Elucidation on pathophysiology of immune-mediated dry eye disease by depleting senolytic reagents

• Project/Area Number: 21K09752
• 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): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ドライアイ / 老化細胞 / 老化細胞除去剤 / 移植片対宿主病 / 眼免疫 / T細胞 / マクロファージ / 免疫老化 / T細胞老化 / 疲弊T細胞 / 造血幹細胞移植 / 間葉系細胞 / 眼移植片対宿主病 / 免疫応答 / 慢性移植片対宿主病 / 細胞老化関連分泌形質

Outline of Research at the Start

移植片対宿主病 (GVHD) 涙腺、眼表面には老化細胞の浸潤と細胞老化関連分泌形質(SASP）は炎症と線維化の病態の発症と遷延化に関与する（Yamane M,Ogawa Y, et al. FASEB J 2020 ）。GVHD涙腺、眼表面の老化細胞に係る分子基盤を調べ、各種老化細胞除去薬の効果を検討する。
1) 眼 GVHD における老化T細胞、マクロファージ、間葉系細胞のサブセットの特定とその局在および動態の解明　2) 眼GVHD におけるSASPと病態機序に関わる分子基盤の解明　3) 各種老化細胞除去剤による前臨床Proof of concept の確立と臨床応用への準備を目標にする。

Outline of Final Research Achievements

Using a mouse GVHD model, we have shown that the infiltration of senescent cells and the cytokines associated with the senescence-associated secretory phenotype (SASP) secreted by these cells are involved in autoimmune-like inflammation and fibrosis in target organs such as the lacrimal glands and ocular surface. We found senescent T cells, B cells and macrophages in ocular GVHD in mice. We investigated and found T cell temporal changes and exibited exhausted T cells and elevation of sensencent T cells in early stage and before oneset of ocular GVHD using spleen cells from this mouse GVHD model.We also elucidated the molecular basis of SASP in ocular GVHD and examined various senolytic agents for their effects.

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観点からすすめる研究はこれまでになく、学術的意義が高いと考える。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加齢性疾患の抑制に繋がり健康寿命の延長に貢献する可能性がある点に社会的意義があると考える。

Research Products

• [Journal Article] Pediatric chronic graft-versus-host disease-related dry eye disease and the diagnostic association of potential clinical findings. (2023)
  • Author(s): Yagi H, Shimizu E, Yagi R, Uchino M, Kamoi M, Asai K, Tsubota K, Negishi K, Ogawa Y.
  • Journal Title: Sci Rep Volume: 13 Issue: 1 Pages: 3575-3575
  • DOI: 10.1038/s41598-023-30288-6
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Science. シェーグレン症候群の新展開. シェーグレン症候群におけるドライアイの病態と治療. (2023)
  • Author(s): 小川 護、小川葉子.
  • Journal Title: 炎症と免疫 Volume: 31 Pages: 53-57
• [Journal Article] ドライアイの治療. (2023)
  • Author(s): 小川葉子.
  • Journal Title: Monthly Book OCULISA Volume: 128 Pages: 53-62
• [Journal Article] Eyelid blood vessel and meibomian gland changes in a sclerodermatous chronic GVHD mouse model. (2022)
  • Author(s): Yang F, Hayashi I, Sato S, Saijo-Ban Y, Yamane M, Fukui M, Shimizu E, He J, Shibata S, Mukai S, Asai K, Ogawa M, Lan Y, Zeng Q, Hirakata A, Tsubota K, Ogawa Y.
  • Journal Title: The Ocular Surface Volume: 26 Pages: 328-341
  • DOI: 10.1016/j.jtos.2021.10.006
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Multicenter prospective validation study for international chronic ocular graft-versus-host disease consensus diagnostic criteria. (2022)
  • Author(s): Ogawa Y, Dana R, Kim S, Jain S, Rosenblatt MI, Perez VL, Clayton JA, Alves M, Rocha EM, Amparo F, Seo KY, Wang Y, Shen J, Oh JY, Vanathi M, Nair S, Na KS, Riemens A, Sippel K, Soifer M, Wang S, Trindade M, Kim MK, Yoon CH, Yagi R, Hiratsuka R, Ogawa M, Shimizu E, Sato Y, Pflugfelder S, Tsubota K.
  • Journal Title: The Ocular Surface Volume: 26 Pages: 200-208
  • DOI: 10.1016/j.jtos.2022.09.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A single institute validation study comparing the international chronic ocular graft-versus-host disease consensus group diagnostic criteria with clinical parameters. (2022)
  • Author(s): Hiratsuka R, Shimizu E, Yamane M, Yazu H, Sato S, Fukui M, Mukai S, Uchino M, Kamoi M, Tatematsu Y, Saijo Y, Negishi K, Tsubota K, Ogawa Y.
  • Journal Title: The Ocular Surface Volume: 24 Pages: 12-14
  • DOI: 10.1016/j.jtos.2021.12.009
  • Peer Reviewed
• [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] Autoimmune epithelitis and chronic inflammation in Sjogren’s syndrome-related dry eye disease. (2021)
  • Author(s): Ogawa Y, Takeuchi T, Tsubota K.
  • Journal Title: Int. J. Mol. Sci. Volume: 22 Issue: 21 Pages: 11820-11820
  • DOI: 10.3390/ijms222111820
  • Peer Reviewed / Open Access
• [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] 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] 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] The Overlap Syndrome: A Case Report of Chronic Graft-Versus-Host Disease After the Development of a Pseudomembrane. (2021)
  • Author(s): Hayashi S, Shimizu E, Uchino M, Yazu H, Aketa N, Tsubota K, Ogawa Y
  • Journal Title: Cornea Volume: 40 Issue: 9 Pages: 1188-1192
  • DOI: 10.1097/ico.0000000000002593
  • 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
• [Presentation] Fibrosis in ocular GVHD (2024)
  • Author(s): Yoko Ogawa
  • Organizer: International Expert Meeting in Ocular GVHD 2024
  • Int'l Joint Research / Invited
• [Presentation] Ocular surface mucosal immunology in ocular graft-versus-host disease and its clinical implication. (2023)
  • Author(s): Yoko Ogawa
  • Organizer: The 22nd Asia Pacific Ophthalmologists Annual Meeting
  • Int'l Joint Research / Invited
• [Presentation] 慢性GVHDの病態に対する免疫老化の影響について. (2023)
  • Author(s): 岡崎貴裕, 小川葉子, 佐藤真理, 清水映輔, ルシュ・ロベルト, 浅井一樹, 平山雅敏, 榛村重人, 坪田一男, 根岸一乃.
  • Organizer: 第23回日本抗加齢医学会総会
• [Presentation] 慢性GVHDの発症前後のT細胞における免疫チェックポイント分子の動向. (2023)
  • Author(s): 岡崎貴裕, 小川葉子, 佐藤真理, 清水映輔, ルシュ・ロベルト, 浅井一樹, 平山雅敏, 榛村重人, 坪田一男, 根岸一乃.
  • Organizer: 第46回日本分子生物学会年会
• [Presentation] 眼GVHDの病態解明へのアプローチと治療の展望. (2023)
  • Author(s): 小川葉子.
  • Organizer: 箱根ドライアイクラブ
  • Invited
• [Presentation] インストラクションコース 土-IC39 難治性ドライアイに対する対策 Part V. (2023)
  • Author(s): 小川葉子, 山口昌彦, 細谷友雅, 猪俣武範, 内野美樹, 清水映輔, 佐藤真理.
  • Organizer: 第77 回日本臨床眼科学会
• [Presentation] 特別講演. GVHDの眼表面粘膜免疫と病的線維化. (2023)
  • Author(s): 小川葉子.
  • Organizer: 第3回Novartis Hematology Web Conference.
  • Invited
• [Presentation] 2023年度cGVHDを学ぼう！NIH基準になれる. 眼GVHDとNIH基準. (2023)
  • Author(s): 小川葉子
  • Organizer: 第5回造血幹細胞移植推進拠点病院セミナー 大阪公立大学 血液腫瘍制御学.
  • Invited
• [Presentation] Special Interest Group. Advances in understanding of pathophysiology, diagnosis, and treatments of ocular graft-versus-host disease. (2022)
  • Author(s): Ogawa Y, Kim SK, Perez VL, Jain S, Steven P, Amparo F.
  • Organizer: ARVO 2022 Annual Meeting.
  • Int'l Joint Research
• [Presentation] Asia Cornea Joint symposium. Dry Eyes and Ocular Surface Disease. Ocular GVHD. (2022)
  • Author(s): Ogawa Y.
  • Organizer: The 8th World Cornea Congress.
  • Int'l Joint Research / Invited
• [Presentation] インストラクションコース 難治性ドライアイに対する対策. (2022)
  • Author(s): 小川葉子, 山口昌彦, 細谷友雅, 猪俣武範, 内野美樹, 清水映輔, 佐藤真理.
  • Organizer: 第76回日本臨床眼科学会
• [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] 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 Virtual Meeting
  • Int'l Joint Research
• [Book] 眼科診療エクレール第２巻 (2023)
  • Author(s): 小川葉子.
  • Total Pages: 386
  • Publisher: 中山出版
  • ISBN: 9784521750521
• [Patent(Industrial Property Rights)] 慢性移植片対宿主病における眼合併症の予防治療用医薬組成物 (2023)
  • Inventor(s): 小川葉子、浅井一樹、佐藤真理、平山雅敏、根岸一乃
  • Industrial Property Rights Holder: 小川葉子、浅井一樹、佐藤真理、平山雅敏、根岸一乃
  • Industrial Property Rights Type: 特許
  • Filing Date: 2023
• [Patent(Industrial Property Rights)] 慢性移植片対宿主病の発症を予測するためのバイオマーカー、および判定 方法 (2023)
  • Inventor(s): 小川葉子、岡崎貴裕、平山雅敏
  • Industrial Property Rights Holder: 小川葉子、岡崎貴裕、平山雅敏
  • Industrial Property Rights Type: 特許
  • Filing Date: 2023