Analyses of cellular component involved in heterogeneous inflammatory pathogenesis of autoimmne diseases in the CNS

• Project/Area Number: 24590108
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: OKI SHINJI 独立行政法人国立精神・神経医療研究センター, 神経研究所 疾病研究第六部, 室長 (50260328)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 自己免疫疾患 / 多発性硬化症 / Th17細胞 / NR4A2 / 細胞間相互作用 / 炎症性ミエロイド細胞 / 病態多様性 / バイオマーカー / 実験的自己免疫性脳脊髄炎 / インターロイキン17 / 慢性炎症 / 核内受容体 / インターロイキン１７

Outline of Final Research Achievements

We have demonstrated that NR4A2 influences Th17 differentiation and controls pathogenic Th17 responses in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis. The prolonged NR4A2 expression in the central nervous system (CNS) is induced by a particular populations of inflammatory myeloid cells (IMC) isolated from the CNS during EAE and drive differentiation of Th17 cells. EAE symptoms in NR4A2cKO mice are greatly reduced concomitant with reduced infiltration of such IMC. Intriguingly, a late/chronic disease irrelevant of NR4A2-mediated Th17 responses emerged in those animals. A unique CD4+ T cell subset accumulated in CNS shows a typical pathogenic property. A specific marker gene upregulated in this Th cell subset is identified. Treatment with siRNA in vivo suppressed the late/chronic symptoms of EAE. Strikingly, human counterpart of this Th cell subset is remarkably increased in the peripheral blood from a particular subtype of MS patients.

Research Products

• [Journal Article] Towards understanding the role of orphan nuclear receptor NR4A2 in Th17 cell- mediated CNS autoimmunity: An experimental approach employing an animal model of multiple sclerosis. (2014)
  • Author(s): Shinji Oki
  • Journal Title: Clin. Exp. Neuroimmunol. Volume: 5 Pages: 137-148
  • Peer Reviewed
• [Journal Article] 多発性硬化症の動物モデル; 横断的アプローチによる病態解明と治療標的の探索 (2014)
  • Author(s): 大木 伸司、山村 隆
  • Journal Title: 日本臨床 Volume: 72 Pages: 1935-1940
• [Journal Article] Plasmablasts as migratory IgG-producing cells in the pathogenesis of neuromyelitis optica. (2013)
  • Author(s): Chihara N, Aranami T, Oki S, Matsuoka T, Nakamura M, Kishida H, Yokoyama K, Kuroiwa Y, Hattori N, Okamoto T, Murata M, Toda T, Miyake S, Yamamura T.
  • Journal Title: PLoS One Volume: 8 Issue: 12 Pages: e83036-e83036
  • DOI: 10.1371/journal.pone.0083036
  • Peer Reviewed
• [Journal Article] NR4A2 orchestrates pathogenic Th17 development and initiates autoimmune inflammation (2013)
  • Author(s): Raveney, B.J.E
  • Journal Title: PLOS ONE Volume: 8 Issue: 2 Pages: e56595-e56595
  • DOI: 10.1371/journal.pone.0056595
  • Peer Reviewed
• [Presentation] NR4A2 controls pathogenic 'switched' Th17 cells in the CNS during autoimmune inflammation (2014)
  • Author(s): Raveney B., S. Oki, T. Yamamura
  • Organizer: 第43回 日本免疫学会総会・学術集会
  • Place of Presentation: 国立京都国際会館、京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] NR4A2 modulation during autoimmune inflammation of the central nervous system reduces pathogenic T cell responses and ameliorates clinical disease (2014)
  • Author(s): Raveney B., S. Oki, T. Yamamura
  • Organizer: The 12th International Congress of Neuroimmunology
  • Place of Presentation: Rheingoldhalle, Mainz, Germany
  • Year and Date: 2014-11-11 – 2014-11-14
• [Presentation] NR4A2 Modulation during Autoimmune Inflammation of the Central Nervous System Reduces Pathogenic T cell Responses and Ameliorates Clinical Disease (2013)
  • Author(s): Raveney BJE, Oki S, Yamamura T
  • Organizer: PACTRIMS2013
  • Place of Presentation: The Westin Miyako Kyoto Hotel, Kyoto, JAPAN
• [Presentation] NR4A2 controls distinct populations of Th17 cells (2013)
  • Author(s): Raveney BJE, Oki S, Yamamura T
  • Organizer: 13th Annual Conference of FOCIS (FOCIS2013)
  • Place of Presentation: The Boston Seaport Hotel and World Trade Center, Boston, USA
• [Presentation] Acute autoimmune inflammation of the central nervous system is controlled by 2 waves of T cells: acute NR4A2-dependent and chronic NR4A2-independent (2013)
  • Author(s): Raveney BJE, Oki S, Yamamura T
  • Organizer: 第42回日本免疫学会総会・学術集会
  • Place of Presentation: 幕張メッセ、千葉
• [Presentation] 中枢神経系の炎症性自己免疫病態形成に関わる病原性T細胞群の解析 (2013)
  • Author(s): 大木伸司、ベン・レイバニー、山村隆
  • Organizer: 第41回日本臨床免疫学会総会
  • Place of Presentation: 海峡メッセ下関、山口
• [Presentation] 病原性IL-17産生T細胞のNR4A2発現維持に関わる細胞間相互作用 (2013)
  • Author(s): 大木伸司、ベン・レイバニー、山村隆
  • Organizer: 第25回日本神経免疫学会総会
  • Place of Presentation: 海峡メッセ下関、山口
• [Presentation] NR4A2 controls Th17-mediated autoimmunity (2012)
  • Author(s): Raveney B., S. Oki, T. Yamamura
  • Organizer: 12th Annual Conference of FOCIS (FOCIS2012)
  • Place of Presentation: Vancouver Convention Centre, Vancouver, CANADA
• [Presentation] Activated Plasmablasts Migrate to the Central Nervous System (2012)
  • Author(s): Chihara N., S. Oki, T. Matsuoka, W. Sato, Y. Lin, T. Okamoto, M. Ogawa, T. Toda, S. Miyake, T. Aranami, T. Yamamura
  • Organizer: 12th Annual Conference of FOCIS (FOCIS2012)
  • Place of Presentation: Vancouver Convention Centre, Vancouver, CANADA
• [Presentation] Acute autoimmune inflammation of the central nervous system by IL-17-secreting T cells is controlled by NR4A2 (2012)
  • Author(s): Raveney B., S. Oki, T. Yamamura
  • Organizer: The 10th International Congress of Neuroimmunology
  • Place of Presentation: The Westin Copley Place, Boston, USA
• [Presentation] 中枢神経系の炎症性自己免疫病態形成に関わるIL-17産生性T細胞群の解析 (2012)
  • Author(s): 大木伸司、ベン・レイバニー、山村隆
  • Organizer: 第24回日本神経免疫学会学術集会
  • Place of Presentation: 軽井沢プリンスホテルウェスト（長野）
• [Presentation] Acute autoimmune inflammation of the central nervous system by IL-17-secreting T cells is controlled by NR4A2 (2012)
  • Author(s): S. Oki, Raveney B., T. Yamamura
  • Organizer: International Symposium on Glyco-minded Biology of Diseases as a Basis of Pharmaceutical Sciences
  • Place of Presentation: 東京大学伊藤謝恩ホール（東京）
• [Presentation] NR4A2 controls Th17-mediated autoimmunity (2012)
  • Author(s): Raveney B., S. Oki, T. Yamamura
  • Organizer: 第41回 日本免疫学会総会・学術集会
  • Place of Presentation: 神戸国際会議場他（兵庫）
• [Book] Chembiomolecular Science: At the Frontier of Chemistry and Biology (2012)
  • Author(s): 2. Oki S., Raveney B.J.E., Yamamura T
  • Total Pages: 7
  • Publisher: Springer, Tokyo
• [Patent(Industrial Property Rights)] 進行型免疫性脱髄疾患治療剤 (2015)
  • Inventor(s): 大木 伸司、山村 隆
  • Industrial Property Rights Holder: 独立行政法人国立精神・神経医療研究センター
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-006142
  • Filing Date: 2015-01-15
• [Patent(Industrial Property Rights)] 進行型免疫性脱髄疾患治療剤 (2014)
  • Inventor(s): 大木 伸司、北條 浩彦、山村 隆
  • Industrial Property Rights Holder: 独立行政法人国立精神・神経医療研究センター
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-135630
  • Filing Date: 2014-07-01