The regulation of metabolic system by IFN and its involvement in B cell and T cell differentiation: new therapeutic strategy for SLE

• Project/Area Number: 16K09928
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: Iwata Shigeru 産業医科大学, 医学部, 助教 (60389434)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: SLE / 免疫細胞代謝 / B細胞 / T細胞 / T-bet / mTORC1 / AMPK / 解糖系 / IFN / リンパ球 / 細胞内代謝システム

Outline of Final Research Achievements

Systemic lupus Erythematosus (SLE) is refractory autoimmune disease. Although corticosteroid and immunosuppressant are mainly used as the therapy, there are some problems such as treatment resistance and adverse effect. Therefore, new therapeutic strategy is further needed. Recently "immunometabolism" attract much attention. Activation and differentiation of immunocompetent cells depends on rapid synthesis of cell structure components and biomolecules, therefore, demanding enormous amounts of energy such as ATP, nucleic acids and lipids. In this study, we have clarified the importance of immunometabolism for B cell and T cell differentiation and its relevance to the pathogenesis of autoimmune diseases such as SLE.

Academic Significance and Societal Importance of the Research Achievements

近年免疫代謝という概念が注目を集めている。免疫学などの基礎医学分野、特にマウスを用いた研究においてその機構は次第に明らかになりつつあるが、ヒト免疫細胞、リンパ球分化における免疫代謝の役割や機序、自己免疫疾患（特にSLE）病態への関与については依然不詳である。本研究では、基礎医学分野では注目されるが、自己免疫疾患領域では未開拓である免疫代謝の研究を、SLE病態解明に繋げることで、SLEの新規治療戦略を探求することを目的としている。また本研究は、感染症、癌治療、アレルギー疾患など他分野への応用も期待される。

Research Products

• [Journal Article] Metabolic Reprogramming Commits Differentiation of Human CD27+IgD+ B Cells to Plasmablasts or CD27-IgD- Cells. (2017)
  • Author(s): 9.Torigoe M, Iwata S, Nakayamada S, Sakata K, Zhang M, Hajime M, Miyazaki Y, Narisawa M, Ishii K, Shibata H, Tanaka Y.
  • Journal Title: The Journal of immunology Volume: 199 Pages: 425-434
  • DOI: 10.4049/jimmunol.1601908
  • Peer Reviewed
• [Presentation] IFN-γ-T-betを介したCD4+T細胞代謝変容とSLE病態への関与 (2018)
  • Author(s): 岩田慈、張明増、元舞子、阪田圭、山形薫、中山田真吾、田中良哉
  • Organizer: 日本臨床免疫学会
• [Presentation] ヒトB細胞分化における免疫代謝の役割と自己免疫病態への関与 (2018)
  • Author(s): 岩田慈、田中良哉
  • Organizer: 日本臨床免疫学会
  • Invited
• [Presentation] mTORC1 phosphorylation in CXCR3+ memory B cells and its relevance to the pathogenesis of rheumatoid arthritis (2018)
  • Author(s): Shigeru Iwata, Mingzeng Zhang, Maiko Hajime, Jie Fan, Kei Sakata, Naoaki Ohkubo, Kazuhisa Nakano, Shingo Nakayamada, Yoshiya Tanaka
  • Organizer: 日本免疫学会
• [Presentation] Metabolic reprogramming in CD4+CD28-CXCR3intT-bethi cells and its relevance to pathogenesis in patients with SLE (2017)
  • Author(s): Shigeru Iwata, Kei Sakata, Maiko Hajime, Masataka Torigoe, Naoaki Ohkubo, Shingo Nakayamada, Yoshiya Tanaka
  • Organizer: LUPUS2017
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2017-03-26
  • Int'l Joint Research
• [Presentation] IFN-γ-T-bet mediated metabolic reprograming in T helper 1 cells and its relevance to pathogenesis of SLE (2017)
  • Author(s): Shigeru Iwata, Yuka Kanno, Kei Sakata, Mingzeng Zhang, Maiko Hajime, Naoaki Ohkubo, Shingo Nakayamada, John J O’Shea and Yoshiya Tanaka
  • Organizer: 第46回免疫学会
• [Presentation] IFN-γ-T-betを介したTh1細胞代謝変容とSLE病態への関与 (2017)
  • Author(s): 岩田慈、菅野由香、阪田圭、元舞子、張明増、中山田真吾、John J. O’Shea, 田中良哉
  • Organizer: 第45回 日本臨床免疫学会
• [Presentation] Metabolic reprogramming in CD4+CD28-CXCR3intT-bethi cells and its relevance to pathogenesis of SLE (2016)
  • Author(s): Shigeru Iwata, Masataka Torigoe, Naoaki Ohkubo, Maiko Hajime, Shingo Nakayamada, Yoshiya Tanaka
  • Organizer: 第45回日本免疫学会
  • Place of Presentation: 沖縄コンベンションセンター、沖縄県宜野湾市
  • Year and Date: 2016-12-05
• [Presentation] 自己免疫疾患におけるB細胞代謝リプログラミングと病態への関与 (2016)
  • Author(s): 岩田慈、鳥越雅隆、阪田圭、元舞子、中山田真吾、田中良哉
  • Organizer: 第44回日本臨床免疫学会
  • Place of Presentation: 京王プラザホテル、東京都新宿区
  • Year and Date: 2016-09-08
  • Invited
• [Presentation] IFNsのT-betを介したT細胞代謝リプログラミングと自己免疫疾患への関与 (2016)
  • Author(s): 岩田慈、菅野由香、阪田圭、中山田真吾、John J. O’Shea, 田中良哉
  • Organizer: 第44回日本臨床免疫学会
  • Place of Presentation: 京王プラザホテル、東京都新宿区
  • Year and Date: 2016-09-08
  • Invited
• [Presentation] ABNORMAL B CELL ACTIVATION THROUGH CELLULAR METABOLIC REPROGRAMMING AND ITS RELEVANCE TO THE PATHOGENESIS OF SLE. (2016)
  • Author(s): Masataka Torigoe, Shigeru Iwata, Kei Sakata, Shingo Nakayamada, Yoshiya Tanaka
  • Organizer: EULAR2016
  • Place of Presentation: London, UK
  • Year and Date: 2016-06-08
  • Int'l Joint Research