Discovery of new drug target modifiying the function of blood-brain barrier and blood-nerve barrier

• Project/Area Number: 18K07526
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Yamaguchi University
• Principal Investigator: Shimizu Fumitaka 山口大学, 医学部附属病院, 助教 (90535254)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 自己免疫性神経疾患 / 血液脳関門 / GRP78抗体 / 視神経脊髄炎 / 傍腫瘍性小脳変性症 / 血液神経関門 / 新規抗体製剤開発 / 細胞モデル / 神経免疫疾患 / 自己免疫性ニューロパチー

Outline of Final Research Achievements

Objective: The purpose of this project is to develop the assay for identifying the antigen against IgG from the patients with neuro-inflammatory disorders, which cause the BBB disruption using our human in vitro BBB model. Methods: We identified IgG from patients with the neuro-inflammatory disease, which induced NF-κB p65 nuclear translocation in human brain microendothelial cell lines (TY10). We developed the novel assay to detect cell-surface antigen against IgG from the neuro-inflammatory disease. Results: IgGs from paraneoplastic cerebellar degeneration (PCD) with Lambert-Eaton myasthenic syndrome (LEMS) [LEMS-PCD] shows the most ability to give rise to nuclear translocation of NF-κB p65. We detected glucose-regulated protein (GRP)78 autoantibodies in the IgG of LEMS-PCD. Conclusions: We identified GRP78 autoantibodies from LEMS-PCD patients having biological effects on BBB-endothelial cells.

Academic Significance and Societal Importance of the Research Achievements

傍腫瘍性小脳変性症を合併したランバート・イートン筋無力症の発症機序が明らかとなった．GRP78は癌細胞とBBB構成内皮細胞の細胞表面に多く発現しており，細胞表面に発現するGRP78はNF-κBシグナル活性に関与する．さらに，担癌患者では血中にGRP78抗体が検出されることが報告されている．傍腫瘍性小脳変性症を合併したランバート・イートン筋無力症発症の病態機序として，GRP78とP/Q型VGCCは癌細胞表面に発現しており，腫瘍との交差免疫により産生されたGRP78抗体によるBBB破綻が，同じ機序より産生されたP/Q型VGCC抗体の脳内流入を促進し小脳機能障害を惹起する可能性が考えられた．

Research Products

• [Journal Article] 総説 ペリサイトと神経系-生理的役割と病理的意義 (2020)
  • Author(s): 清水 文崇、神田 隆
  • Journal Title: BRAIN and NERVE Volume: 72 Issue: 2 Pages: 151-158
  • DOI: 10.11477/mf.1416201495
  • ISSN: 1344-8129, 1881-6096
  • Year and Date: 2020-02-01
• [Journal Article] Advancing human induced pluripotent stem cell‐derived blood‐brain barrier models for studying immune cell interactions (2020)
  • Author(s): Nishihara Hideaki、Gastfriend Benjamin D.、Soldati Sasha、Perriot Sylvain、Mathias Amandine、Sano Yasuteru、Shimizu Fumitaka、Gosselet Fabien、Kanda Takashi、Palecek Sean P.、Du Pasquier Renaud、Shusta Eric V.、Engelhardt Britta
  • Journal Title: The FASEB Journal Volume: 34 Issue: 12 Pages: 16693-16715
  • DOI: 10.1096/fj.202001507rr
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serotonin/5-HT1A Signaling in the Neurovascular Unit Regulates Endothelial CLDN5 Expression (2020)
  • Author(s): Sugimoto Kotaro、Ichikawa-Tomikawa Naoki、Nishiura Keisuke、Kunii Yasuto、Sano Yasuteru、Shimizu Fumitaka、Kakita Akiyoshi、Kanda Takashi、Imura Tetsuya、Chiba Hideki
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 1 Pages: 254-254
  • DOI: 10.3390/ijms22010254
  • Peer Reviewed / Open Access
• [Journal Article] Contribution of brain pericytes in blood-brain barrier formation and maintenance: a transcriptomic study of cocultured human endothelial cells derived from hematopoietic stem cells (2020)
  • Author(s): Heymans Marjolein、Figueiredo Ricardo、Dehouck Lucie、Francisco David、Sano Yasuteru、Shimizu Fumitaka、Kanda Takashi、Bruggmann Rumy、Engelhardt Britta、Winter Peter、Gosselet Fabien、Culot Maxime
  • Journal Title: Fluids and Barriers of the CNS Volume: 17 Issue: 1 Pages: 37-37
  • DOI: 10.1186/s12987-020-00208-1
  • Peer Reviewed
• [Journal Article] Design and Validation of a Human Brain Endothelial Microvessel-on-a-Chip Open Microfluidic Model Enabling Advanced Optical Imaging (2020)
  • Author(s): Salman Mootaz M.、Marsh Graham、Kusters Ilja、Delinc Matthieu、Di Caprio Giuseppe、Upadhyayula Srigokul、de Nola Giovanni、Hunt Ronan、Ohashi Kazuka G.、Gray Taylor、Shimizu Fumitaka、Sano Yasuteru、Kanda Takashi、Obermeier Birgit、Kirchhausen Tom
  • Journal Title: Frontiers in Bioengineering and Biotechnology Volume: 8 Pages: 573755-573755
  • DOI: 10.3389/fbioe.2020.573775
  • Peer Reviewed
• [Journal Article] Development of a human in vitro blood-brain tumor barrier model of diffuse intrinsic pontine glioma to better understand the chemoresistance (2020)
  • Author(s): Deligne Clmence、Hachani Johan、Duban-Deweer Sophie、Meignan Samuel、Leblond Pierre、Carcaboso Angel M.、Sano Yasuteru、Shimizu Fumitaka、Kanda Takashi、Gosselet Fabien、Dehouck Marie-Pierre、Mysiorek Caroline
  • Journal Title: Fluids and Barriers of the CNS Volume: 17 Issue: 1 Pages: 37-37
  • DOI: 10.1186/s12987-020-00198-0
  • Peer Reviewed
• [Journal Article] GRP78 antibodies are associated with blood-brain barrier breakdown in paraneoplastic cerebellar degeneration in Lambert-Eaton myasthenic syndrome. (2020)
  • Author(s): Shimizu F, Kanda T.
  • Journal Title: Clin. Exp. Neuroimmunol Volume: 11 Issue: 2 Pages: 88-89
  • DOI: 10.1111/cen3.12575
  • Peer Reviewed
• [Journal Article] Lambert-Eaton筋無力症とGRP78自己抗体 (2020)
  • Author(s): 清水 文崇, 神田 隆
  • Journal Title: 医学のあゆみ Volume: 274 Pages: 1299-1300
• [Journal Article] 【免疫性神経疾患update-基礎・臨床研究の最新知見-】自己免疫性神経疾患でのGRP78抗体 (2020)
  • Author(s): 清水 文崇, 神田 隆
  • Journal Title: 日本臨床 Volume: 78 Pages: 1951-1956
• [Journal Article] GRP78 antibodies damage the blood-brain barrier and relate to cerebellar degeneration in Lambert-Eaton myasthenic syndrome. (2019)
  • Author(s): Shimizu F, Takeshita Y, Sano Y, Hamamoto Y, Shiraishi H, Sato T, Yoshimura S, Maeda T, Fujikawa S, Nishihara H, Kitanosono H, Tsujino A, Motomura M, Kanda T.
  • Journal Title: Brain. Volume: 142 Issue: 8 Pages: 2253-2264
  • DOI: 10.1093/brain/awz168
  • Peer Reviewed / Open Access
• [Journal Article] GRP 78 antibodies are associated with clinical phenotype in neuromyelitis optica (2019)
  • Author(s): Shimizu Fumitaka、Takeshita Yukio、Hamamoto Yuka、Nishihara Hideaki、Sano Yasuteru、Honda Masaya、Sato Ryota、Maeda Toshihiko、Takahashi Toshiyuki、Fujikawa Susumu、Kanda Takashi
  • Journal Title: Annals of Clinical and Translational Neurology Volume: 6 Issue: 10 Pages: 2079-2087
  • DOI: 10.1002/acn3.50905
  • Peer Reviewed / Open Access
• [Journal Article] Increased IP-10 production by blood-nerve barrier in multifocal acquired demyelinating sensory and motor neuropathy and multifocal motor neuropathy. (2019)
  • Author(s): Shimizu F, Oishi M, Sawai S, Beppu M, Misawa S, Matsui N, Miyashiro A, Maeda T, Takeshita Y, Nishihara H, Sano Y, Sato R, Kaji R, Kuwabara S, Kanda T.
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 90 Issue: 4 Pages: 444-450
  • DOI: 10.1136/jnnp-2018-319270
  • NAID: 120006713015
  • Peer Reviewed
• [Journal Article] Blood-brain barrier dysfunction in immuno-mediated neurological diseases. (2018)
  • Author(s): Shimizu F, Nishihara H, Kanda T.
  • Journal Title: Immunol Med Volume: 41 Issue: 3 Pages: 120-128
  • DOI: 10.1080/25785826.2018.1531190
• [Presentation] 中国四国地域発で世界的に展開した学術業績 GRP78抗体とNMO この研究の発展から見えてきたこと (2020)
  • Author(s): 清水文崇
  • Organizer: 第61回日本神経学会学術大会．
  • Invited
• [Presentation] Blood-brain barrier-activation in myelin oligodendrocyte glycoprotein antibody associated disorders (2020)
  • Author(s): Shimizu F, Ogawa R, Takahashi T, Takeshita Y, Misu T, Sano Y, Maeda T, Nakashima I, Fujihara K, Kanda T
  • Organizer: 第61回日本神経学会学術大会．
• [Presentation] 当院で診療したCIDP30例の臨床病型と長期経過 (2020)
  • Author(s): 清水 文崇, 前田 敏彦, 佐藤 亮太, 大石 真莉子, 竹下 幸男, 松尾 欣也, 佐野 泰照, 古賀 道明, 神田 隆
  • Organizer: 第31回日本末梢神経学会学術集会
• [Presentation] MOG抗体関連疾患での血液脳関門破綻メカニズムの解明 (2020)
  • Author(s): 清水 文崇, 小川 諒, 原 佳那子, 門野 ちひろ, 高橋 利幸, 竹下 幸男, 三須 建郎, 佐野 泰照, 前田 敏彦, 中島 一郎, 藤原 一男, 神田 隆
  • Organizer: 第32回日本神経免疫学会学術集会
• [Presentation] 自己免疫性神経疾患から血液脳関門/血液神経関門を人為的に操作する新規標的分子の同定とその臨床応用 (2019)
  • Author(s): 清水文崇
  • Organizer: 第60回 日本神経学会学術大会
  • Invited
• [Presentation] 血液神経関門に注目したギラン・バレー症候群患者の新規バイオマーカーの探索． (2019)
  • Author(s): 清水文崇，古賀道明，藤井菜月美，竹下幸男，佐野泰照，前田敏彦，佐藤亮太，神田 隆.
  • Organizer: 第30回日本末梢神経学会学術集会
• [Presentation] 小脳性運動失調を合併したLambert-Eaton筋無力症候群患者から血液脳関門破綻に関与するGRP78抗体の同定． (2019)
  • Author(s): 清水文崇，竹下幸男，佐野泰照，前田敏彦，藤川 晋，吉村俊祐，北之園寛子，白石 裕一，辻野 彰, 本村政勝，神田 隆．
  • Organizer: 第31回神経免疫学会学術集会
• [Presentation] Blood-brain barrier-activation in anti-myelin oligodendrocyte glycoprotein antibody associated disorders. (2019)
  • Author(s): Fumitaka Shimizu, Ryo Ogawa, Kanako Hara, Toshiyuki Takahashi, Yukio Takeshita, Tatsuro Misu, Yasuteru Sano, Toshihiko Maeda, Susumu Fujikawa, Ichiro Nakashima, Kazuo Fujihara, Takashi Kanda.
  • Organizer: EctriMS 2019
  • Int'l Joint Research
• [Presentation] Blood-brain barrier-activation in anti-myelin oligodendrocyte glycoprotein antibody associated disorders. (2019)
  • Author(s): Fumitaka Shimizu, Ryo Ogawa, Kanako Hara, Toshiyuki Takahashi, Yukio Takeshita, Tatsuro Misu, Yasuteru Sano, Toshihiko Maeda, Susumu Fujikawa, Ichiro Nakashima, Kazuo Fujihara, Takashi Kanda.
  • Organizer: Sendai Conference
• [Presentation] Blood-brain barrier-activation induced by immunoglobulin G in neuromyelitis optica spectrum disorder. (2018)
  • Author(s): Fumitaka Shimizu , Yuka Hamamoto, Yukio Takeshita, Yasuteru Sano, Toshihiko Maeda, Susumu Fujikawa, Masaya Honda and Takashi Kanda
  • Organizer: 日本神経学会学術集会
• [Presentation] 血液脳関門と血液神経関門を破綻させる自己免疫性神経疾患患者免疫グロブリンGの同定 (2018)
  • Author(s): 清水文崇，竹下幸男，古賀道明，佐野泰照，藤井菜月美，浜本優佳，前田敏彦，藤川 晋，神田 隆．
  • Organizer: 第30回神経免疫学会学術集会
• [Presentation] ギラン・バレー症候群患者由来の免疫グロブリンＧは血液神経関門を破綻させる． (2018)
  • Author(s): 清水文崇，古賀道明，藤井菜月美，竹下幸男，佐野泰照，前田敏彦，神田 隆.
  • Organizer: 第29回日本末梢神経学会学術集会
• [Presentation] Identification of antibody-target from patients with central nervous system autoimmune diseases to modify the drug penetration in the blood-brain barrier. (2018)
  • Author(s): Fumitaka Shimizu, Yukio Takeshita, Yuka Hamamoto, Yasuteru Sano and Takashi Kanda.
  • Organizer: lood-Brain Barrier - World Preclinical Congress
  • Int'l Joint Research
• [Presentation] Blood-brain barrier-activation induced by immunoglobulin G in multiple sclerosis. (2018)
  • Author(s): Fumitaka Shimizu, Kanako Hara, Yukio Takeshita, Yasuteru Sano, Toshihiko Maeda, Susumu Fujikawa, Masaya Honda, Ryota Sato and Takashi Kanda.
  • Organizer: EctriMS
  • Int'l Joint Research