New therapeutic strategy for multiple sclerosis modifying pathogenetic T cell differentiation

• Project/Area Number: 18K07038
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Chiba University
• Principal Investigator: Sakamoto Akemi 千葉大学, バイオメディカル研究センター, 准教授 (90359597)
• Co-Investigator(Kenkyū-buntansha): 幡野 雅彦 千葉大学, 大学院医学研究院, 教授 (20208523) ; 藤村 理紗 千葉大学, バイオメディカル研究センター, 助教 (30376363)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 実験的自己免疫性脳脊髄膜炎 / リンパ球 / 転写因子 / 神経疾患 / T細胞

Outline of Final Research Achievements

Multiple sclerosis is serious inflammatory neurological disease and number of patients is increasing in Japan. To establishment of new therapies, we searched transcription factors (TF) which affect neurological symptom of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We found TFX played vital roles because TFX flox/flox CD4Cre mice did not develop EAE. TFX was critical TF for development of pathogenetic CD4 T cells in neurological organs. Furthermore, TFX inhibition induced recovery of neurological symptoms. We searched inhibitors of TFX among small chemical drug library and found 29 chemical drugs classified 4 groups. These results could be useful for establishment of novel therapeutic method for multiple sclerosis.

Academic Significance and Societal Importance of the Research Achievements

多発性硬化症は再発を繰り返し、歩行障害、視力障害などの重篤な機能障害をきたす難治性慢性炎症性疾患である。さらに本国でも患者数が増加しており、完全寛解できる治療法の確立は喫緊の課題である。現在、ステロイド剤、血漿交換などが一部症例に有効であること、またインターフェロンが再発予防に有効であることから、免疫学的な異常が病態に関わることが示唆されるが、詳細な発症機序は明らかにされていない。疾患発症、増悪に関わる免疫応答を標的とした新規治療法が開発できれば有用性は計り知れない。

Research Products

• [Journal Article] Genetic background-dependent abnormalities of the enteric nervous system and intestinal function in Kif26a-deficient mice. (2021)
  • Author(s): Ohara Y, Fujimura L, Sakamoto A, Teratake Y, Hiraoka S, Koseki H, Saito T, Terui K, Mitsunaga T, Nakata M, Yoshida H, Hatano M.
  • Journal Title: Sci Rep. Volume: 4;11(1) Issue: 1 Pages: 3191-3191
  • DOI: 10.1038/s41598-021-82785-1
  • Peer Reviewed / Open Access
• [Journal Article] Essential role of microgrial transforming growth factor-b1 in antidepressant actions of ®-ketamine and the novel antidepressant TGF-b1. (2020)
  • Author(s): Zang K, Chun Y, Chang L, Sakamoto A, Suzuki T, Fujita Y, Youge Q, Siming W, Yoayu P, Yunfei T, Xingming W, Ishima T, Shirayama Y, Hatano M, Tanaka K, Hashimoto K.
  • Journal Title: Translational Psychiatry Volume: 10 Pages: 32-43
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Splenic NKG2D confers resilience versus susceptibility in mice after chronic social defeat stress: beneficial effects of (R)-ketamine (2019)
  • Author(s): Zhang K, Sakamoto A, Chang L, Qu Y, Wang S, Pu Y, Tan Y, Wang X, Fujita Y, Ishima T, Hatano M, Hashimoto K.
  • Journal Title: Eur Arch Psychiatry Clin Neurosci. Volume: 270 Issue: 3 Pages: 1-10
  • DOI: 10.1007/s00406-019-01092-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Allergic TH2 Response Governed by B-Cell Lymphoma 6 Function in Naturally Occurring Memory Phenotype CD4+ T Cells (2018)
  • Author(s): Takashi Ogasawara,Yuko Kohashi,Jun Ikari,Toshibumi Taniguchi,Nobuhide Tsuruoka,Haruko Watanabe-Takano,Lisa Fujimura,Akemi Sakamoto,Masahiko Hatano,Hirokuni Hirata,Yasutsugu Fukushima,Takeshi Fukuda,Kazuhiro Kurasawa,Koichiro Tatsumi,Takeshi Tokuhisa,Masafumi Arima
  • Journal Title: Frontiers in Immunology Volume: 9 Pages: 750-750
  • DOI: 10.3389/fimmu.2018.00750
  • Peer Reviewed / Open Access
• [Journal Article] Establishment and analyses of a mouse model that regulates sex-related differences in drug metabolism in the liver. (2018)
  • Author(s): Chikada H, Ida K, Ando E, Inagaki Y, Sakamoto A, Kamiya A.
  • Journal Title: Laboratory Investigation Volume: 98 Issue: 11 Pages: 1500-1511
  • DOI: 10.1038/s41374-018-0088-6
  • Peer Reviewed / Open Access
• [Presentation] 腸管炎症における制御性T細胞の役割とオートファジーの関与 (2019)
  • Author(s): 中嶋利典、坂本明美、藤村理紗、清宮航、文田貴志、大森智瑛、幡野雅彦
  • Organizer: 第42回日本分子生物学会総会
• [Presentation] Ncx KOマウスを用いたプロポリスの腸管バリア機能改善に及ぼす効果の検討 (2019)
  • Author(s): 清宮航、藤村理紗、坂本明美、中嶋利典、文田貴志、幡野雅彦
  • Organizer: 第42回日本分子生物学会総会
• [Presentation] Role of enteric neuron in eosinophil induction (2019)
  • Author(s): Lisa Fujimura, Akemi Sakamoto, Takashi Fumita, Masahiko Hatano
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Analysis of the frequency and function of regulatory T-cell using human blood samples in biliary atresia. (2019)
  • Author(s): Satoru Oita, Takeshi Saito, Akemi Sakamoto, Keita Terui, Shugo Komatsu, Kazuaki Harada, Yoshitaka Shinno, Lisa Fujimura, Masahiko Hatano, Hideo Yoshida
  • Organizer: The Pacific Association of Pediatric Surgeons 52nd Annual Meeting
  • Int'l Joint Research
• [Presentation] 胆道閉鎖症の病態形成における制御性T細胞の意義 (2018)
  • Author(s): 笈田 諭, 齋藤 武, 坂本 明美, 照井 慶太, 中田 光政, 小松 秀吾, 原田 和明, 秦 佳孝, 勝海 大輔, 古金 遼也, 藤村理紗, 幡野 雅彦, 吉田 英生
  • Organizer: 第45回日本胆道閉鎖症研究会
• [Presentation] Roles of enteric neurons in gut mucosal immunity (2018)
  • Author(s): Lisa Fujimura, Akemi Sakamoto, Masahiko Hatano
  • Organizer: 第47回日本免疫学会学術集会
• [Remarks] 千葉大学 バイオメディカル研究センター
• [Remarks] 千葉大学大学院医学研究院 疾患生命医学
• [Remarks] 千葉大学 バイオメディカル研究センター
• [Remarks] 千葉大学大学院医学研究院 疾患生命医学
• [Remarks] 千葉大学 バイオメディカル研究センター
• [Remarks] 千葉大学大学院医学研究院 疾患生命医学