 Pages: 2624-2629
  • DOI: 10.4049/jimmunol.1601507
  • Peer Reviewed / Open Access
• [Journal Article] Clinical utility of 18F-fluorodeoxyglucose/positron emission tomography in diagnosis of immunoglobulin G4-related sclerosing sialadenitis (2017)
  • Author(s): Takano Kenichi、Yajima Ryoto、Kamekura Ryuta、Yamamoto Motohisa、Takahashi Hiroki、Yama Naoya、Hatakenaka Masamitsu、Himi Tetsuo
  • Journal Title: The Laryngoscope Volume: 128 Issue: 5 Pages: 1120-1125
  • DOI: 10.1002/lary.26945
  • Peer Reviewed
• [Journal Article] 各種吸入性抗原の感作と口腔咽頭過敏症を起こす原因食物 (2017)
  • Author(s): 山本哲夫、朝倉光司、白崎英明、亀倉隆太、氷見徹夫
  • Journal Title: 日本耳鼻咽喉科学会会報 Volume: 120 Pages: 1147-1154
  • NAID: 130006880952
  • Peer Reviewed
• [Journal Article] IMPORTANCE OF “EPIMMUNOME” AS A NEW THERAPEUTIC TARGET FOR ALLERGIC RHINITIS (2017)
  • Author(s): 亀倉隆太、一宮慎吾、氷見徹夫
  • Journal Title: Japanese Journal of Allergology Volume: 66 Issue: 2 Pages: 91-96
  • DOI: 10.15036/arerugi.66.91
  • NAID: 130005466714
  • ISSN: 0021-4884, 1347-7935
• [Journal Article] Lipid mediators foster the differentiation of T follicular helper cells (2017)
  • Author(s): Nagaya T
  • Journal Title: Immunology Letters Volume: 181 Pages: 51-57
  • DOI: 10.1016/j.imlet.2016.11.006
  • Peer Reviewed
• [Journal Article] Functional RNAs control T follicular helper cells (2017)
  • Author(s): Ichimiya S, Kamekura R, Kawata K, Kamei M, Asai M, Akasaka S, Himi T
  • Journal Title: J Hum Genet Volume: 62 Issue: 1 Pages: 81-86
  • DOI: 10.1038/jhg.2016.88
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clarithromycin prevents human respiratory syncytial virus-induced airway epithelial responses by modulating activation of interferon regulatory factor-3. (2016)
  • Author(s): Yamamoto K, Yamamoto S, Ogasawara N, Takano K, Shiraishi T, Sato T, Miyata R, Kakuki T, Kamekura R, Kojima T, Tsutsumi H, Himi T, Yokota S.
  • Journal Title: Pharmacol Res Volume: 111 Pages: 804-814
  • DOI: 10.1016/j.phrs.2016.07.033
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Novel Mechanisms of Compromised Lymphatic Endothelial Cell Homeostasis in Obesity: The Role of Leptin in Lymphatic Endothelial Cell Tube Formation and Proliferation (2016)
  • Author(s): Sato A, Kamekura R, Kawata K, Kawada M, Jitsukawa S, Yamashita K, Sato N, Himi T, Ichimiya S
  • Journal Title: PLoS One Volume: 11 Issue: 7 Pages: 1-17
  • DOI: 10.1371/journal.pone.0158408
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of crosstalk between epithelial and immune cells, the epimmunome, in allergic rhinitis pathogenesis (2016)
  • Author(s): Kamekura R, Yamashita K, Jitsukawa S, Nagaya T, Ito F, Ichimiya S, Himi T
  • Journal Title: Adv Otorhinolaryngol Volume: 77 Pages: 75-82
  • DOI: 10.1159/000441878
  • ISBN: 9783318056501, 9783318056518
• [Journal Article] Studies of Tonsils in Basic and Clinical Perspectives: From the Past to the Future (2016)
  • Author(s): Yamashita K, Ichimiya S, Kamekura R, Nagaya T, Jitsukawa S, Matsumiya H, Takano K, Himi T.
  • Journal Title: Adv Otorhinolaryngol Volume: 77 Pages: 119-124
  • DOI: 10.1159/000441902
  • ISBN: 9783318056501, 9783318056518
• [Journal Article] Expression and localization of human defensins in palatine tonsils (2016)
  • Author(s): Kamekura R, Imai R, Takano K, Yamashita K, Jitsukawa S, Nagaya T, Ito F, Hirao M, Tsubota H, Himi T
  • Journal Title: Adv Otorhinolaryngol Volume: 77 Pages: 112-118
  • DOI: 10.1159/000441888
  • ISBN: 9783318056501, 9783318056518
• [Journal Article] Bob1 limits cellular frequency of T follicular helper cells (2016)
  • Author(s): Yamashita K, Kawata K, Matsumiya H, Kamekura R, Jitsukawa S, Nagaya T, Ogasawara N, Takano K, Kubo T, Kimura S, Shigehara K, Himi T, Ichimiya S.
  • Journal Title: European Journal of Immunology Volume: in press Issue: 6 Pages: 1361-1370
  • DOI: 10.1002/eji.201545499
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinicopathological analysis of salivary gland tissue from patients with IgG4-related disease. (2016)
  • Author(s): Takano K, Nomura K, Abe A, Kamekura R, Yamamoto M, Ichimiya S, Takahashi H, Himi T
  • Journal Title: Acta Otolaryngol Volume: 未定 Issue: 7 Pages: 1-5
  • DOI: 10.3109/00016489.2016.1154605
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 14-3-3 Proteins regulate Akt Thr308 phosphorylation in intestinal epithelial cells (2016)
  • Author(s): Gomez-Suarez M, Gutierrez-Martinez IZ, Hernandez-Trejo JA, Hernandez-Ruiz M, Suarez-Perez D, Candelario A, Kamekura R, Medina-Contreras O, Schnoor M, Ortiz-Navarrete V, Villegas-Sepulveda N, Parkos C, Nusrat A, Nava P
  • Journal Title: Cell Death Differ Volume: In press Issue: 6 Pages: 0-0
  • DOI: 10.1038/cdd.2015.163
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ヒト臨床検体を用いた研究がもたらすアレルギー性鼻炎の新規治療戦略 (2016)
  • Author(s): 亀倉隆太
  • Journal Title: 日鼻誌 Volume: 55 Pages: 66-69
  • NAID: 130005149445
• [Journal Article] Functional RNAs control T follicular helper cells (2016)
  • Author(s): Ichimiya S, Kamekura R, Kawata K, Kamei M, Asai M, Akasaka S, Himi T
  • Journal Title: J Hum Genet Volume: In press Pages: 0-0
  • Peer Reviewed
• [Journal Article] Bob1 limits the cellular frequency of T follicular helper cells (2016)
  • Author(s): Yamashita K, Kawata K, Matsumiya H, Kamekura R, Jitsukawa S, Nagaya T, Ogasawara N, Takano K, Kubo T, Kimura S, Shigehara K, Himi T, Ichimiya S
  • Journal Title: Eur J Immunol Volume: In press Pages: 0-0
  • Peer Reviewed
• [Journal Article] Inflammation-induced desmoglein-2 ectodomain shedding compromises the mucosal barrier (2015)
  • Author(s): Kamekura R, Nava P, Feng M, Quiros M, Nishio H, Weber DA, Parkos CA, Nusrat A
  • Journal Title: Mol Biol Cell Volume: 26 Issue: 18 Pages: 3165-77
  • DOI: 10.1091/mbc.e15-03-0147
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Alteration of circulating type 2 follicular helper T cells and regulatory B cells underlies the comorbid association of allergic rhinitis with bronchial asthma (2015)
  • Author(s): 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
  • Journal Title: Clinical Immunology Volume: in press Issue: 2 Pages: 120-5
  • DOI: 10.1016/j.clim.2015.02.016
  • Peer Reviewed / Open Access
• [Presentation] Unique profiles of lesional T follicular helper cells in the pathogenesis of IgG4-related disease (2018)
  • Author(s): Ryuta Kamekura, Hayato Yabe, Kenichi Takano, Motohisa Yamamoto, Ippei Ikegami, Fumie Ito, Hiroki Takahashi, Tetsuo Himi, Shingo Ichimiya
  • Organizer: AAAAI/WAC 2018 米国アレルギー・喘息・免疫学会議
  • Int'l Joint Research
• [Presentation] Role of lesional BCL6hiPD-1hi T follicular helper cells as a cardinal B-cell helper to produce IgG4 in IgG4-related disease (2017)
  • Author(s): Ryuta Kamekura, Kenichi Takano, Motohisa Yamamoto, Koji Kawata, Sumito Jitsukawa, Tomonori Nagaya, Fumie Ito, Chieko Tsubomatsu, Hiroki Takahashi, Tetsuo Himi, Shingo Ichimiya
  • Organizer: 第73回米国アレルギー・喘息・免疫学会議 (AAAAI 2016)
  • Place of Presentation: 米国 アトランタ
  • Year and Date: 2017-03-04
  • Int'l Joint Research
• [Presentation] IgG4関連涙腺・唾液腺炎の病変部位における濾胞ヘルパーT細胞の機能的役割 (2017)
  • Author(s): 亀倉隆太、高野賢一、伊藤史恵、一宮慎吾、氷見徹夫
  • Organizer: 第 35 回日本耳鼻咽喉科免疫アレルギー学会
• [Presentation] 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 (2017)
  • Author(s): 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
  • Organizer: 第66回日本アレルギー学会学術大会
• [Presentation] IgG4関連涙腺唾液腺炎のステロイド治療前後での血液機能性リンパ球サブセットの動態 (2017)
  • Author(s): 亀倉隆太、高野賢一、伊藤史恵、一宮慎吾、氷見徹夫
  • Organizer: 第30回日本口腔・咽頭科学会総会ならびに学術講演会
• [Presentation] 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 (2017)
  • Author(s): 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
  • Organizer: 第45回日本臨床免疫学会総会
• [Presentation] Role of activated T follicular helper cells in the pathogenesis of IgG4-related disease (2016)
  • Author(s): Ryuta Kamekura, Koji Kawata, Sumito Jitsukawa, Fumie Ito, Katsunori Shigehara, Tetsuo Himi, Shingo Ichimiya
  • Organizer: 第 45 回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター（宜野湾市）
  • Year and Date: 2016-12-05
• [Presentation] 活性化濾胞ヘルパー T 細胞によるシラカバ花粉症の病態形成のメカニズムの解明 (2016)
  • Author(s): 亀倉隆太、實川純人、長屋朋典、伊藤史恵、坪松ちえ子、一宮慎吾、氷見徹夫
  • Organizer: 第 55 回日本鼻科学会総会・学術講演会
  • Place of Presentation: 栃木県総合文化センター（宇都宮市）
  • Year and Date: 2016-10-13
• [Presentation] IgG4 関連涙腺・唾液腺炎における活性化濾胞ヘルパー T 細胞のIgG4 産生への関与 (2016)
  • Author(s): 亀倉隆太、高野賢一、長屋朋典、實川純人、伊藤史恵、坪松ちえ子、一宮慎吾、氷見徹夫
  • Organizer: 第 29 回日本口腔・咽頭科学会総会ならびに学術講演会
  • Place of Presentation: 松江テルサ（松江市）
  • Year and Date: 2016-09-08
• [Presentation] シンポジウム2 アレルギー性鼻炎：ここまで解った病態―治療への展望― (2016)
  • Author(s): 亀倉隆太、高野賢一、實川純人、伊藤史恵、小笠原徳子、一宮慎吾、氷見徹夫
  • Organizer: 第 65 回日本アレルギー学会学術大会
  • Place of Presentation: 東京国際フォーラム(東京都千代田区）
  • Year and Date: 2016-06-17
• [Presentation] Role of circulating ICOS+ follicular helper T cells in the pathogenesis of birch pollen allergy (2016)
  • Author(s): Ryuta Kamekura, Koji Kawata, Sumito Jitsukawa, Tomonori Nagaya, Keiji Yamashita, Fumie Ito, Kenichi Takano, Katsunori Shigehara, Tetsuo Himi, Shingo Ichimiya
  • Organizer: 第 72 回米国アレルギー・喘息・免疫学会議（AAAAI 2016）
  • Place of Presentation: 米国 ロサンゼルス
  • Year and Date: 2016-03-04
  • Int'l Joint Research
• [Presentation] 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 (2016)
  • Author(s): 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
  • Organizer: 第 34 回日本耳鼻咽喉科免疫アレルギー学会
  • Place of Presentation: 鳥羽国際ホテル（鳥羽市）
  • Year and Date: 2016-02-04
• [Presentation] Relative decrease in regulatory B cells is associated with the progression of allergic rhinitis to bronchial asthma under the unique skewing of type 2 follicular helper T cells (2015)
  • Author(s): Ryuta Kamekura, Katsunori Shigehara, Sumito Jitsukawa, Tomonori Nagaya, Koji Kawata, Tetsuo Himi, Shingo Ichimiya
  • Organizer: 第 44 回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（札幌市）
  • Year and Date: 2015-11-18
• [Presentation] The analysis of follicular helper T cell in the patients with chronic obstructive pulmonary disease (2015)
  • Author(s): Katsunori Shigehara, Ryuta Kamekura, Koji Kawata, Tomonori Nagaya, Tetsuo Himi, Shingo Ichimiya
  • Organizer: 第 44 回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（札幌市）
  • Year and Date: 2015-11-18
• [Presentation] Functional involvement of BOB1 in the numerical regulation of follicular helper T cells (2015)
  • Author(s): Koji Kawata, Keiji Yamashita, Hiroshi Matsumiya, Ryuta Kamekura, Sumito Jitsukawa, Tomonori Nagaya, Katsunori Shigehara, Nobuhiko Seki, Tetsuo Himi, Shingo Ichimiya
  • Organizer: 第 44 回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（札幌市）
  • Year and Date: 2015-11-18
• [Presentation] 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 (2015)
  • Author(s): 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
  • Organizer: 第 64 回日本アレルギー学会学術大会
  • Place of Presentation: グランドプリンスホテル新高輪 国際館パミール（東京都港区）
  • Year and Date: 2015-05-26
• [Presentation] 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 (2015)
  • Author(s): 亀倉隆太、重原克則、實川純人、川田耕司、氷見徹夫、一宮慎吾
  • Organizer: 第 104 回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
  • Year and Date: 2015-04-30
• [Presentation] 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 (2015)
  • Author(s): 重原克則、亀倉隆太、宮島さつき、高橋弘毅、伊藤 進、一宮慎吾
  • Organizer: 第 55 回日本呼吸器学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2015-04-17
• [Remarks] 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〕
  • URL: http://web.sapmed.ac.jp/immunology/index.html
• [Remarks] 札幌医大耳鼻咽喉科
  • URL: http://web.sapmed.ac.jp/otol/
• [Remarks] 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 ホームページ
  • URL: http://web.sapmed.ac.jp/immunology/index.html