Pathophysiology and genetic predispositions of severe chronic allergic keratoconjunctivitis

• Project/Area Number: 19K09980
• 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: Juntendo University
• Principal Investigator: Matsuda Akira 順天堂大学, 大学院医学研究科, 准教授 (00312348)
• Co-Investigator(Kenkyū-buntansha): 岩本 怜 順天堂大学, 医学部, 助教 (10568207) ; 海老原 伸行 順天堂大学, 医学部, 教授 (20255699) ; 浅田 洋輔 順天堂大学, 医学部, 非常勤助教 (70596626)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: マウスモデル / 春季カタル / アトピー性角結膜炎 / サイトカイン / 遺伝的素因 / IL-33 / 中和抗体 / アトピー角核結膜炎 / モデルマウス / 遺伝子多型 / アレルギー性角結膜炎 / 遺伝素因 / 病態解析

Outline of Research at the Start

春季カタル(VKC)ならびにアトピー性角結膜炎(AKC)は慢性重症アレルギー性角結膜炎であり、視機能を障害する。治療はタクロリムス点眼が施されているが、20％は抵抗性を示す。申請者はタクロリムス治療に抵抗する難治症例由来組織のトランスクリプトーム解析を施行したところ、イムノグロブリン遺伝子とブドウ球菌に対する生体防御反応に関連する遺伝子発現の亢進を発見した。そこで、イムノグロブリン発現を亢進させ、ブドウ球菌毒素を投与することで、慢性VKCモデルマウスの作成を着想した。本研究では、慢性重症アレルギー性角結膜炎の病態解明のため、VKC/AKC発症関連遺伝子の同定とマウスモデルの作成を目指す。

Outline of Final Research Achievements

We generated mouse chronic allergic keratoconjunctivitis model using house dust mite and ragweed antigen eye drop administrations. We obtained gene expression profile of the model mouse and found increase of typical allergy-related genes including keratin16 and Muc5ac. The results suggested that the mouse model reflect the pathophysiology of human chronic allergic keratoconjunctivitis partially. To further mimic the pathophysiology of human chronic allergic keratoconjunctivitis, we generated IL-25 transgenic mouse using human keratin 14 promoter. The IL-25 transgenic mouse showed proliferative change of conjunctival tissue which is one of the characters of human chronic allergic keratoconjunctivitis. So we now try to refine mouse chronic allergic keratoconjunctivitis model by house dust mite and ragweed antigen eye drop administrations using IL-25 transgenic mouse.

Academic Significance and Societal Importance of the Research Achievements

今回の研究で、ヒトの慢性重症アレルギー性角結膜炎の病態を反映したマウスモデルの作成に成功した。このモデルは、今後慢性重症アレルギー性角結膜炎の新規治療法の開発、抗体療法をはじめとする新規治療法の評価に役立つものと期待される。また、今回のモデルの樹立には上皮由来サイトカインの働きが重要であったことから、現在喘息などの分野で開発が進んでいる上皮由来サイトカインの中和抗体を用いた治療が慢性重症アレルギー性角結膜炎の分野にも応用されることが今後期待される。

Research Products

• [Int'l Joint Research] University College of London(英国)
• [Journal Article] The protective role of conjunctival goblet cell mucin sialylation (2023)
  • Author(s): Matsuzawa M, Ando T, Fukase S, Kimura M, Kume Y, Ide T, Izawa K, Kaitani A, Hara M, Nakamura E, Kamei A, Matsuda A, Nakano N, Maeda K, Tada N, Ogawa H, Okumura K, Murakami A, Ebihara N, Kitaura J.
  • Journal Title: Nat Commun Volume: 14 Issue: 1 Pages: 1417-1417
  • DOI: 10.1038/s41467-023-37101-y
  • Peer Reviewed / Open Access
• [Journal Article] Role of Oncostatin M in the Pathogenesis of Vernal Keratoconjunctivitis: Focus on the Barrier Function of the Epithelium and Interleukin-33 Production by Fibroblasts (2022)
  • Author(s): Ninomiya I, Yamatoya K, Mashimo K, Matsuda A, Ouchi A, Araki Y, Ebihara N.
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 63 Issue: 13 Pages: 26-26
  • DOI: 10.1167/iovs.63.13.26
  • Peer Reviewed / Open Access
• [Journal Article] miR103a-3p in extracellular vesicles from FcεRI-aggregated human mast cells enhances IL-5 production by group 2 innate lymphoid cells (2021)
  • Author(s): Toyoshima S, Sakamoto-Sasaki T, Kurosawa Y, Hayama K, Matsuda A, Watanabe Y, Terui T, Gon Y, Matsumoto K, Okayama Y
  • Journal Title: J Allergy Clin Immunol Volume: In press Issue: 5 Pages: 1878-1891
  • DOI: 10.1016/j.jaci.2021.01.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Operative Complications of Glaucoma Drainage Implant Tube Insertion Through the Sulcus for Pseudophakic Eye (2021)
  • Author(s): Asaoka Satoko、Kasuga Toshimitsu、Matsunaga Toru、Hayashi Yusuke、Asada Yosuke、Iwamoto Satoshi、Hirakata Toshiaki、Honda Rio、Obazawa Hanako、Sasaki Hidenori、Ohta Toshihiko、Matsuda Akira
  • Journal Title: Journal of Glaucoma Volume: 30 Issue: 4 Pages: e169-e174
  • DOI: 10.1097/ijg.0000000000001783
  • Peer Reviewed / Open Access
• [Journal Article] Role of Oncostatin M in the Pathogenesis of Vernal Keratoconjunctivitis: Focus on tissue remodeling. (2021)
  • Author(s): Mashimo K, Usui-Ouchi A, Ito Y, Wakasa-Arai R, Yokoi N, Kawasaki S, Murakami A, Matsuda A, Ebihara N.
  • Journal Title: Jpn J Ophthalmol. Volume: 65 Issue: 1 Pages: 144-153
  • DOI: 10.1007/s10384-020-00791-8
  • NAID: 40022476310
  • Peer Reviewed
• [Journal Article] Experimental mouse models of ragweed- and papain-induced allergic conjunctivitis. (2021)
  • Author(s): Matsuda A, Hirakata T, Asada Y
  • Journal Title: Method in Molecular Biology Volume: 2223 Pages: 133-149
  • DOI: 10.1007/978-1-0716-1001-5_10
  • ISBN: 9781071610008, 9781071610015
  • Peer Reviewed
• [Journal Article] Critical role of IL-33, but not IL-25 or TSLP, in silica crystal-mediated exacerbation of allergic airway eosinophilia (2020)
  • Author(s): Unno Hirotoshi、Arae Ken、Matsuda Akira、Ikutani Masashi、Tamari Masato、Motomura Kenichiro、Toyama Sumika、Suto Hajime、Okumura Ko、Matsuda Akio、Morita Hideaki、Sudo Katsuko、Saito Hirohisa、Matsumoto Kenji、Nakae Susumu
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 533 Issue: 3 Pages: 493-500
  • DOI: 10.1016/j.bbrc.2020.09.046
  • Peer Reviewed / Open Access
• [Journal Article] Alteration of gene expression in mice after glaucoma filtration surgery. (2020)
  • Author(s): Adachi K, Asada Y, Hirakata T, Onoue M, Iwamoto S, Kasuga T, Matsuda A.
  • Journal Title: Sci Rep. Volume: 10 Issue: 1 Pages: 15036-15036
  • DOI: 10.1038/s41598-020-72036-0
  • Peer Reviewed / Open Access
• [Journal Article] Proline-assisted tube insertion through sulcus in Ahmed valve. (2020)
  • Author(s): Kasuga T, Asaoka S, Asada Y, Iwamoto S, Hirakata T, Honda R, Ohta T, Matsuda A.
  • Journal Title: J Glaucoma Volume: 29 Issue: 9 Pages: e106-e107
  • DOI: 10.1097/ijg.0000000000001602
  • Peer Reviewed
• [Journal Article] Survival of Alpha and Intrinsically Photosensitive Retinal Ganglion Cells in NMDA-Induced Neurotoxicity and a Mouse Model of Normal Tension Glaucoma (2019)
  • Author(s): Honda Sari、Namekata Kazuhiko、Kimura Atsuko、Guo Xiaoli、Harada Chikako、Murakami Akira、Matsuda Akira、Harada Takayuki
  • Journal Title: Investigative Opthalmology & Visual Science Volume: 60 Issue: 12 Pages: 3696-3707
  • DOI: 10.1167/iovs.19-27145
  • Peer Reviewed / Open Access
• [Journal Article] Effects of the Numbers and the Shapes of Venting Slits on Intraocular Pressure after Baerveldt Glaucoma Drainage Implant (2019)
  • Author(s): Honda Rio、Kasuga Toshimitsu、Murakami Akira、Matsuda Akira
  • Journal Title: Current Eye Research Volume: 44 Issue: 8 Pages: 921-924
  • DOI: 10.1080/02713683.2019.1597892
  • Peer Reviewed
• [Journal Article] Transcriptome profiling of refractory atopic keratoconjunctivitis by RNA sequencing (2019)
  • Author(s): Matsuda Akira、Asada Yosuke、Suita Naomasa、Iwamoto Satoshi、Hirakata Toshiaki、Yokoi Norihiko、Ohkawa Yasuyuki、Okada Yukinori、Yokomizo Takehiko、Ebihara Nobuyuki
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 143 Issue: 4 Pages: 1610-1614
  • DOI: 10.1016/j.jaci.2018.11.007
  • Peer Reviewed / Open Access
• [Journal Article] Periostin deletion suppresses late-phase response in mouse experimental allergic conjunctivitis (2019)
  • Author(s): Asada Y, Okano M, Ishida W, Iwamoto S, Fukuda K, Hirakata T, Tada N, Fukushima A, Ebihara N, Kudo A, Matsuda A.
  • Journal Title: Allergology International Volume: 68 Issue: 2 Pages: 233-239
  • DOI: 10.1016/j.alit.2018.09.007
  • NAID: 130007633580
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Presentation] Refractory ocular complications of atopic dermatitis. (2022)
  • Author(s): Matsuda Akira
  • Organizer: World Allergy Congress 2022
  • Int'l Joint Research / Invited
• [Presentation] 抗IL-33抗体の腹腔内注射によるアレルギー性結膜炎モデルの症状抑制効果について (2021)
  • Author(s): 足立 啓介、浅田 洋輔、平形 寿彬、松田 彰
  • Organizer: 第７０回日本アレルギー学会
• [Presentation] アレルギー性結膜疾患病態と新知見 (2021)
  • Author(s): 松田 彰
  • Organizer: 第７０回日本アレルギー学会
  • Invited