関節リウマチを中心とした自己免疫病の免疫学的基盤の解明と新規治療法・予防法の確立

2014 Fiscal Year Annual Research Report

• Project/Area Number: 26253030
• Research Institution: Osaka University
• Principal Investigator: 坂口 志文 大阪大学, 免疫学フロンティア研究センター, 教授 (30280770)
• Co-Investigator(Kenkyū-buntansha): 廣田 圭司 大阪大学, 免疫学フロンティア研究センター, 特任准教授 (90631250)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 関節リウマチ / 自己抗原 / ZAP-70

Outline of Annual Research Achievements

本研究では、自己免疫病の免疫学的基盤の解明と新規治療法・予防法の確立にむけて、特に自己反応性T細胞の胸腺における産生機構、認識する自己抗原の同定、エフェクターTh細胞への分化機構について解析を行っている。本年度、TCR下流のシグナル伝達を減弱させる変異ZAP-70ノックインとTet-onシステムによりZAP-70の発現量を調節する２種類のマウスモデルを用いることにより、TCRシグナルの質的、量的変化による胸腺T細胞レパトア解析とT細胞の機能不全に与える影響を解析した。ZAP-70シグナル伝達を減弱させることにより、明らかなT細胞レパトアの偏移、自己反応性の獲得、自己免疫疾患惹起能を見いだした。また、ヒト免疫不全症候群を理解するためのモデルとなりうるZAP-70シグナル伝達強度と、胸腺でのT細胞発生不全の相関も見いだした。
また、関節炎症部位から複数のT細胞クローンを分離・確立した。その後、関節滑膜細胞に反応するクローンを選択し、レトロジェニックマウスを作製することにより単クローンT細胞による自己免疫性関節炎モデルを確立した。さらに、この関節炎惹起性T細胞が認識する自己抗原がRPL23Aであることを同定した。RPL23Lは、様々な組織に発現が見られるとともに動物種間においても高く保存された分子である。ヒト関節リウマチ患者のRPL23Lに対する血清自己抗体を測定したところ、一部患者群に高い反応性があることを見いだし、臨床的にも非常に重要な知見を得た。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

本研究課題では、動物モデルの解析から自己免疫疾患患者の病態・病理の理解および治療法・予防法の確立を目的とする。本年度の成果、即ち、TCRシグナル強度の変化による自己免疫性T細胞産生と免疫不全症発症に関する良いモデルを提供できたと考える。また、臨床的にも重要な新規の自己抗体の発見は、今後、疾患バイオマーカーとしての応用が期待できる。

Strategy for Future Research Activity

本研究課題では、引き続き、ZAP-70の質的・量的異常と特定のT細胞依存性自己免疫病の発症感受性スペクトラムについて分子生物学的、構造学的、免疫学的手法を用いて詳細な検討を行っていく。また、関節炎症部位に浸潤しているIL-17産生エフェクターTh細胞のTCRレパトア解析を行い、炎症局所に存在するエフェクターTh細胞の特異的な自己抗原認識機構、そして抗原特異的なエフェクターTh細胞を標的とした免疫制御の方法を探る。

Research Products

• [Journal Article] Detection of self-reactive CD8+ T cells with an anergic phenotype in healthy individuals (2014)
  • Author(s): Maeda Y, Nishikawa H, Sugiyama D, Ha D, Hamaguchi M, Saito T, Nishioka M, Wing JB, Adeegbe D, Katayama I, Sakaguchi S.
  • Journal Title: Science Volume: 346 Pages: 1536-1540
  • DOI: 10.1126
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Detection of T-cell responses to a ubiquitous cellular protein in autoimmune disease (2014)
  • Author(s): Ito Y, Hashimoto M, Hirota K, Ohkura N, Morikawa H, Nishikawa H, Tanaka A, Furu M, Ito H, Fujii T, Nomura T, Yamazaki S, Morita A, Vignali DA, Kappler JW, Matsuda S, Mimori T, Sakaguchi N, Sakaguchi S.
  • Journal Title: Science Volume: 346 Pages: 363-368
  • DOI: 10.1126
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Regulatory T-cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4 (2014)
  • Author(s): Wing JB, Ise W, Kurosaki T, Sakaguchi S.
  • Journal Title: Immunity Volume: 41 Pages: 1013-1025
  • DOI: 10.1016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Interleukin-10- Producing Plasmablasts Exert Regulatory Function in Autoimmune Inflammation (2014)
  • Author(s): Matsumoto M, Baba A, Yokota T, Nishikawa H, Ohkawa Y, Kayama H, Kallies A, Nutt SL, Sakaguchi S, Takeda K, Kurosaki T, and Baba Y.
  • Journal Title: Immunity Volume: 41 Pages: 1040-1051
  • DOI: 10.1016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Schmidt-Supprian M. Continuous T Cell Receptor Signals Maintain a Functional Regulatory T Cell Pool (2014)
  • Author(s): Vahl JC, Drees C, Heger K, Heink S, Fischer JC, Nedjic J, Ohkura N, Morikawa H, Poeck H, Schallenberg S, RieB D, Hein MY, Buch T, Polic B, Schonle A, Zeiser R, Schmitt-Graff A, Kretschmer K, Klein L, Korn T, Sakaguchi S
  • Journal Title: Immunity Volume: 41 Pages: 722-736
  • DOI: 10.1016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Homeostasis of Thymus-Derived Foxp3+ Regulatory T Cells Is Controlled by Ultraviolet B Exposure in the Skin. (2014)
  • Author(s): Yamazaki S, Nishioka A, Kasuya S, Ohkura N, Hemmi H, Kaisho T, Taguchi O, Sakaguchi S, Morita A.
  • Journal Title: J Immunol Volume: 193 Pages: 5488-5497
  • DOI: 10.4049
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Epigenetic control of thymic Treg-cell development. (2014)
  • Author(s): Kitagawa Y, Ohkura N, Sakaguchi S.
  • Journal Title: Eur. J. Immunol Volume: 45 Pages: 11-16
  • DOI: 10.1002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] FRT - Fondation Rene Touraine: Pour La Dermatologie. (2014)
  • Author(s): Sakaguchi S, Sallusto F, Gebhardt T, Stingl G, Clark RA, Santamaria-Babí LF, Guttman-Yassky E, Schuler G, Koenen HJ.
  • Journal Title: Exp Dermatol Volume: 23 Pages: 772-785
  • DOI: 10.1111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation. (2014)
  • Author(s): Morikawa H, Ohkura N, Vandenbon A, Itoh M, Nago-Sato S, Kawaji H, Lassmann T, Carninci P, Hayashizaki Y, Forrest A, Standley D, Date D, Sakaguchi S, and the FANTOM consortium.
  • Journal Title: PNAS Volume: 111 Pages: 5289-5294
  • DOI: 10.1073
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Transient Ablation of Regulatory T cells Improves Antitumor Immunity in Colitis-Associated Colon Cancer. (2014)
  • Author(s): Pastille E, Bardini K, Fleissner D, Adamczyk A, Frede A, Wadwa M, von Smolinski D, Kasper S, Sparwasser T, Gruber AD, Schuler M, Sakaguchi S, Roers A, Miiller W, Hansen W, Buer J, Westendorf AM.
  • Journal Title: Cancer Res. Volume: 74 Pages: 4258-4269
  • DOI: 10.1158
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comprehensive exploration of autoantibody in Behçet's disease: A novel autoantibody to claudin-1, an essential protein for tight junctions, is identified. (2014)
  • Author(s): Morishima A, Hirano T, Nishikawa H, Nakai K, Sakaguchi S, Kumanogoh A.
  • Journal Title: Joint Bone Spine. Volume: 81 Pages: 546-548
  • DOI: 10.1016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CD28 signals the differential control of regulatory T cells and effector T cells. (2014)
  • Author(s): Mikami N, Sakaguchi S.
  • Journal Title: Eur J Immunol Volume: 44 Pages: 955-957
  • DOI: 10.1002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] TREG-cell therapies for autoimmune rheumatic diseases. (2014)
  • Author(s): Miyara M, Ito Y, Sakaguchi S.
  • Journal Title: Nat Rev Rheumatol. Volume: 10 Pages: 543-551
  • DOI: 10.1038
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genetic and epigenetic basis of Treg cell development and function: From a FoxP3-centered view to an epigenome-defined view of natural Treg cells (2014)
  • Author(s): Morikawa H, Sakaguchi S.
  • Journal Title: Immunol. Rev Volume: 259 Pages: 192-205
  • DOI: 10.1111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A promoter level mammalian expression atlas. (2014)
  • Author(s): Forrest A, ..., Morikawa H., ..., Hamaguchi M., ..., Ohkura N., ...,Sakaguchi S., ...,Hayashizaki Y, et al.,
  • Journal Title: Nature Volume: 507 Pages: 462-470
  • DOI: 10.1038
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Foxp3+ Treg cells in humoral immunity. (2014)
  • Author(s): Wing JB, Sakaguchi S.
  • Journal Title: Int Immunol. Volume: 26 Pages: 61-69
  • DOI: 10.1093
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CD8+ tumor-infiltrating lymphocytes at primary sites as a possible prognostic factor of cutaneous angiosarcoma (2014)
  • Author(s): Fujii H, Arakawa A, Utsumi D, Sumiyoshi S, Yamamoto Y, Kitoh A, Ono M, Matsumura Y, Kato M, Konishi K, Shiga T, Sano S, Sakaguchi S, Miyagawa-Hayashino A, Takahashi K, Uezato H, Miyachi Y, Tanioka M.
  • Journal Title: Int J Cancer Volume: 134 Pages: 2393-2402
  • DOI: 10.1002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Regulatory T cells in cancer immunotherapy. (2014)
  • Author(s): Nishikawa H, Sakaguchi S.
  • Journal Title: Curr Opin Immunol. Volume: 27 Pages: 1-7
  • DOI: 10.1016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Control of Immune Responses by Regulatory T cells (2015)
  • Author(s): Shimon Sakaguchi
  • Organizer: KEYSTONE SYMPOSIA T Cells: Regulation and Effector Function
  • Place of Presentation: Utah（USA）
  • Year and Date: 2015-03-29 – 2015-04-03
  • Invited
• [Presentation] APC and T Regs (2015)
  • Author(s): Shimon Sakaguchi
  • Organizer: KEYSTONE SYMPOSIA Dendritic Cells and Macrophages Reunited
  • Place of Presentation: Montreal（Canada）
  • Year and Date: 2015-03-08 – 2015-03-13
  • Invited
• [Presentation] Control of immune responses by regulatory T cells. (2015)
  • Author(s): Shimon Sakaguchi
  • Organizer: The 4th NIF Winter School on Advanced Immunology
  • Place of Presentation: Singapore
  • Year and Date: 2015-01-18 – 2015-01-23
  • Invited
• [Presentation] Regulatory T Cells and Immune Tolerance. (2015)
  • Author(s): Shimon Sakaguchi
  • Organizer: Sushruta Lecture Transplantation Update-2015
  • Place of Presentation: Ahmedabad（India）
  • Year and Date: 2015-01-09 – 2015-01-11
  • Invited
• [Presentation] Control of autoimmunity and tumor immunity by regulatory T cells (2014)
  • Author(s): 坂口志文
  • Organizer: 日本研究皮膚科学会第39回年次学術大会・総会
  • Place of Presentation: ホテル阪急エキスポパーク（大阪）
  • Year and Date: 2014-12-14 – 2014-12-14
  • Invited
• [Presentation] The soluble form of CTLA-4 in regulatory T cells-mediated suppression (2014)
  • Author(s): Osaki Motonao, Sakaguchi Shimon
  • Organizer: 第43回日本免疫学会総会・学術総会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] The genome organizer Satb1 differentially controls thymic and peripheral development of regulatory T cells. (2014)
  • Author(s): 4.Kitagawa Yohko, Ohkura Naganari, Hirota Keiji, Adeegbe Olakunle, Yasada Keiko, Kondo Motonari, Taniuchi Ichiro, Kohwi-ShigematuTerumi, Sakaguchi Shimon
  • Organizer: 第43回日本免疫学会総会・学術総会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Regulatory T cells (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: development, maintenance and function in normal and disease states 22nd FRT –Fondation Rene Touraine Annual Scientific Meeting
  • Place of Presentation: Paris（France）
  • Year and Date: 2014-12-05 – 2014-12-05
  • Invited
• [Presentation] Keynote Address Immune Regulation for Cancer Immunotherapy The 45th International Symposium of The Princess Takamatsu Cancer Research Fund (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: Recent Advances in Cancer Immunotherapy
  • Place of Presentation: パレスホテル東京（東京）
  • Year and Date: 2014-11-18 – 2014-11-20
  • Invited
• [Presentation] 制御性T細胞と自己免疫・癌 (2014)
  • Author(s): 坂口志文
  • Organizer: 第57回日本甲状腺学会学術集会
  • Place of Presentation: ナレッジキャピタル コングレコンベンションセンター（大阪）
  • Year and Date: 2014-11-13 – 2014-11-15
  • Invited
• [Presentation] Control of immune responses by regulatory T cells (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: BK seminar Integrative Biosciences and Biotechnology
  • Place of Presentation: Pohan（Korea）
  • Year and Date: 2014-11-10 – 2014-11-10
  • Invited
• [Presentation] Genetic and epigenetic basis of Treg cell development and function. (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: Academy of Immunology and Microbiology Workshop on Immunology 2014
  • Place of Presentation: Pohan（Korea）
  • Year and Date: 2014-11-09 – 2014-11-10
  • Invited
• [Presentation] Regulatory T Cells (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: Development, Maintenance and Function in Normal and Disease States The 2014 Fall Conference of Korean Association of Immunologists
  • Place of Presentation: Seoul（Korea）
  • Year and Date: 2014-11-06 – 2014-11-07
  • Invited
• [Presentation] Treg-mediated control of the cell fate of autoimmune T cells (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: The Fourth International Conference on Regulatory T Cells and T Helper Cell Subsets and Clinical Application in Human Diseases
  • Place of Presentation: Shanghai（China）
  • Year and Date: 2014-11-01 – 2014-11-04
  • Invited
• [Presentation] 制御性T細胞による免疫応答制御 (2014)
  • Author(s): 坂口志文
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] Control of Treg cells for immune tolerance (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: Novo nordisk innovation summit Tokyo
  • Place of Presentation: 東京大学医科学研究所（東京）
  • Year and Date: 2014-10-01 – 2014-10-02
  • Invited
• [Presentation] 制御性T細胞による免疫応答制御 (2014)
  • Author(s): 坂口志文
  • Organizer: 第51回補体シンポジウム
  • Place of Presentation: 神戸常盤大学（神戸）
  • Year and Date: 2014-08-22 – 2014-08-23
  • Invited
• [Presentation] Control of Tumor Immunity by Regulatory T Cells. (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: IAAO(International Academy for Advanced Oncology) Convergence for Breakthroughs in Oncology Therapy
  • Place of Presentation: 六本木ヒルズ（東京）
  • Year and Date: 2014-08-01 – 2014-08-02
  • Invited
• [Presentation] 制御性T細胞による免疫応答制御 (2014)
  • Author(s): 坂口志文
  • Organizer: 第33回分子病理学研究会
  • Place of Presentation: 宮城蔵王ロイヤルホテル（蔵王）
  • Year and Date: 2014-07-25 – 2014-07-26
  • Invited
• [Presentation] 制御性T細胞による免疫応答制御 (2014)
  • Author(s): 坂口志文
  • Organizer: 第51回日本消化器免疫学会総会
  • Place of Presentation: 京都大学医学部 芝蘭会館（京都）
  • Year and Date: 2014-07-10 – 2014-07-11
  • Invited
• [Presentation] Control of autoimmunity and tumor immunity by regulatory T cells. (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: RJKEN IMS-JSI International Symposium on Immunology 2014 Decoding Immune Complexity Bench to Bedside
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Year and Date: 2014-06-26 – 2014-06-27
  • Invited
• [Presentation] 制御性T細胞による免疫応答制御 (2014)
  • Author(s): 坂口志文
  • Organizer: 第38回日本リンパ学会総会東京
  • Place of Presentation: 北里大学白金キャンパス薬学部コンベンションホール（東京）
  • Year and Date: 2014-06-21 – 2014-06-21
  • Invited
• [Presentation] Regulatory T cells in autoimmunity and tumor immunity (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: The 1st joint symposium of Karolinska Institute and Osaka University 2014 Immunology and Infection biology
  • Place of Presentation: Stockholm（Sweden）
  • Year and Date: 2014-06-10 – 2014-06-10
  • Invited
• [Presentation] Epigenetic changes and Treg cell development. (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: European Academy of Allergy and Clinical Immunology Congress 2014
  • Place of Presentation: Copenhagen（Denmark）
  • Year and Date: 2014-06-07 – 2014-06-11
  • Invited
• [Presentation] 胸腺と末梢の制御性T細胞発生におけるSATB1の役割 (2014)
  • Author(s): 北川瑤子、大倉永也、廣田圭司、安田佳子、谷内一郎、近藤元就、重松照美、坂口志文
  • Organizer: 第24回Kyoto T Cell Conference
  • Place of Presentation: 京都平安ホテル(京都）
  • Year and Date: 2014-05-16 – 2014-05-17
• [Presentation] Genetic and epigenetic basis of Treg cell development and function. (2014)
  • Author(s): Shimon Sakaguchi
  • Organizer: 2014 Beijing-Shanghai Immunology Joint Symposium
  • Place of Presentation: Hangzhou（China）
  • Year and Date: 2014-04-12 – 2014-04-12
  • Invited