Role of IL-10 on phenotypical change from RA to SLE using FcgRIIB-deficient mice

• Project/Area Number: 16K09907
• 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: Amano Hirofumi 順天堂大学, 医学部, 准教授 (50318474)
• Research Collaborator: HIROSE Sachiko
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: SLE / モデルマウス / IL-10 / Fcレセプター / RA / 疾患モデルマウス / 遺伝子 / 全身性エリテマトーデス / 免疫学

Outline of Final Research Achievements

By introducing TLR7 duplicated Yaa gene into Rheumatoid Arthritis (RA)-developing FcγreceptorIIB(FcγRIIB)deficient (B6.FcγRIIB-/-)mice, we produced lupus model(FcγRIIB-/-Yaa) mice. From the experimental results, we confirmed the importance of IL-10 in the phenotypical change of the model. We crossed FcγRIIB-/-Yaa mice with IL-10 deficient mice and tried to develop IL-10-deficient FcγRIIB-/-Yaa mice. Since these mice died early, next we used IL-10 blocking antibody. The intra-peritoneal injection of IL-10 blocking antibody did not show any therapeutic effect on FcγRIIB-/-Yaa mice concerning proteinuria and survival rate. We did not confirm the therapeutic effect the anti-IL-10 antibody on this lupus model.

Academic Significance and Societal Importance of the Research Achievements

全身性エリテマトーデス(SLE)は原因不明の全身性自己免疫疾患であり、多彩な免疫異常がその発症に関与する。関節リウマチ（RA）も類似する自己免疫疾患であり、その両疾患の遺伝的背景因子は重複するものの、自然経過や障害される臓器は大きく異なる。
われわれは、その自己免疫疾患を代表する2つの疾患モデルマウスを用いてその原因となる鍵としてIL-10に注目した。SLEを自然発症するFcγRIIB欠損Yaaマウスを用いて、IL-10を遺伝的に欠くマウスの作製に着手した。このマウスは早期に死亡する結果であったため、抗IL-10抗体投与による治療効果について検討したが、明らかな治療効果を示すことはなかった。

Research Products

• [Int'l Joint Research] Leiden University(オランダ)
• [Journal Article] FcgRIIB on B cells and myeloid cells modulates B cell activation and autoantibody responses via different but synergistic pathways in Lupus-Prone Yaa mice. (2018)
  • Author(s): Qingshum Lin, Mareki Ohtsuji, Hirofumi Amano, Hiromichi Tsurui, Norihiro Tada, Ryota Sato, Hidehiro Fukuyama, Hiroyuki Nishimura, J Sjef Verbeek, Sachiko Hisose
  • Journal Title: Journal of Immunology Volume: 201 Issue: 11 Pages: 3199-3210
  • DOI: 10.4049/jimmunol.1701487
  • Peer Reviewed
• [Journal Article] Anti-CD11b antibody treatment suppresses the osteoclast generation, inflammatory cell infiltration, and autoantibody production in arthritis-prone FcγRIIB-deficient mice. (2018)
  • Author(s): Ohtsuji M, Lin Q, Okazaki H, Takahashi K, Amano H, Yagita H, Nishimura H, and Hirose S.
  • Journal Title: Arthritis Res. Ther. Volume: 20:25 Issue: 1 Pages: 1-11
  • DOI: 10.1186/s13075-018-1523-1
  • Peer Reviewed / Open Access
• [Journal Article] Splicing variant ofWDFY4augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis (2018)
  • Author(s): Kochi Yuta et al.
  • Journal Title: Annals of the Rheumatic Diseases Volume: 77 Issue: 4 Pages: 602-611
  • DOI: 10.1136/annrheumdis-2017-212149
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of the alternative classification criteria of systemic lupus erythematosus established by Systemic Lupus International Collaborating Clinics (SLICC) (2017)
  • Author(s): Oku Kenji、Atsumi Tatsuya、Akiyama Yuji、Amano Hirofumi、Azuma Naoto、Bohgaki Toshiyuki、Asanuma Yu Funakubo、Horita Tetsuya、Hosoya Tadashi、Ichinose Kunihiro、Kato Masaru、Katsumata Yasuhiro、Kawaguchi Yasushi、Kawakami Atsushi、Koga Tomohiro et al
  • Journal Title: Modern Rheumatology Volume: 9 Issue: 4 Pages: 1-7
  • DOI: 10.1080/14397595.2017.1385154
  • Peer Reviewed / Open Access
• [Journal Article] Disease flare patterns and predictors of systemic lupus erythematosus in a monocentric cohort of423 Japanese patients during a long-term follow-up:The JUDE study. (2017)
  • Author(s): Minowa K,Amano H,Ando S,Watanabe T,Ogasawara M,Kawano S, Kaneko T,Morimoto S,Yamaji K,Tamura N,Tokano Y,Hashimoto H,Takasaki Y.
  • Journal Title: Mod Rheumatol. Volume: 27 Issue: 1 Pages: 72-76
  • DOI: 10.1080/14397595.2016.1192745
  • Peer Reviewed / Open Access
• [Journal Article] Outcomes of the Re-classification of WHO Class IV Lupus Nephritis Using the ISN/RPS Classification: a Single Center Retrospective Observational Study from the JUDE Study. (2017)
  • Author(s): Miyashita T, Morimoto S, Honda D, Nakano S, Amano H, Osawa I, Yamaji K, Tomino Y, Takasaki Y, Tamura N.
  • Journal Title: Juntendo Med J. Volume: 63 Pages: 362-9
  • NAID: 130006219741
  • Peer Reviewed
• [Journal Article] Independent Association of HLA-G 3’ Untranslated Region 14bp Indel Polymorphism with Systemic Lupus Erythematosus in a Japanese Population: a Case-control Association Study. (2016)
  • Author(s): Hachiya Y, Kawasaki A, Oka S, Kondo Y, Ito S, Matsumoto I, Kusaoi M, Amano H, Suda A, Setoguchi K, Nagai T,Shimada K, Sugii S, Okamoto A, Chiba N, Suematsu E, Ohno S, Katayama M, Kono H, Hirohata S, Takasaki Y, Hashimoto H, Sumida T, Nagaoka S, Tohma S, Furukawa H, Tsuchiya N.
  • Journal Title: PLoS ONE. Volume: 11 Issue: 6 Pages: 22-22
  • DOI: 10.1371/journal.pone.0158065
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 日本人集団における全身性エリテマトーデスおよび 全身性強皮症とGTF21遺伝子多型との関連 (2018)
  • Author(s): 横山望,川崎綾,松下貴史,古川宏,近藤裕也,松本功,草生真規雄,天野浩文,長岡章平,瀬戸口京吾,永井立夫,島田浩太,杉井章二,岡本亨,千葉実行,末松栄一,大野滋,片山雅夫,右田清志,河野肇,長谷川稔,藤本学,田村直人,髙崎芳成,橋本博史,佐藤伸一,住田孝之,當間重人,竹原和彦,土屋尚之
  • Organizer: 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酸化ストレスと抗酸化力の解析 (2018)
  • Author(s): 浅井悠貴,安藤誠一郎,天野浩文,山路健,田村直人.
  • Organizer: 日本リウマチ学会総会・学術集会
• [Presentation] 安定期SLE患者へのヒドロキシクロロキン追加投与効果. (2018)
  • Author(s): 箕輪健太郎,天野浩文,浅井悠貴,河野晋也,山路健,田村直人.
  • Organizer: 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MAT細胞に関する解析CD11b陽性細胞の機能抑制による関節炎自然発症モデルマウスの病態抑制効果. (2018)
  • 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: 日本リウマチ学会総会・学術集会
• [Presentation] CD11b陽性細胞の機能抑制による関節炎自然発症モデルマウスの病態抑制効果. (2018)
  • Author(s): 大辻希樹, 林青順, 天野浩文,岡崎英規, 西村裕之,広瀬幸子.
  • Organizer: 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合併した心疾患で手術が施行された35症例の検討. (2018)
  • Author(s): 河本敏雄, 天野浩文, 松下訓, 箕輪健太郎, 浅井悠貴, 山路健, 天野篤, 田村直人.
  • 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 (2018)
  • Author(s): 天野浩文
  • Organizer: 第33回臨床リウマチ学会スポンサードシンポジウム
• [Presentation] MAIT cells as a new therapeutic target for systemic lupus erythematosus. (2018)
  • Author(s): Asako Chiba, Goh Murayama, Tomohiro Mizuno, Hirofumi Amono, Sachiko Hirose, Ken Yamaji, Naoto Tamura, Sachiko Miyake.
  • Organizer: The 47th Annual Meeting of the Japanese Society for Immunology
  • Int'l Joint Research
• [Presentation] Treatment with anti-CD11b antibody ameliorates arthritis in a novel arthritis-prone mouse model (2018)
  • Author(s): Mareki Ohtsuji, Qingshun Lin, Hirofumi Amano, Hideo Yagita, Kazuko Takahashi, Hideki Okazaki, Hiroyuki Nishimura, Sachiko Hirose.
  • Organizer: The 47th Annual Meeting of the Japanese Society for Immunology
  • Int'l Joint Research
• [Presentation] Slam遺伝子異常マウスにおける末梢血中の単球増加とYaa遺伝子変異による自己免疫疾患の病態変化 (2017)
  • Author(s): 天野浩文, 西川桂子, 小城敬, 林青順, 河野晋也, 山路健, 田村直人,広瀬幸子
  • Organizer: 日本リウマチ学会総会・学術集会
• [Presentation] 免疫アレルギー疾患の病態と分子標的療法ー全身性エリテマトーデス (2017)
  • Author(s): 天野浩文
  • Organizer: 日本皮膚アレルギー・接触皮膚炎学会総会学術大会
  • Invited
• [Presentation] Role of Inhibitory IgG Fc Receptor IIB on B cells and monocytes in Yaa-related murine lupus. (2017)
  • Author(s): Sachiko Hirose, Qingshun Lin, Mareki Otsuji, Hiroyuki Nishimura, Hirofumi Amano, J.Sjef Verbeek.
  • Organizer: EULAR（The European League Against Rheumatism:ヨーロッパリウマチ学会）
  • Int'l Joint Research
• [Presentation] Lupus-prone SLAM haplotype exerts monocytosis and develops mixed connective tissue disease-like phenotype introduced by Yaa mutation. (2017)
  • Author(s): Hirofumi Amano, Keiko Nishikawa, Qingshun Lin, Shinya Kawano, Ken Yamaji, Sachiko Hirose, Naoto Tamura
  • Organizer: APLAR(Asia Pacific League of Associations for Rhematology:アジアリウマチ学会）
  • Int'l Joint Research
• [Presentation] Slam 遺伝子異常マウスにおける末梢血中の単球増加と Yaa 遺伝子変異による自己免疫疾患の病態変化 (2017)
  • Author(s): 天野浩文，西川桂子，林 青順，河野晋也， 山路 健，広瀬幸子，田村直人
  • Organizer: 日本臨床免疫学会
• [Presentation] Inhibitory IgG Fc Receptor IIB on B cells and monocytes independently controls Yaa-induced murine lupus. (2016)
  • Author(s): Qingshun Lin, Hiromichi Tsurui, Hirofumi Amano, Keiko Nishikawa, Mareki Otsuji, Hiroyuki Nishimura, J.Sjef Verbeek, Sachiko Hirose.
  • Organizer: 第45回日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄
  • Year and Date: 2016-12-05
• [Presentation] Blocking of CD11b+ cell-migration ameliorates rheumatoid arthritis-like disease spontaneously occurring in a unique FcRIIB-deficient mouse model. (2016)
  • Author(s): Mareki Otsuji, Qingshun Lin, Hideki Okazaki, Shuri Ikeda, Hinako Sasaki, Hirofumi Amano, Hideo Yagita, Hiroyuki Nishimura, Sachiko Hirose.
  • Organizer: 第45回日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄
  • Year and Date: 2016-12-05
• [Presentation] Role of Mucosal-associated Invariant T(MAIT) Cells In Lupus Dermatitis. (2016)
  • Author(s): 120.Goh Murayama, Asako Chiba, Hirofumi Amano, Ken Yamaji, Naoto Tamura, Sachiko Miyake.
  • Organizer: 第45回日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄
  • Year and Date: 2016-12-05
• [Presentation] 日本人全身性エリテマトーデスとHLA-G多型の関連 (2016)
  • Author(s): 川崎 綾, 八谷有紀, 古川 宏, 近藤裕也, 伊藤 聡, 松本 功, 草生真規雄, 天野浩文, 須田昭子, 長岡章平, 瀬戸口京吾, 永井立夫, 廣畑俊成, 島田浩太, 杉井章二, 岡本 亨, 千葉実行, 末松栄一, 大野 滋, 片岡雅夫, 岡本明子, 河野 肇, 髙崎芳成, 橋本博史, 住田孝之, 當間重人, 土屋尚之
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-04-21
• [Presentation] 全身性エリテマトーデス患者における酸化ストレスマーカーd-ROMsと抗酸化力BAP (2016)
  • Author(s): 安藤誠一郎, 天野浩文, 浅井悠貴、山路健, 田村直人, 髙崎芳成
  • Organizer: 第60本リウマチ学会総会・学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-04-21
• [Funded Workshop] EULAR 2017 (2017)