Immunoregulatory roles of glycolipid ligand-stimulated natural killer T cells

• Project/Area Number: 19590095
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: OKI Shinji National Center of Neurology and Psychiatry, 神経研究所・疾病研究第六部, 第三室長 (50260328)
• Co-Investigator(Kenkyū-buntansha): YAMAMURA Takashi 国立精神神経センター, 神経研究所・疾病研究第六部, 部長 (90231670)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2007: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 免疫学 / 自己免疫疾患 / NKT細胞 / サイトカイン / レチノイン酸 / IL-17 / 核内受容体 / アレルギー疾患 / 糖脂質

Research Abstract

ナチュラルキラーT(NKT)細胞は、抗原である糖脂質分子を認識して活性化すると、様々なサイトカインを産生し、生体の免疫応答を調節する。我々は、活性化NKT細胞が炎症性サイトカインであるIL-17を産生することを見出したが、種々のレチノイドがNKT細胞やT 細胞のIL-17産生を、効果的に抑制することを発見した。レチノイドによるIL-17依存性自己免疫疾患に対する新たな治療法の可能性が示された。

Research Products

• [Journal Article] Retinoid signals and Th17-mediated pathology (2009)
  • Author(s): Christian Klemann, Benjamin JE Raveney, Shinji Oki and Takashi Yamamura
  • Journal Title: 日本臨床免疫学会会誌 32巻1号 Pages: 20-28
  • NAID: 10024961769
• [Journal Article] Identification of a possible therapeutic target through pathogenic T cell analysis of multiple sclerosis (2009)
  • Author(s): Shinji Oki and Takashi Yamamura
  • Journal Title: 日本臨床免疫学会会誌 印刷中 Pages: 0-0
  • NAID: 10026352065
• [Journal Article] Synthetic retinoid AM80 inhibits Th17 cells and ameliorates EAE (2009)
  • Author(s): Christian Klemann, Benjamin JE Raveney, Anna K Klemann, Tomoko Ozawa, Stephan von Horsten, Koichi Shudo, Shinji Oki, Takashi Yamamura
  • Journal Title: Am. J. Pathol. (印刷中)
  • Peer Reviewed
• [Journal Article] Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines (2008)
  • Author(s): Yoshimitsu Doi, Shinji Oki, Tomoko Ozawa, Hirohiko Hohjoh, Sachiko Miyake, and Takashi Yamamura
  • Journal Title: Proc. Natl. Acad. Sci. USA 105 Pages: 8381-8386
  • Peer Reviewed
• [Journal Article] NKT cell-dependent amelioration of a mouse model of multiple sclerosis by altering gut flora (2008)
  • Author(s): Hiroaki Yokote, Sachiko Miyake, J. Ludovic Croxford, Shinji Oki, Hidehiro Mizusawa, and Takashi Yamamura
  • Journal Title: Am. J. Pathol. 173 Pages: 1714-1723
  • Peer Reviewed
• [Journal Article] Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines (2008)
  • Author(s): Yoshimitsu Doi, Shinji Oki, Tomoko Ozawa, Hirohiko Hohjoh, Sachiko Miyake, Takashi Yamamura
  • Journal Title: Proc. Natl. Acad. Sci. USA 105 Pages: 8381-8386
  • Peer Reviewed
• [Journal Article] NKT Cell-Dependent Amelioration of a Mouse Model of Multiple Sclerosis by Altering Gut Flora (2008)
  • Author(s): Hiroaki Yokote, Sachiko Miyake, John L. Croxford, Shinji Oki, Hidehiro Mizusawa, Takashi Yamamura
  • Journal Title: Am. J. Pathol. 173 Pages: 1714-1723
  • Peer Reviewed
• [Journal Article] Invariant NKT cells Biased for IL-5 Production Act as Crucial Regulators of Inflammation. (2007)
  • Author(s): Kaori Sakuishi, Shinji Oki, Manabu Araki, Steven A. Porcelli, Sachiko Miyake, Takashi Yamamura
  • Journal Title: J. Immunol. 179 Pages: 3452-3462
  • Peer Reviewed
• [Journal Article] Invariant NKT Cells Biased for IL-5 Production Act as Crucial Regulators of Inflammation (2007)
  • Author(s): Kaori Sakuishi
  • Journal Title: Journal of Immunology 179 Pages: 3452-3462
  • Peer Reviewed
• [Journal Article] Activation of invariant naturaI killer T cells by glycolipid ligands suppresses autoantibody-induced arthritis (2007)
  • Author(s): Shinjiro Kaieda
  • Journal Title: Arthritis & Rheumatism 56 Pages: 1836-1845
  • Peer Reviewed
• [Journal Article] Synthetic retinoid AM80 inhibits Th17 cells and ameliorates EAE
  • Author(s): Christian Klemann, Benjamin JE Raveney, Anna K Klemann, Tomoko Ozawa, Stephan von Horsten, Koichi Shudo, Shinji Oki, Takashi Yamamura
  • Journal Title: Am. J. Pathol. 印刷中 Pages: 0-0
  • Peer Reviewed
• [Presentation] 実験的自己免疫性ブドウ膜炎(EAU)に対する合成レチノイドAm80の病態抑制効果 (2009)
  • Author(s): 大木伸司, ベン・レイバニー, クリスチャン・クレマン, 首藤紘一, 山村隆
  • Organizer: 第21回日本神経免疫学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2009-03-13
• [Presentation] 実験的自己免疫性ブドウ膜炎(EAU)に対する合成レチノイドAm80の病態抑制効果 (2009)
  • Author(s): 大木伸司、レイバニー・ベン、クレマン・クリスチャン、首藤紘一、山村隆
  • Organizer: 第21回日本神経免疫学会学術集会
  • Place of Presentation: 新潟
  • Year and Date: 2009-03-12
• [Presentation] Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines (2008)
  • Author(s): 大木伸司, 土居芳充, Benjamin JE Raveney, 小澤智子, 北條浩彦, 三宅幸子, 山村隆
  • Organizer: 第38回日本免疫学会総会・学術集会(招待講演)
  • Place of Presentation: 京都
  • Year and Date: 2008-12-02
• [Presentation] Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines(シンポジウム招待講演) (2008)
  • Author(s): Shinji Oki, Yoshimitsu Doi, Benjamin JE Raveney, Tomoko Ozawa, Hirohiko Hohjoh, Sachiko Miyake, Takashi Yamamura
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
  • Year and Date: 2008-12-01
• [Presentation] Synthetic Retinoid Am80 ameliorates EAE by attenuating Th17-mediated inflammation (2008)
  • Author(s): Christian Klemann, Shinji Oki, Benjamin J.E. Raveney, Takashi Yamamura
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
  • Year and Date: 2008-12-01
• [Presentation] 合成レチノイドAm80のTh17細胞分化制御を介した自己免疫応答抑制効果について (2008)
  • Author(s): 大木伸司、Christian Klemann、Benjamin JE Raveney、Anna K Klemann、小澤智子、首藤紘一、山村隆
  • Organizer: 第19回日本レチノイド研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-11-21
• [Presentation] Synthetic Retinoid Am80 ameliorates EAE by attenuating Th17-mediated inflammation (2008)
  • Author(s): Christian Klemann, Shinji Oki, Anna K Klemann, Tomoko Ozawa, Yoshimutsu Doi, Koichi Shudo, Takashi Yamamura
  • Organizer: 9th International Congress of Neuroimmunology (ISNI2008)
  • Place of Presentation: Fort Worth USA
  • Year and Date: 2008-10-29
• [Presentation] Synthetic Retinoid Am80 ameliorates EAE by attenuating Th17-mediated inflammation (2008)
  • Author(s): Christian Klemann, Shinji Oki, Anna K Klemann, Tomoko Ozawa, Yoshimitsu Doi, Koichi Shudo, Takashi Yamamura
  • Organizer: The 9th International Congress of Neuroimmunology
  • Place of Presentation: Fort Worth
  • Year and Date: 2008-10-26
• [Presentation] Th17細胞機能制御を介した合成レチノイドAm80の自己免疫応答抑制効果について (2008)
  • Author(s): 大木伸司, Christian Klemann, Benjamin JE Raveney, Anna K Klemann, 小澤智子, 首藤紘一, 山村隆
  • Organizer: 日本レチノイド研究会・第19回学術集会
  • Place of Presentation: 東京
  • Year and Date: 2008-10-21
• [Presentation] Synthetic retinoid Am80 ameliorates experimental autoimmune encephalomyelitis (EAE) by attenuating Th17-mediated inflammation (2008)
  • Author(s): Christian Klemann, Shinji Oki, Anna K Klemann, Ben JE Raveney, Tomoko Ozawa, Koichi Shudo, Takashi Yamamura
  • Organizer: 第36回日本臨床免疫学会総会
  • Place of Presentation: 東京
  • Year and Date: 2008-10-17
• [Presentation] MR1拘束性Vα19iT細胞のコラーゲン誘導関節炎(CIA)における機能解析 (2008)
  • Author(s): 八子徹、田島良亮、海江田信二郎、大木伸司、三宅幸子
  • Organizer: 第52回日本リウマチ学会総会・学術集会・第17回国際リウマチシンポジウム
  • Place of Presentation: 札幌
  • Year and Date: 2008-04-20
• [Presentation] Alteration of Th17 differentiation by retinoic acid signals ameliorate EAE development (2008)
  • Author(s): Christian Klemann, Shinji Oki, Tomoko Ozawa, Yoshimitsu Doi, & Takashi Yamamura
  • Organizer: 第20回日本神経免疫学会学術集会
  • Place of Presentation: 新潟
  • Year and Date: 2008-04-17
• [Presentation] Functional involvement of NR4A2 in the pathogenesis of inflammatory demyelinating disease. (2008)
  • Author(s): Shinji Oki, Yoshimitsu Doi, Tomoko Ozawa, Sachiko Miyake, Takashi Yamamura
  • Organizer: Keystone Symposia 2008 : Nuclear Receptors: Orphan Brothers (Z1)
  • Place of Presentation: Whistler CA
  • Year and Date: 2008-04-01
• [Presentation] Functional involvement of NR4A2 in the pathogenesis of inflammatory demyelinating disease (2008)
  • Author(s): Shinji Oki, Yoshimitsu Doi, Tomoko Ozawa, Sachiko Miyake, Takashi Yamamura
  • Organizer: Keystone Symposia'Nuclear Receptors : Orphan Brothers'
  • Place of Presentation: Whistler CA
  • Year and Date: 2008-04-01
• [Presentation] プロテオミクスを用いたアナジーT細胞内タンパク質の解析 (2007)
  • Author(s): 大木 伸司
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2007-11-22
• [Presentation] 実験的自己免疫性脳脊髄炎における腸内フローラの役割に関する検討 (2007)
  • Author(s): 横手 裕明
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2007-11-22
• [Presentation] MR1拘束性T細胞によるマウス関節炎モデルの抑制 (2007)
  • Author(s): 八子 徹
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2007-11-21
• [Presentation] プロテオミクスを用いたアナジーT細胞内タンパク質の解析 (2007)
  • Author(s): 大木伸司、市川大樹、山村隆、三宅幸子
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2007-11-20
• [Presentation] 実験的自己免疫性脳脊髄炎における腸内フローラの役割に関する検討 (2007)
  • Author(s): 横手裕明、J. Ludovic Croxford、水澤英洋、大木伸司、三宅幸子、山村隆
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2007-11-20
• [Presentation] MR1拘束性T細胞によるマウス関節炎モデルの抑制 (2007)
  • Author(s): 八子徹、海江田信二郎、大木伸司、山村隆、三宅幸子
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2007-11-20
• [Presentation] MR1-restricted Va19i T cells ameliorate murine models of arthritis (2007)
  • Author(s): Toru Yago
  • Organizer: American College of Rheumatology, 2007 Annual Meeting
  • Place of Presentation: Boston, USA
  • Year and Date: 2007-11-06
• [Presentation] 多発性硬化症における病原性T細胞のサイトカイン産生制御機構 (2007)
  • Author(s): 土居芳充、大木伸司、三宅幸子、山村隆
  • Organizer: 第35回日本臨床免疫学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2007-10-19
• [Presentation] 実験的自己免疫性脳脊髄炎における腸内フローラの役割に関する検討 (2007)
  • Author(s): 横手裕明、J. Ludovic Croxford、水澤英洋、大木伸司、三宅幸子、山村隆
  • Organizer: 第35回日本臨床免疫学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2007-10-19
• [Presentation] Functional lnvolvement of NR4A2 in the Pathogenesis of Multiple Sclerosis (2007)
  • Author(s): 土居 芳充
  • Organizer: 第20回内藤コンファレンス
  • Place of Presentation: 葉山、神奈川
  • Year and Date: 2007-10-11
• [Presentation] Functional Involvement of NR4A2 in the Pathogenesis of Multiple Sclerosis (2007)
  • Author(s): Yoshimitsu Doi, Shiji Oki, Sachiko Miyake, Takashi Yamamura
  • Organizer: 第20回内藤コンファレンス
  • Place of Presentation: 葉山、神奈川
  • Year and Date: 2007-10-09
• [Presentation] Functional analysis of carcinoembryonic antigen-related cellular adhesion molecule 1 in experimental autoimmune encephalomyelitis (2007)
  • Author(s): Shhji Oki
  • Organizer: 6th Annual Conference of FOCIS
  • Place of Presentation: San Diego, USA
  • Year and Date: 2007-06-10
• [Presentation] Functional involvement of NR4A2 in the pathogenesis of multiple sclerosis (2007)
  • Author(s): Yoshimitsu Doi
  • Organizer: 6th Annual Conference of FOCIS
  • Place of Presentation: San Diego, USA
  • Year and Date: 2007-06-10
• [Presentation] Functional involvement of NR4A2 in the pathogenesis of multiple sclerosis. (2007)
  • Author(s): Yoshimitsu Doi, Shinji Oki, Sachiko Miyake, Takashi Yamamura
  • Organizer: 7th Annual Conference of FOCIS
  • Place of Presentation: San Diego
  • Year and Date: 2007-06-07
• [Presentation] Functional analysis of carcinoembryonic antigen-related cellular adhesion molecule 1 in experimental autoimmune encephalomyelitis. (2007)
  • Author(s): Shinji Oki, Mayumi Fujita, Takao Ootsuka, Miho Mizuno, Chiharu Tomi, Shinjiro Kaieda, Takashi Yamamura,Sachiko Miyake
  • Organizer: 7th Annual Conference of FOCIS
  • Place of Presentation: San Diego
  • Year and Date: 2007-06-07
• [Presentation] 抗体誘導関節炎におけるNKT細胞の機能解析 (2007)
  • Author(s): 田島良亮、海江田信二郎、大木伸司、三宅幸子
  • Organizer: 第51回日本リウマチ学会総会・学術集会・第16回国際リウマチシンポジウム
  • Place of Presentation: 横浜
  • Year and Date: 2007-04-27
• [Presentation] SKGマウスにおける結核死菌投与による関節炎の誘導 (2007)
  • Author(s): 海江田信二郎、田島良亮、大木伸司、坂口志文、三宅幸子
  • Organizer: 第51回日本リウマチ学会総会・学術集会・第16回国際リウマチシンポジウム
  • Place of Presentation: 横浜
  • Year and Date: 2007-04-27
• [Presentation] 多発性硬化症における病原性T 細胞のサイトカイン産生制御機構 (2007)
  • Author(s): 土居芳充、大木伸司、三宅幸子、山村隆
  • Organizer: 第19回日本神経免疫学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2007-04-12
• [Presentation] 多発性硬化症における病原性T細胞のサイトカイン産生制御機構 (2007)
  • Author(s): 土居 芳充
  • Organizer: 第19回日本神経免疫学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2007-04-12
• [Presentation] MR1-restricted Va19i T cells ameliorate murine models of arthritis. (2007)
  • Author(s): Toru Yago, Ryosuke Tajima, Shinjiro Kaieda, Shinji Oki, Takashi Yamamura, Sachiko Miyake
  • Organizer: 2007 Annual Scientific Meeting of ACR
  • Place of Presentation: Boston
• [Book] サイトカインネットワークのパラダイムシフト Frontiers in Rheumatology & Clinical Immunology 第1巻第2号 (2008)
  • Author(s): 大木伸司
• [Book] Topics/Review : 多発性硬化症の新しい治療戦略HUMAN SCIENCE(ヒューマンサイエンス振興財団編)第19巻第4号 (2008)
  • Author(s): 大木伸司、山村隆
• [Book] 生化学辞典(第4版) (2008)
  • Author(s): 大木伸司
  • Publisher: 東京化学同人
• [Book] 初めての国際学会と英語プレゼンテーション Frontiers in Rheumatology & Clinical Immunology第3巻第2号 (2008)
  • Author(s): 大木伸司
• [Book] 改変糖脂質抗原によるNKT細胞を介した免疫制御 生化学(日本生化学会編)第79巻 (2007)
  • Author(s): 大木伸司
• [Remarks] NR4A2 の論文(Doi et al. Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines. PNAS 105: 8381,2008)が掲載されるにあたり、関連のニュースが共同通信から全国に配信された。
• [Patent(Industrial Property Rights)] IL-17産生抑制物質及びそのスクリーニング方法 (2008)
  • Inventor(s): 大木伸司、北條浩彦、三宅幸子、山村隆
  • Industrial Property Rights Holder: (財)ヒューマンサイエンス振興財団
  • Patent Publication Number: 2008-211985
  • Filing Date: 2008-02-28
• [Patent(Industrial Property Rights)] IL-17に起因する炎症を改善するための医薬組成物 (2008)
  • Inventor(s): 大木伸司、北條浩彦、三宅幸子、山村隆
  • Industrial Property Rights Holder: (財)ヒューマンサイエンス振興財団
  • Filing Date: 2008-02-28