Development of a new therapy for immune related dry eye disease using senolytic reagents

• Project/Area Number: 18K09421
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Keio University
• Principal Investigator: OGAWA Yoko 慶應義塾大学, 医学部(信濃町), 講師(非常勤) (30160774)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ドライアイ / 眼移植片体宿主病 / 造血幹細胞移植 / 老化細胞 / マクロファージ / 老化細胞除去剤 / 線維化抑制 / 炎症抑制 / 眼移植片対宿主病 / 眼免疫 / 間葉系細胞 / T細胞 / 涙腺 / 慢性移植片対宿主病 / ABT-263 / 老化細胞分泌形質 / 治療薬 / GVHD / 移植片対宿主病 / 細胞老化 / 老化関連分泌形質

Outline of Final Research Achievements

Aging in immune system is thought to be a factor in the development of chronic ocular GVHD, which is currently treated primarily with immunosuppressive therapies. Our findings suggest a potential association between chronic ocular GVHD pathogenesis and stress-induced cellular senescence through the senescence-associated secretory phenotype (SASP). Senescent cells produce cytokines and chemokines, such as IL-6 and CXCL9 a major components of SASP. Senescent cell accumulation was presumably associated with cGVHD development in lacrimal glands(LGs), as evidenced by the improvement in LGs after the selective elimination of senescent cells (senolysis) with ABT-263. Results in the sclerodermatous cGVHD mouse model suggest that inhibiting the SASP, including IL-6 and CXCL9, with senolytics is a potential novel strategy for treating cGVHD-affected LGs.

Academic Significance and Societal Importance of the Research Achievements

免疫老化を軸に考えたGVHDによるドライアイおよび全身GVHDに対し,抗加齢治療として全く新しい病態解明と治療法開発の観点からすすめる研究はこれまでになく、学術的独自性と意義があると考える。本研究成果は、GVHDの病態が自己免疫疾患に類似するため広く自己免疫疾患による重症ドライアイの病態解明と抗加齢療法としての観点からの治療法の開発にも繋がる可能性がある。重症ドライアイの疾病予防のみならず老化細胞除去による病態解明が広く自己免疫疾患や加齢性疾患の病態解明につながり、健康寿命の延長に貢献する可能性がある点に学術的意義や社会的意義があると考える。

Research Products

• [Journal Article] Cascade of inflammatory, fibrotic processes and stress-induced senescence in chronic GVHD-related dry eye disease. (2021)
  • Author(s): Ogawa Y, Kawakami Y, Tsubota K.
  • Journal Title: Int. J. Mol. Sci. Volume: 22 Issue: 11 Pages: 6114-6114
  • DOI: 10.3390/ijms22116114
  • Peer Reviewed / Open Access
• [Journal Article] Update on ocular graft-versus-host disease. (2021)
  • Author(s): Nair S, Vanathi M, Mukhija R, Tandon R, Jain S, Ogawa Y.
  • Journal Title: Indian J Ophthalmol Volume: 69 Issue: 5 Pages: 1038-1050
  • DOI: 10.4103/ijo.ijo_2016_20
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IIa. The 2020 Clinical Implementation and Early Diagnosis Working Group Report. (2021)
  • Author(s): Kitko CL, Pidala J, Schoemans HM, Lawitschka A, Flowers ME, G, SCowen EW, Tkaczyk E, Farhadfar N, Jain S, Steven P, Luo ZK, Ogawa Y, Stern M, Yanik GA, Cuvelier GDE, Cheng GS, Holtan Schultz KR, Martin PJ, Lee SJ, Pavletic SZ, Wolff D, Paczesny S, Blazar BR, Sarantopoulos S, Socie G, Greinix H, Cutler C:
  • Journal Title: Transplant Cell Ther Volume: 27 Issue: 7 Pages: 545-557
  • DOI: 10.1016/j.jtct.2021.03.033
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2020 Highly morbid forms report. (2021)
  • Author(s): Wolff D,----Teshima T,-----, Jain S, Ogawa Y, Steven P, Luo ZK, Dietrich-Ntoukas T, Saban D, Bilic E, Penack O, Griffith LM, Cowden M, Martin PJ, Greinix HT, Sarantopoulos S, Socie G, Blazar BR, Pidala J, Kitko CL, Couriel DR, Cutler C, Schultz KR, Pavletic SZ, Lee SJ, Paczesny S.
  • Journal Title: Transplant Cell Ther Volume: 27 Issue: 10 Pages: 817-835
  • DOI: 10.1016/j.jtct.2021.06.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Positive Effects of Oral Antibiotic Administration in Murine Chronic Graft-Versus-Host Disease. (2021)
  • Author(s): Sato S, Shimizu E, He J, Ogawa M, Asai K, Yazu H, Rusch R, Yamane M, Yang F, Fukuda S, Kawakami Y, Tsubota K, Ogawa Y.
  • Journal Title: Int J Mol Sci. Volume: 22 Issue: 7 Pages: 374-374
  • DOI: 10.3390/ijms22073745
  • Peer Reviewed / Open Access
• [Journal Article] Observation of Chronic Graft-Versus-Host Disease Mouse Model Cornea with In Vivo Confocal Microscopy. (2021)
  • Author(s): Shimizu S, Sato S, Taniguchi H, Shimizu E, He J, Hayashi S, Negishi K, Ogawa Y, Shimmura S:
  • Journal Title: Diagnostics (Basel) Volume: 11 Issue: 8 Pages: 1515-1515
  • DOI: 10.3390/diagnostics11081515
  • Peer Reviewed / Open Access
• [Journal Article] MSCs Become Collagen-Type I Producing Cells with Different Phenotype in Allogeneic and Syngeneic Bone Marrow Transplantation. (2021)
  • Author(s): Rusch RM, Ogawa Y, Sato S, Morikawa S, Inagaki E, Shimizu E, Tsubota K, Shimmura S.
  • Journal Title: Int J Mol Sci Volume: 22 Issue: 9 Pages: 4895-4895
  • DOI: 10.3390/ijms22094895
  • Peer Reviewed / Open Access
• [Journal Article] Senescence-associated secretary phenotype promotes chronic ocular graft-versus-host disease. (2020)
  • Author(s): Yamane M, Sato S, Shimizu E, Shibata S, Hayano M, Yaguchi T, Kamijuku H, Ogawa M, Suzuki T, Mukai S, Shimmura S, Okano H, Takeuchi T, Kawakami Y, Ogawa Y, Tsubota K.
  • Journal Title: FASEB J Volume: 34 Issue: 8 Pages: 10778-10800
  • DOI: 10.1096/fj.201900218r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 慢性移植片対宿主病による重症ドライアイが軽快した1例 (2020)
  • Author(s): 箱崎 瑠衣子, 矢津 啓之, 清水 映輔, 明田 直彦, 内野 美樹, 鴨居 瑞加, 西條 裕美子, 立松 由佳子, 山根 みお, 加藤 淳, 森 毅彦, 岡本 真一郎, 坪田 一男, 小川 葉子.
  • Journal Title: あたらしい眼科 Volume: 37 Pages: 752-757
  • NAID: 40022295800
  • Peer Reviewed / Open Access
• [Journal Article] 男性Sjoegren症候群の3症例にみられたドライアイの特徴の検討. (2020)
  • Author(s): 林 俊介, 清水 映輔, 内野 美樹, 鴨居 瑞加, 西條 裕美子, 立松 由佳子, 矢津 啓之, 鈴木 勝也, 竹内 勤, 坪田 一男, 小川 葉子.
  • Journal Title: あたらしい眼科 Volume: 37 Pages: 747-751
  • Peer Reviewed / Open Access
• [Journal Article] Ocular graft-versus-host disease after hematopoietic cell transplantation: Expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT. (2019)
  • Author(s): Inamoto Y, Valdes-Sanz N, Ogawa Y, Alves M, Berchicci L, Galvin J, Greinix H, Hale GA, Horn B, Kelly D, Liu H, Rowley S, Schoemans H, Shah A, Lupo Stanghellini MT, Agrawal V, Ahmed I, Ali A, Bhatt N, Byrne M, Chhabra S, DeFilipp Z, Fahnehjelm K, Shaw BE, Petricek I
  • Journal Title: Bone Marrow Transplant Volume: 54 Issue: 5 Pages: 662-673
  • DOI: 10.1038/s41409-018-0340-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cluster of differentiation 30 expression in lacrimal gland and conjunctival tissues in patients with Sjogren's syndrome: Case series. (2019)
  • Author(s): Ogawa A, Ogawa Y, Mukai S, Shimizu E, Kuwana M, Kawakami Y, Tsubota K
  • Journal Title: Medicine (Baltimore) Volume: 98: Issue: 29 Pages: e16390-e16390
  • DOI: 10.1097/md.0000000000016390
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Commensal microflora in human conjunctiva; characteristics of microflora in the patients with chronic ocular graft-versus-host disease (2019)
  • Author(s): Shimizu Eisuke、Ogawa Yoko、Saijo Yumiko、Yamane Mio、Uchino Miki、Kamoi Mizuka、Fukui Masaki、Yang Fan、He Jingliang、Mukai Shin、Tsubota Kazuo
  • Journal Title: The Ocular Surface Volume: 印刷中 Issue: 2 Pages: 265-271
  • DOI: 10.1016/j.jtos.2019.02.001
  • Peer Reviewed
• [Journal Article] "Smart Eye Camera": An innovative technique to evaluate tear film breakup time in the murine dry eye disease model. (2019)
  • Author(s): Shimizu E, Ogawa Y, Yazu H, Aketa N, Yang F, Yamane M, Kawakami Y, Tsubota K.
  • Journal Title: PLoS ONE. Volume: 14 Issue: 5 Pages: e0215130-e0215130
  • DOI: 10.1371/journal.pone.0215130
  • Peer Reviewed / Open Access
• [Journal Article] A novel and innovative paper-based analytical device for assessing tear lactoferrin of dry eye patients. (2019)
  • Author(s): Sonobe H, Ogawa Y, Yamada K, Shimizu E, Uchino Y, Kamoi M, Saijo Y, Yamane M, Citterio D, Suzuki K, Tsubota K.
  • Journal Title: Ocul Surf Volume: 17 Issue: 1 Pages: 160-166
  • DOI: 10.1016/j.jtos.2018.11.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 特集 免疫異常と眼炎症. シェーグレン症候群によるドライアイの臨床像と免疫異常による病態. (2019)
  • Author(s): 小川葉子. 企画・監修 後藤 浩、寺崎浩子. 148(5):, 2019. 小川 葉子，西條裕美子，谷口 紗織. 日本眼科学会ドライアイ診療ガイドライン. 第 3 章推奨トピックス 8 「慢性移植片対宿主病に伴うドライアイの特徴と治療について」日本眼科学会雑誌. 123(5):570-571, 2019
  • Journal Title: 日本医師会雑誌 Volume: 148 Pages: 890-892
  • Peer Reviewed
• [Journal Article] ドライアイ診療ガイドライン. 第 3 章推奨トピックス 8 「慢性移植片対宿主病に伴うドライアイの特徴と治療について」 (2019)
  • Author(s): 小川 葉子，西條裕美子，谷口 紗織. 123(5):, 2019
  • Journal Title: 日本眼科学会雑誌 Volume: 123 Pages: 570-571
  • Peer Reviewed / Open Access
• [Journal Article] Special Issue. Sjogren's Syndrome, Non-Sogren's Syndrome, and Graft-Versus-Host Disease-Related Dry Eye. (2018)
  • Author(s): Ogawa Y
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 59
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel elucidation and treatment of pancreatic chronic graft-versus-host disease in mice. (2018)
  • Author(s): Mukai S, Ogawa Y, Urano F, Kawakami Y, Tsubota K.
  • Journal Title: R Soc Open Sci. Volume: 5 Issue: 10 Pages: 181067-181067
  • DOI: 10.1098/rsos.181067
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Therapeutic potential of tranilast for the treatment of chronic graft-versus-host disease in mice. (2018)
  • Author(s): Mukai S, Ogawa Y, Saya H, Kawakami Y, Tsubota K. .
  • Journal Title: PLoS One Volume: 13 Issue: 10 Pages: e0203742-e0203742
  • DOI: 10.1371/journal.pone.0203742
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of Vascular Adhesion Protein-1 for Treatment of Graft-Versus-Host Disease in Mice. (2018)
  • Author(s): Mukai S, Ogawa Y, Kawakami Y, Mashima Y, Tsubota K.
  • Journal Title: FASEB J. Volume: 32 Issue: 8 Pages: 4085-4095
  • DOI: 10.1096/fj.201700176r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long-term Topical Diquafosol Tetrasodium Treatment of Dry Eye Disease Caused by Chronic Graft-Versus-Host-Disease: A Retrospective Study. (2018)
  • Author(s): Yamane M, Ogawa Y, Fukui M, Kamoi M, Uchino M, Saijo-Ban Y, Kozuki N, Mukai S, Mori T, Okamoto S, Tsubota K.
  • Journal Title: Eye Contact Lens. Volume: 44 Issue: 2 Pages: S215-S220
  • DOI: 10.1097/icl.0000000000000455
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 慢性移植片対宿主病モデルマウスの結膜嚢におけるドナー由来線維芽細胞の集積. (2018)
  • Author(s): 五十嵐秀人, 小川葉子, 山根みお, 清水映輔, 福井正樹, 榛村重人, 坪田一男.
  • Journal Title: あたらしい眼科 Volume: 35 Pages: 693-697
  • Peer Reviewed / Open Access
• [Presentation] New-Perspective: Ocular Graft-versus-Host Disease is more than just another form of dry-eye disease. (2021)
  • Author(s): Steven P, Jain S, Ogawa Y, Luo Z, Victor P.
  • Organizer: The Association for Research in Vision and Ophthalmology (ARVO) 2021 Annual Meeting .
  • Int'l Joint Research
• [Presentation] オキュラーサーフェス免疫研究の最前線. GVHDの免疫学的機序と新規治療法 (2021)
  • Author(s): 小川葉子
  • Organizer: 第125回日本眼科学会総会
  • Invited
• [Presentation] インストラクションコース土IC-52 角結膜 免疫性疾患と難治性ドライアイ症例への対策. Part II. (2020)
  • Author(s): 小川葉子, 山口昌彦, 細谷友雅, 猪俣武範, 清水映輔, 矢津啓之.
  • Organizer: 第74回臨床眼科学会 Web開催
• [Presentation] Special Interest Group (SIG) Panel Session. Ocular GVHD: What have we learned and what do we still not know? (2020)
  • Author(s): Ogawa Y, Kim SK, Dana R, Perez VL, Alves M, Shimizu E, Jain S.
  • Organizer: The Association for Research in Vision and Ophthalmology (ARVO) 2020 Annual Meeting
  • Int'l Joint Research
• [Presentation] IL-6 producing donor-derived macrophages contribute the development of ocular chronic graft-versus-host disease in mice. (2020)
  • Author(s): Sato S, Ogawa Y, Yamane M, Shimizu E, Kamijuku H, Shibata S, Hayano M, Ogawa M, Suzuki T, Mukai S, Shimmura S, Okano H, Takeuchi T, Kawakami Y, Tsubota K.
  • Organizer: The Association for Research in Vision and Ophthalmology (ARVO) 2020 Annual Meeting
  • Int'l Joint Research
• [Presentation] Correlation in the microbiome analysis between the Ocular Graft-versus-host disease case and the model mice. (2020)
  • Author(s): Shimizu E, Ogawa Y, Yazu H, Sato S, Fukuda S, Kawakami Y, Tsubota, K.
  • Organizer: The Association for Research in Vision and Ophthalmology (ARVO) 2020 Annual Meeting
  • Int'l Joint Research
• [Presentation] Eyelid vascular changes in a sclerodermatous GVHD mouse model. (2020)
  • Author(s): Yang F, Ogawa Y, Hayashi I, Yamane M, Fukui M, Shimizu E, Saijo-Ban Y, Shibata S, Mukai S, Ogawa M, Zeng Q, Tsubota K.
  • Organizer: The Association for Research in Vision and Ophthalmology (ARVO) 2020 Annual Meeting
  • Int'l Joint Research
• [Presentation] Stress-induced senescence in chronic ocular graft-versus-host disease in mice. (2019)
  • Author(s): Ogawa Y, Yamane M, Shimizu E, Shibata S, Hayano M, Suzuki T, Mukai S, Shimmura S, Okano H, Takeuchi T, Kawakami Y, Tsubota K.
  • Organizer: The Association for Research in Vision and Ophthalmology (ARVO) 2019 Annual Meeting
  • Int'l Joint Research
• [Presentation] A novel and effective oral antibiotics treatment to the graft-versus-host disease model mouse. (2019)
  • Author(s): Shimizu E, Ogawa Y, Yazu H, Fukui M, Fukuda S, Kawakami Y, Tsubota K.
  • Organizer: The Association for Research in Vision and Ophthalmology (ARVO) 2019 Annual Meeting
  • Int'l Joint Research
• [Presentation] シンポジウム１. 皮膚粘膜症候群Up to date. 眼GVHDの病態と治療. (2019)
  • Author(s): 小川葉子
  • Organizer: 角膜カンファレンス2019. 第43回日本角膜学会総会/第35回日本角膜移植学会
  • Invited
• [Presentation] Sjogren’s Syndrome, Non-Sjogren’s Syndrome, and GVHD Related Dry Eye. (2019)
  • Author(s): 小川葉子
  • Organizer: 第12回 箱根ドライアイクラブ
  • Invited
• [Presentation] 造血幹細胞移植の長期follow up -眼・口のケア、QOL- (2019)
  • Author(s): 小川葉子
  • Organizer: 造血幹細胞移植後の眼科領域の合併症と治療.和元年度 造血幹細胞拠点病院研修会 第1回造血幹細胞移植セミナー
  • Invited
• [Presentation] 移植片対宿主病によるドライアイの基礎と臨床. (2019)
  • Author(s): 小川葉子
  • Organizer: 杏林アイセンター・オープンカンファレンス
  • Invited
• [Presentation] シンポジウム2 SS・IgG4RD診断の新機軸. シェーグレン症候群によるドライアイの臨床像と免疫異常による病態. (2019)
  • Author(s): 小川葉子
  • Organizer: 第28回日本シェーグレン症候群学会学術集会 徳島
  • Invited
• [Presentation] シェーグレン症候群学会賞受賞講演. シェーグレン症候群によるドライアイの病態解明と治療法の開発. (2019)
  • Author(s): 小川葉子
  • Organizer: 第28回日本シェーグレン症候群学会学術集会 徳島
  • Invited
• [Presentation] インストラクションコース土IC-52 角結膜 免疫性疾患と難治性ドライアイ症例への対策. (2019)
  • Author(s): 小川葉子, 山口昌彦, 細谷友雅, 内野美樹, 清水映輔, 矢津啓之.
  • Organizer: 第73回臨床眼科学会
• [Presentation] Consecutive ocular phenotypes in chronic graft-versushost disease murine model. (2019)
  • Author(s): 清水映輔, 小川葉子, 明田直彦, 矢津啓之, 楊帆, 坪田 一男.
  • Organizer: 第123回日本眼科学会総会
• [Presentation] シンポジウム 1 皮膚粘膜症候群 up to date S1-4 移植片対宿主病における眼表面粘膜病変の病態機序 (2019)
  • Author(s): 小川葉子
  • Organizer: 角膜カンファレンス2019. 第43回日本角膜学会総会/第35回日本角膜移植学会
  • Invited
• [Presentation] Positive effects of oral antibiotics administration to murine graft-versus-host disease. (2018)
  • Author(s): Shimizu E, Ogawa Y, He J, Fukuda S, Tsubota K.
  • Organizer: The Association for Research in Vision and Ophthalmology (ARVO) 2018 Annual Meeting
  • Int'l Joint Research
• [Book] シェーグレン症候群の診断と治療マニュアル (2018)
  • Author(s): 小川葉子、坪田一男
  • Total Pages: 235
  • Publisher: 診断と治療社
• [Remarks] プレスリリース 細胞老化が骨髄移植による合併症、眼慢性GVHDに寄与することを発見
  • URL: https://www.keio.ac.jp/ja/press-releases/2020/9/24/28-75178/
• [Patent(Industrial Property Rights)] 移植片対宿主病の治療剤または予防剤 (2019)
  • Inventor(s): 小川葉子, 坪田一男, 清水映輔, 山根みお
  • Industrial Property Rights Holder: 小川葉子, 坪田一男, 清水映輔, 山根みお
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
• [Patent(Industrial Property Rights)] 移植片対宿主病の治療剤又は予防剤 (2019)
  • Inventor(s): 小川葉子、山根みお、清水映輔、坪田一男
  • Industrial Property Rights Holder: 小川葉子、山根みお、清水映輔、坪田一男
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-004730
  • Filing Date: 2019