A significant role of senescent cells and donor mesenchymal stem cells in ocular chronic graft-versus-host disease and development of new therapy

• Project/Area Number: 26462668
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Keio University
• Principal Investigator: Ogawa Yoko 慶應義塾大学, 医学部(信濃町), 特任准教授 (30160774)
• Co-Investigator(Renkei-kenkyūsha): Kazuo Tsubota 慶應義塾大学, 医学部, 教授 (40163878) ; Shimmura Shimmura 慶應義塾大学, 医学部, 准教授 (00235780)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 眼GVHD / ドライアイ / 間葉系幹細胞 / 細胞老化 / 慢性移植片対宿主病 / 角膜 / 涙腺 / 造血幹細胞 / 免疫 / 線維化 / 眼免疫 / 老化細胞 / 造血幹細胞移植 / マクロファージ / 免疫応答

Outline of Final Research Achievements

We found that a significant role of mesenchymal stem cells（MSCs）and senescent macrophages in the pathogenic fibrosis in ocular graft-versus-host disease (GVHD).　Donor MSCs and senescent macrophages expressing p16 were infiltrated into lacrimal glands and activated by interacting each other in early onset of ocular GVHD by secreting senescent related factors. We confirmed immunogenic and MHC class II+ MSCs infiltrated into cGVHD target organs especially lacrimal gland. We analysed the effectiveness of depletion of MSCs transplantation or suppression of a senescent associated cytokine in development of fibrosis and inflammation in ocular GVHD.

Research Products

• [Journal Article] Heavy Chain-Hyaluronan/Pentraxin 3 from Amniotic Membrane Suppresses Inflammation and Scarring in Murine Lacrimal Gland and Conjunctiva of Chronic Graft-versus-Host Disease. (2017)
  • Author(s): Ogawa Y, He H, Mukai S, Imada T, Nakamura S, Su CW, Mahabole M, Tseng SC, Tsubota K
  • Journal Title: Scientific Reports Volume: 7 Issue: 1
  • DOI: 10.1038/srep42195
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Novel Treatment of Chronic Graft-Versus-Host Disease in Mice Using the ER Stress Reducer 4-Phenylbutyric Acid. (2017)
  • Author(s): Mukai S, Ogawa Y, Urano F, Kudo-Saito C, Kawakami Y, Tsubota K.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 41939-41939
  • DOI: 10.1038/srep41939
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Comparison of performance of the 2016 ACR-EULAR classification criteria for primary Sjogren’s syndrome with other sets of criteria in Japanese patients. (2017)
  • Author(s): Tsuboi H., Hagiwara S., Asashima H., Takahashi H., Harota T., Noma H., Umehara H., Kawakami A., Nakamura H., Sano H., Tsubota K., Ozawa Y., Takamura E., Saito I., Inoue H., Nakamura S., Moriyama M., Takeuchi T., Tanaka Y., Hirata S., Mimori T., Matsumoto I., Sumida T.
  • Journal Title: Ann. Rheum. Dis. Volume: 3 Issue: 12 Pages: 2016-210758
  • DOI: 10.1136/annrheumdis-2016-210758
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MHC-compatible bone marrow stromal/stem cells trigger fibrosis by activating host T cells in a scleroderma mouse model. (2016)
  • Author(s): Ogawa Y, Morikawa S, Okano H, Mabuchi Y, Suzuki S, Yaguchi T, Sato Y, Mukai S, Yaguchi S, Inaba T, Okamoto S, Kawakami Y, Tsubota K, Matsuzaki Y, Shimmura S.
  • Journal Title: eLife Volume: 5
  • DOI: 10.7554/elife.09394
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tissue renin angiotensin system in lacrimal gland fibrosis in a murine model of chronic graft-versus-host Disease. (2015)
  • Author(s): Yaguchi S, Ogawa Y, Kawakita T, Shimmura S, Tsubota K.
  • Journal Title: Cornea Volume: 34 Issue: Supplement 11 Pages: S142-S152
  • DOI: 10.1097/ico.0000000000000586
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Possible involvement of epithelial mesenchymal transition in the fibrosis associated with IgG4-related Mikulicz’s disease. (2015)
  • Author(s): Fukui M, Ogawa Y, Shimmura S, Hatou S, Ichihashi Y, Yaguchi S, Hirayama M, Kawakita T, Tsubota K.
  • Journal Title: Modern Rheumatology Volume: 25 Issue: 5 Pages: 737-743
  • DOI: 10.3109/14397595.2014.1002968
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Long-term topical rebamipide and diquafosol in two cases of immune-mediated dry eye. (2015)
  • Author(s): Yamane M, Ogawa Y, Fukui M, Kamoi M, Saijo-Ban Y, Yaguchi S, Mukai S, Kawakita T, Simmura S, Tsubota K.
  • Journal Title: Opt Vis Sci. Volume: 92 Issue: 4S Pages: S25-S32
  • DOI: 10.1097/opx.0000000000000523
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comparisons for grading chronic ocular graft-versus-host disease: NIH eye score, Japanese dry eye score, and DEWS 2007 score. (2014)
  • Author(s): Tatematsu Y, Ogawa Y, Abe T, Kamoi M, Uchino M, Saijyo-Ban Y, Yaguchi S, Mukai S, Mori T, Okamoto S, Tsubota K.
  • Journal Title: Sci Rep. Volume: 4 Issue: 1 Pages: 6680-6680
  • DOI: 10.1038/srep06680
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mice lacking inositol 1,4,5-trisphosphate receptors exhibit dry eye. (2014)
  • Author(s): Inaba T, Hisatsune C, Sasaki Y, Ogawa Y, Ebisui E, Ogawa N, Matsui M, Takeuchi T, Mikoshiba K, Tsubota K.
  • Journal Title: PLoS One. Volume: 9 Issue: 6 Pages: e99205-e99205
  • DOI: 10.1371/journal.pone.0099205
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Primary and secondary surveys on epidemiology of Sjogren's syndrome in Japan (2014)
  • Author(s): Tsuboi, H. Asashima, H. Takai, C. Hagiwara, S. Hagiya, C. Yokosawa, M. Hirota, T. Umehara, H. Kawakami, A. Nakamura, H. Sano, H. Tsubota, K. Ogawa, Y. Takamura, E. Saito, I. Inoue, H. Nakamura, S. Moriyama, M. Takeuchi, T. Tanaka, Y. Hirata, S. Mimori, T. Yoshifuji, H. Ohta, A. Matsumoto, I. Sumida, T.
  • Journal Title: Mod Rheumatol Volume: 24 Issue: 3 Pages: 464-70
  • DOI: 10.3109/14397595.2013.843765
  • Peer Reviewed / Open Access
• [Presentation] 慢性移植片対宿主病によるドライアイに対する治療用コンタクトレンズの有用性 (2017)
  • Author(s): 小川葉子.
  • Organizer: 第39回 日本造血細胞移植学会総会 2017年3月2日―4日(3日)
  • Place of Presentation: 島根県民会館（島根県松江市）
  • Year and Date: 2017-03-02
  • Invited
• [Presentation] Ocular Inflammatory Insults: Advances in understanding their mechanism and treatment. Keynote address. Chronic ocular graft-versus-host disease. (2016)
  • Author(s): Ogawa Y.
  • Organizer: 8th International Conference on the Tear Film & Ocular Surface: Basic Science and Clinical relevance. Montpellier, France.
  • Place of Presentation: フランス（モンペリエ）
  • Year and Date: 2016-09-07
  • Int'l Joint Research / Invited
• [Presentation] 若手ドライアイ研究者育成プログラム. ドライアイのスペシャリストへの第一歩 (日本から世界へ）GVHD 克服への道. (2016)
  • Author(s): 小川葉子.
  • Organizer: 第10回 箱根ドライアイクラブ
  • Place of Presentation: 小田原ヒルトン（神奈川県小田原市）
  • Year and Date: 2016-05-20
  • Invited
• [Presentation] Minisymposium. 147 - Basic and clinical research in chronic ocular graft-versus-host disease. Stem Cells Migration and Immune Mediated Fibrosis in Chronic Ocular GVHD. (2016)
  • Author(s): Ogawa Y.
  • Organizer: The Association of Research for Vision and Ophthalmology 2016 (ARVO2016), 1-5 May 2016.
  • Place of Presentation: アメリカ（シアトル）
  • Year and Date: 2016-05-01
  • Int'l Joint Research / Invited
• [Presentation] Chronic GVHD. Intersecting Basic Aspects. Session I. Ocular GVHD: Diagnostic &Classification criteria. (2016)
  • Author(s): Ogawa Y.
  • Organizer: Chronic GVHD. Intersecting Basic and Clinical Aspects.
  • Place of Presentation: アメリカ（シカゴ）
  • Int'l Joint Research / Invited
• [Presentation] 移植医に必要な合併症の知識 2；眼科的合併症について. (2016)
  • Author(s): 小川葉子.
  • Organizer: 厚生労働省「造血幹細胞移植医療体制整備事業」第1回造血幹細胞移植後合併症セミナー ～移植医に役立つスペシャリストからのレクチャー～ 東京2016/9/22.
  • Place of Presentation: ステーションコンファレンス東京(東京都中央区）
  • Invited
• [Presentation] Diagnostic criteria of ocular GVHD (2015)
  • Author(s): Ogawa Y, Tsubota K.
  • Organizer: The Chicago Chronic GVHD Meeting 2015
  • Place of Presentation: Chicago, USA
  • Year and Date: 2015-10-24
  • Int'l Joint Research / Invited
• [Presentation] 慢性移植片対宿主病によるドライアイの臨床像と末梢血免疫担当細胞の活性化の関連性. (2015)
  • Author(s): 山根みお, 小川葉子, 林 勇海, 福井正樹, 向井 慎, 坪田一男.
  • Organizer: 第69回日本臨床眼科学会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市熱田区）
  • Year and Date: 2015-10-22
• [Presentation] 眼慢性移植片対宿主病の国際診断基準の感度と特異度の検討. (2015)
  • Author(s): 福井正樹, 小川葉子, レザ ダナ, キム ステラ, ビクター ペレッツ, 立松由佳子, 山根みお, 小川護, 西條裕美子, 鴨居瑞加, 坪田一男.
  • Organizer: 第69回日本臨床眼科学会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市熱田区）
  • Year and Date: 2015-10-22
• [Presentation] 教育講演10. シェーグレン症候群の病態に迫る～眼科医の視点から～ シェーグレン症候群とドライアイ. (2015)
  • Author(s): 小川葉子
  • Organizer: 第36回 日本炎症・再生医学会
  • Place of Presentation: 虎ノ門ヒルズフォーラム(東京都港区)
  • Year and Date: 2015-07-21
  • Invited
• [Presentation] マウスGVHD涙腺における免疫担当細胞の相互作用. (2015)
  • Author(s): 山根みお, 小川葉子, 鈴木孝典, 向井慎, 坪田一男.
  • Organizer: 第36回 日本炎症・再生医学会
  • Place of Presentation: 虎ノ門ヒルズフォーラム(東京都港区)
  • Year and Date: 2015-07-21
• [Presentation] Lacrimal obstruction as the basis for dry eye. Complex phenotypes. (2015)
  • Author(s): Ogawa Y.
  • Organizer: Dry Eye Workshop II Pathophysiology Subcommittee Paris Meeting.
  • Place of Presentation: Paris, France
  • Year and Date: 2015-06-20
  • Int'l Joint Research / Invited
• [Presentation] 若手ドライアイ研究者育成プログラム ドライアイのスペシャリストへの第一歩. 若者が育つGVHD研究. (2015)
  • Author(s): 小川葉子.
  • Organizer: 第9回箱根ドライアイクラブ
  • Place of Presentation: ホテルマロウド軽井沢（長野県北佐久郡軽井沢町）
  • Year and Date: 2015-06-05
  • Invited
• [Presentation] 眼慢性移植片対宿主病における小胞体ストレスの関与. (2015)
  • Author(s): 小川葉子、向井慎、坪田一男.
  • Organizer: 第15回 日本抗加齢医学会総会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市博多区）
  • Year and Date: 2015-05-29
• [Presentation] Development of autoimmune type lacrimal gland GVHD in adoptively transferred mice with recipient derived T cells. (2015)
  • Author(s): Ogawa Y, Shimmura S, Tsubota K.
  • Organizer: The Annual Meeting of Association for Research in Vision and Ophthalmology 2015 (ARVO2015)
  • Place of Presentation: Denver, USA
  • Year and Date: 2015-05-03
  • Int'l Joint Research
• [Presentation] Reduction of endoplasmic reticulum stress for treatment of ocular chronic graft-versus-host-disease. (2015)
  • Author(s): Mukai S, Ogawa Y, Tsubota K.
  • Organizer: The Annual Meeting of Association for Research in Vision and Ophthalmology 2015 (ARVO2015)
  • Place of Presentation: Denver, USA
  • Year and Date: 2015-05-03
  • Int'l Joint Research
• [Presentation] Development of a transgenic mouse with R124H human TGFBI mutation associated with Avellino corneal dystrophy (2015)
  • Author(s): Yamazoe K, Yoshida S, Hatou S, Yasuda M, Inagaki E, Ogawa Y, Tsubota K, Shimmura S. .
  • Organizer: The Annual Meeting of Association for Research in Vision and Ophthalmology 2015 (ARVO2015)
  • Place of Presentation: Denver, USA
  • Year and Date: 2015-05-03
  • Int'l Joint Research
• [Presentation] Efficacy and safety of tranilast treatment for ocular chronic graft-versus-host disease. (2015)
  • Author(s): Mukai S, Ogawa Y, Saya H, Kawakami Y, Tsubota K.
  • Organizer: The 18th International Ocular Surface Society Conference.
  • Place of Presentation: Denver, USA
  • Year and Date: 2015-05-02
  • Int'l Joint Research
• [Presentation] Adoptive transferによる涙腺慢性GVHD発症機序の解明. (2015)
  • Author(s): 小川葉子, 榛村重人, 坪田一男.
  • Organizer: 第119回日本眼科学会総会
  • Place of Presentation: ロイトン札幌 (北海道札幌市中央区)
  • Year and Date: 2015-04-16
• [Presentation] Macrophage expressing oxidative stress marker play some role in lacrimal gland of chronic graft-versus-host disease (2014)
  • Author(s): Ogawa Y, Shimmura S, Suzuki T, Kawai M, Tsubota K.
  • Organizer: The Annual Meeting of Association for Research in Vision and Ophthalmology 2014 (ARVO2014)
  • Place of Presentation: Orlando, USA
  • Year and Date: 2014-05-02 – 2014-05-06
• [Presentation] Comparison of 3 Measurement Scales for Grading Ocular Chronic Graft-Versus-Host Disease Patients (2014)
  • Author(s): Tatematsu Y, Ogawa Y, Abe T, Kamoi M, Uchino M, Saijyo-Ban Y, Yaguchi S, Mori T, Okamoto S, Tsubota K.
  • Organizer: World Ophthalmology Congress of the International Council of Ophthalmology (WOC2014)
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2014-04-02 – 2014-04-06
• [Presentation] [IS-SA-167] New Concepts in Ocular Surface Inflammation. The Role of Donor Mesenchymal Stem Cells in cGVHD (2014)
  • Author(s): Ogawa Y
  • Organizer: World Ophthalmology Congress of the International Council of Ophthalmology (WOC2014)
  • Place of Presentation: Tokyo,Japan
  • Year and Date: 2014-04-02 – 2014-04-06
• [Book] 日本眼科学会雑誌 (2016)
  • Author(s): 小川葉子. 巻頭言. 眼疾患と上皮間葉転換.
  • Publisher: 日本眼科学会
• [Book] ドライシンドロームの基礎と臨床. (2016)
  • Author(s): 小川葉子
  • Publisher: メディカルレビュー社
• [Book] 眼科 (2016)
  • Author(s): 中山直彦, 小川葉子, 大高 功, 坪田一男.
  • Publisher: 金原出版株式会社
• [Book] Keynote R・A. Rheumatic & Autoimmune Diseases. (2016)
  • Author(s): 小川葉子.
  • Publisher: 先端医学社
• [Book] 眼科臨床エクスパート. シリーズ編集 吉村長久,後藤 浩, 谷原秀信. 編集 島崎潤. 角結膜疾患の治療戦略. 薬物治療と手術の最前線. (2016)
  • Author(s): 小川葉子
  • Publisher: 医学書院
• [Book] 坪田一男・小澤洋子. 編集主幹 別冊 Bio Clinica 慢性炎症と疾患 眼疾患と炎症 慢性炎症と重症ドライアイ (2015)
  • Author(s): 小川葉子.
  • Total Pages: 6
  • Publisher: 北隆館
• [Book] II 病気・病態の応じた使い方. 8. 眼科疾患患者に投与するときの注意. 田中廣壽. 編集 一冊で極めるステロイド診療ガイド. 第一版 第一刷 (2015)
  • Author(s): 小川葉子, 坪田一男. 文光堂 東京114-117, 2015.
  • Total Pages: 4
  • Publisher: 文光堂
• [Book] IV剤型別 使い分けのコツ・注意 ２．ステロイド外用剤 ②眼科. 田中廣壽. 編集 一冊で極めるステロイド診療ガイド. 第一版 第一刷 (2015)
  • Author(s): 小川葉子, 坪田一男
  • Total Pages: 7
  • Publisher: 文光堂
• [Book] 月刊「アレルギーの臨床」 ＜眼アレルギー診療のminimal essential＞ 特集編集 内尾英一 (2015)
  • Author(s): 小川葉子.
  • Total Pages: 4
  • Publisher: 北隆館
• [Book] 特集 ドライアイのあたらしい治療 炎症制御による治療法. あたらしい眼科 (2015)
  • Author(s): 小川葉子
  • Total Pages: 7
  • Publisher: メディカル葵出版
• [Book] シェーグレン症候群の診断と治療マニュアル 改訂第2版 監修 住田孝之, 川上 純 編集 シェーグレン症候群学会 (2014)
  • Author(s): 小川葉子, 坪田一男.
  • Publisher: 診断と治療社
• [Book] 今日の治療指針2014年版 (2014)
  • Author(s): 小川葉子.
  • Publisher: 医学書院
• [Book] 小児科 (2014)
  • Author(s): 小川葉子.
  • Publisher: 金原出版株式会社
• [Book] 専門医のための眼科診療クオリファイ 21 眼救急疾患スクランブルシリーズ 総編集 大鹿哲郎, 大橋裕一, 坂本泰二 初版 第一刷 (2014)
  • Author(s): 小川葉子, 小澤洋子.
  • Publisher: 中山書店
• [Patent(Industrial Property Rights)] Phenyl butyric acidによる慢性移植片対宿主病における炎症と線維化の抑制と新規治療法の開発 (2016)
  • Inventor(s): 向井慎、小川葉子、坪田一男
  • Industrial Property Rights Holder: 向井慎、小川葉子、坪田一男
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-04-05
  • Overseas