Establishment of world-premier pachymeningitis animal model and development of new therapeutic option targeting TGF-beta.

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K19663
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: General internal medicine and related fields
• Research Institution: Kyushu University
• Principal Investigator: Kira Jun-ichi 九州大学, 医学研究院, 教授 (40183305)
• Co-Investigator(Kenkyū-buntansha): 山崎 亮 九州大学, 医学研究院, 准教授 (10467946) ; 渡邉 充 九州大学, 医学研究院, 助教 (30748009) ; 篠田 紘司 九州大学, 医学研究院, 助教 (70747998)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Keywords: 肥厚性硬膜炎

Outline of Final Research Achievements

IgG4-related disease is a major cause of hypertrophic pachymeningitis (HP). HP lacks an animal model. We longitudinally evaluated dura in mice with a mutation (Y136F) in the linker for activation of T cells (LAT), which induced Th2 cell proliferation and IgG1 (IgG4 human equivalent) overexpression. Mice were administered daily oral irbesartan. Human IgG4-related, ANCA-related, and idiopathic HP dura were also examined. LATY136F mice had massive infiltration of B cells, IgG1+ cells, plasma cells, T cells, macrophages, and neutrophils in the dura, followed by marked fibrotic thickening. In dural lesions, TGF-β1 was produced in B cells and macrophages while TGF‐β receptor I (TGF-β RI) was upregulated on fibroblasts. A similar upregulation of TGF-β RI and pSMAD2/3 was present in autopsied dura of all three types of human HP. Irbesartan abolished dural inflammation and fibrotic thickening in treated LATY136F mice. TGF-β/SMAD pathway is a potential novel therapeutic target for HP.

Free Research Field

神経免疫

Academic Significance and Societal Importance of the Research Achievements

肥厚性硬膜炎の根本的原因は不明であり、これまで動物モデルの報告も無く病態機序の検討や新規治療法開発といった基礎研究は全く進められていなかった。今回、私たちはLATY136Fマウスが世界初の肥厚性硬膜炎動物モデルとなることを報告し、さらにTGF-β/SMADシグナルが硬膜炎や線維性肥厚に対する治療標的となることをはじめて証明した。肥厚性硬膜炎の基礎研究を推進し、新規バイオマーカー探索や治療法開発を見据えた本研究の学術的・社会的意義は充分に高いと考えられる。