MAIT cells as therapeutic targets in lupus.

• Project/Area Number: 17K09983
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Juntendo University
• Principal Investigator: Chiba Asako 順天堂大学, 医学部, 准教授 (40532726)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: MAIT細胞 / 自己免疫疾患 / 全身性エリテマトーデス / 自己抗体 / ループス腎炎 / ループス / 腎炎 / ループスモデル / 自然リンパ球

Outline of Final Research Achievements

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies and tissue inflammation caused by the deposition of immune complexes with autoantibodies. In this study, we revealed that Mucosal-associated invariant T (MAIT) cells augment the disease course of lupus by enhancing autoantibody production and tissue inflammation in a murine model of lupus. We further demonstrated that the suppression of MAIT cell activation by the MR1 ligand reduced autoantibody production and lupus nephritis. Our results indicate the potential of MAIT cells as novel therapeutic targets for autoimmune diseases such as lupus.

Academic Significance and Societal Importance of the Research Achievements

全身性エリテマトーデスは自己抗体による組織炎症を特徴とした全身性自己免疫疾患である。20-40歳の女性に多く発症し長期の経過をたどる。治療の中心となる副腎皮質ステロイドは副作用の問題も多く新規治療法の開発が望まれている。本研究では、Mucosal-associated invariant (MAIT)細胞がSLE病態の増悪に寄与すること、またMAIT細胞の働きを抑制することにより病態が改善することを明らかにした。MAIT細胞が免疫疾患の治療ターゲットとなる可能性を初めて示した研究であり、臨床応用への発展が期待される。

Research Products

• [Journal Article] Critical role for mucosal-associated invariant T cells as regulators and therapeutic targets in systemic lupus erythematosus (2019)
  • Author(s): Murayama G, Chiba A, Suzuki H, Nomura A, Mizuno T, Kuga T, Nakamura S, Amano H, Hirose S, Yamaji K, Suzuki Y, Tamura N, Miyake S
  • Journal Title: Frontiers in Immunology Volume: 29 Pages: 2681-2681
  • DOI: 10.3389/fimmu.2019.02681
  • Peer Reviewed / Open Access
• [Journal Article] Expanded circulating peripheral helper T cells in systemic lupus erythematosus: association with disease activity and B cell differentiation (2019)
  • Author(s): Makiyama Ayako、Chiba Asako、Noto Daisuke、Murayama Goh、Yamaji Ken、Tamura Naoto、Miyake Sachiko
  • Journal Title: Rheumatology Volume: ー Pages: 1861-1869
  • DOI: 10.1093/rheumatology/kez077
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Breastfeeding regulates development of immune system through TGF-β in mice pups (2018)
  • Author(s): Sakaguchi Keita、Koyanagi Akemi、Kamachi Fumitaka、Harauma Akiko、Chiba Asako、Hisata Ken、Moriguchi Toru、Shimizu Toshiaki、Miyake Sachiko
  • Journal Title: Pediatr Int Volume: 60(3) Issue: 3 Pages: 224-231
  • DOI: 10.1111/ped.13507
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mucosal-Associated invariant T cells in autoimmune diseases (2018)
  • Author(s): Chiba A, Murayama G, Miyake S
  • Journal Title: Front Immunol Volume: 9 Pages: 1333-1333
  • DOI: 10.3389/fimmu.2018.01333
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MR1拘束性T細胞の最近の話題 免疫疾患とMAIT細胞 (2018)
  • Author(s): 千葉麻子、三宅幸子
  • Journal Title: 医学のあゆみ Volume: 265 Pages: 283-386
• [Journal Article] 全身性エリテマトーデスにおけるIFNα産生とTLR7 (2018)
  • Author(s): 村山豪、千葉麻子、三宅幸子
  • Journal Title: リウマチ科 Volume: 60 Pages: 84-89
• [Journal Article] TPH細胞と全身性エリテマトーデス (2018)
  • Author(s): 千葉麻子
  • Journal Title: 炎症と免疫 Volume: 26 Pages: 544-547
• [Presentation] MAIT 細胞 全身性エリテマトーデスの新規治療ターゲット (2019)
  • Author(s): 村山豪、千葉麻子、牧山彩子、山路健、田村直人、三宅幸子
  • Organizer: 第 63 回日本リウマチ学会・学術集会
• [Presentation] MAIT cells enhance autoreactive B cell responses in a murine model of lupus. (2019)
  • Author(s): Taiga Kuga, Goh Murayama, Asako Chiba, Tomohiro Mizuno, Atsushi Nomura, Hirofumi Amano, Sachiko Hirose, Ken Yamaji, Naoto Tamura, Sachiko Miyake
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] A critical role for MAIT cells as regulators and therapeutic targets in lupus. (2019)
  • Author(s): Goh Murayama, Asako Chiba, Taiga Kuga, Tomohiro Mizuno, Ken Yamaji, Naoto Tamura, Sachiko Miyake
  • Organizer: EMBO Workshop-CD1-MR1: beyond MHC restricted lymphocytes
  • Int'l Joint Research
• [Presentation] Mucosal-associated Invariant T Cells Can Be Therapeutically Targeted in Lupus. (2019)
  • Author(s): Goh Murayama, Asako Chiba, Tomohiro Mizuno, Atsushi Nomura, Taiga Kuga, Hirofumi Amano, Ken Yamaji, Naoto Tamura and Sachiko Miyake.
  • Organizer: 2019ACR/ARP Annual Meeting
  • Int'l Joint Research
• [Presentation] MAIT細胞と免疫疾患 (2018)
  • Author(s): 千葉麻子
  • Organizer: 第29回日本生体防御学会学術総会
  • Invited
• [Presentation] 全身性エリテマトーデスにおけるSTING経路を介した骨髄系細胞のinterferon-α産生増加 (2018)
  • Author(s): 村山豪、千葉麻子、牧山彩子、山路健、田村直人、三宅幸子
  • Organizer: 第62回日本リウマチ学会総会・学術集会
• [Presentation] 全身性エリテマトーデス患者におけるperipheral helper T細胞（TPH）の解析 (2018)
  • Author(s): 牧山彩子、千葉麻子、村山豪、山路健、田村直人、三宅幸子
  • Organizer: 第62回日本リウマチ学会総会・学術集会
• [Presentation] ループスモデルにおけるMAIT細胞に関する解析 (2018)
  • Author(s): 村山豪、千葉麻子、山路健、田村直人、三宅幸子
  • Organizer: 第62回日本リウマチ学会総会・学術集会
• [Presentation] 全身性エリテマトーデスにおけるI型インターフェロン過剰産生機構の解析. (2018)
  • Author(s): 村山豪、千葉麻子、牧山彩子、山路健、田村直人、三宅幸子
  • Organizer: 第46回日本臨床免疫学会総会
• [Presentation] 全身性エリテマトーデス新規治療標的としてのMAIT細胞 (2018)
  • Author(s): 村山豪、千葉麻子、水野智弘、天野浩史、廣瀬幸子、山路健、田村直人、三宅幸子
  • Organizer: 第46回日本臨床免疫学会総会
• [Presentation] 全身性エリテマトーデス患者におけるperipheral helper T細胞の解析 (2018)
  • Author(s): 牧山彩子、千葉麻子、村山豪、山路健、田村直人、三宅幸子
  • Organizer: 第46回日本臨床免疫学会総会
• [Presentation] MAIT cells as a new therapeutic target for systemic lupus erythematosus (2018)
  • Author(s): Chiba A, Murayama G, Mizuno T, Amano H, Hirose S, Yamaji K, Tamura N, Miyake S
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Expansion of peripheral helper T cell are associated with disease activity and B cell differentiation in systemic lupus erythematosus. (2018)
  • Author(s): Makiyama A, Chiba A, Muramaya G, Yamaji K, Tamura N, Miyake S
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Enhanced TLR7 and STING pathways in systemic lupus erythematosus. (2018)
  • Author(s): Murayama G, Chiba A, Makiyama A, Yamaji K, Tamura N, Miyake S
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Peripheral Helper T Cells in Systemic Lupus Erythematosus. (2018)
  • Author(s): Makiyama A, Chiba A, Murayama G, yamaji K, Naoto T, Miyake S
  • Organizer: 2018 ACR/ARHP Annual Meeting
  • Int'l Joint Research
• [Presentation] Enhanced IFN-α Production By Plasmacytoid Dendritic Cells Is Associated with Increased Toll-like Receptor 7 Retention in the Lysosomes and Exosure to Type I IFN in Systemic Lupus Erythematosus (2018)
  • Author(s): Murayama G, Chiba A, Makiyama A, Yamaji K, Tamura N, Miyake S
  • Organizer: 2018 ACR/ARHP Annual Meeting
  • Int'l Joint Research
• [Presentation] Mucosal-Associated Invariant T(MAIT) Cells As a Potential Therapeutic Target for Systemic Lupus Erythematosus. (2018)
  • Author(s): Murayama G, Chiba A, Nomura A, Amano H, Yamaji K, Tamura N, Miyake S
  • Organizer: 2018 ACR/ARHP Annual Meeting
  • Int'l Joint Research
• [Presentation] Role of mucosal-associated invariant T cells in lupus pathogenesis (2017)
  • Author(s): Murayama Goh , Chiba Asako, Amano Hirofumi, Yamaji Ken, Tamura Naoto, Miyake Sachiko
  • Organizer: The 46th Meeting of The Japanese Society for Immunology
• [Presentation] ループスモデルにおける MAIT 細胞の解析 (2017)
  • Author(s): 村山豪、千葉麻子、山路 健、田村直人、三宅幸子
  • Organizer: 第45回日本臨床免疫学会総会
• [Presentation] ループスモデルにおけるMAIT細胞に関する解析 (2017)
  • Author(s): 村山豪、 千葉麻子、天野浩文、山路健、田村直人、三宅幸子
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] Role of mucosal-associated invariant T cells in lupus pathogenesis. (2017)
  • Author(s): Goh Murayama, Asako Chiba, Ken Yamaji, Naoto Tamura, Sachiko Miyake.
  • Organizer: CD1-MR1 2017
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 炎症性疾患および虚血性疾患の改善剤(仮) (2017)
  • Inventor(s): 三宅幸子、千葉麻子
  • Industrial Property Rights Holder: 学校法人順天堂
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017