Development of the new treatment applying microbiome analysis in the graft-versus-host disease related dry eye disease

• Project/Area Number: 20K18394
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Keio University
• Principal Investigator: Shimizu Eisuke 慶應義塾大学, 医学部(信濃町), 特任講師 (10793812)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ドライアイ / 腸内細菌 / GVHD / 自己免疫 / 予防 / オーファン / 移植片対宿主病 / 免疫 / 抗菌薬 / 加齢 / 細胞老化 / 視機能 / Microbiome / 炎症 / 新規治療法開発

Outline of Research at the Start

本研究は眼表面および腸管の細菌叢 (Microbiome)と眼免疫系の関連性を解き明かし、その病態に応じた眼免疫疾患の新規治療/予防法開発と実用化を目的とする。本申請では、眼免疫疾患の中で代表的な慢性眼移植片対宿主病 (Graft-versus-host disease: GVHD)関連ドライアイにおけるMicrobiomeを応用した疾患機序に基づく新規治療/予防法開発を行う。本申請は医療現場で、対症療法しか存在しないという現状の問題点を、その病態の根本から解決する可能性を秘めたものである。

Outline of Final Research Achievements

Hematopoietic stem cell transplantation is a curative therapy for hematologic malignant diseases, but can lead to complications of graft-versus-host disease (GVHD), which causes inflammation and fibrosis in organs throughout the body, especially in the eye, affecting the quality of daily life and life expectancy. Conventional GVHD therapies are mainly symptomatic treatments with strong side effects, such as steroids, and the social problems associated with treatment have become apparent. In this study, we focus on the autoimmune-like pathogenesis of GVHD and attempt to develop new treatment methods. Recent studies have revealed that intestinal bacteria are deeply involved in the immune system and play an important role in autoimmune diseases. We believe that conjunctival and intestinal bacteria are highly associated with GVHD-related dry eye and propose a novel approach to treat GVHD by immunosuppression through changes in the bacterial flora, and also to prevent GVHD.

Academic Significance and Societal Importance of the Research Achievements

本研究では、病態に基づいた新規治療法の開発に注目し、その学術的な特色を発揮しています。特に、移植片対宿主病（GVHD）の合併症に対する治療という未開拓の領域において、病態に直接作用する治療法の開発を試みています。GVHDモデルにおいて、GM（グラム陰性菌）の経口投与によりGVHDの表現型が改善されることが確認されました。これは、新規かつ臨床的に有用な治療戦略として認識されており、2022年度にはそのエビデンスが公表されました。新規治療法の開発は、副作用の少ない病態に基づいた治療法を提供し、学術的にも貢献する可能性があると考えられます。

Research Products

• [Journal Article] Biomarkers enable prediction of tacrolimus resistance in patients with severe allergic conjunctivitis (2022)
  • Author(s): Okada Naoko、Yazu Hiroyuki、Shimizu Eisuke、Fukagawa Kazumi、Nunomura Satoshi、Saito Hirohisa、Matsumoto Kenji、Kawaguchi Atsushi、Izuhara Kenji、Fujishima Hiroshi
  • Journal Title: Allergy Volume: 78 Issue: 1 Pages: 319-321
  • DOI: 10.1111/all.15535
  • Peer Reviewed
• [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] 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
• [Presentation] Gut microbiota promotes chronic ocular graft-versus-host disease (cGVHD) through cellular senescence. (2021)
  • Author(s): Shinri Sato , Eisuke Shimizu , Shinji Fukuda , Yoko Ogawa , Kazuo Tsubota
  • Organizer: The Association for Research in Vision and Ophthalmology 2021
  • Int'l Joint Research