Novel strategy for the development of therapeutics against autoimmune disease of the central nervous system, utilizing the crosstalk of cells forming blood-brain barrier.

• Project/Area Number: 17H04197
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Yamaguchi University
• Principal Investigator: KANDA Takashi 山口大学, 大学院医学系研究科, 教授 (40204797)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
• Keywords: 血液脳関門 / ペリサイト / 内皮細胞 / 低分子化合物 / アストロサイト / 脂質メディエーター / ぺリサイト / 免疫 / 薬物送達 / 脳神経疾患

Outline of Final Research Achievements

Twenty selective lipid mediator receptor agonists, screened to be permeable through blood-brain barrier (BBB), were analyzed. After adding in the culture media for BBB multi-culture model composed of human endothelial cell, pericyte and astrocyte, upregulation of BDNF in aliquot was observed in two compounds, EP4 agonist and S1P5 agonist. Since these two compounds also increase the production of BDNF in astrocyte monoculture, we concluded that they may go through endothelial cell/pericyte layer, and affect astrocyte directly to enhance the production of BDNF.

Academic Significance and Societal Importance of the Research Achievements

今回同定した2種類の脂溶性化合物は、中枢神経内での神経栄養因子の産生を促すことによって中枢神経実質の内部環境を神経再生の方向に改変する神経変性疾患治療薬のリード化合物としての可能性があるだけでなく、BBB調節のための栄養因子の分泌を人為的に制御できる可能性があり、高分子治療薬を中枢神経内に流入させる際の補助治療薬となりうると考えられた。

Research Products

• [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] 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] 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] Fingolimod promotes blood-nerve barrier properties in vitro (2018)
  • Author(s): Nishihara Hideaki、Maeda Toshihiko、Sano Yasuteru、Ueno Maho、Okamoto Nana、Takeshita Yukio、Shimizu Fumitaka、Koga Michiaki、Kanda Takashi
  • Journal Title: Brain and Behavior Volume: 8 Issue: 4
  • DOI: 10.1002/brb3.924
  • Peer Reviewed / Open Access
• [Journal Article] A perfused human blood-brain barrier on-a-chip for high throughoutput assessment of barrier function and antibody transport. (2018)
  • Author(s): Nienke R Wevers, Dhanesh G Kasi, Taylor Gray, Karlijn J Wilschut, Benjamin Smith, Remko van Vught, Fumitaka Shimizu, Yasuteru Sano, Takashi Kanda, Graham Marsh, Sebastiaan J Trietsch, Paul Vulto, Henriette L Lanz, Birgit Obermeier
  • Journal Title: Fluids Barriers CNS Volume: 15 Issue: 1 Pages: 23-23
  • DOI: 10.1186/s12987-018-0108-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glucose-regulated protein 78 autoantibody associates with blood-brain barrier disruption in neuromyelitis optica. (2017)
  • Author(s): Fumitaka Shimizu, Kritin L. Schaller, Gregory P. Owens, Anne C. Cotleur, Debra Kellner, Yukio Takeshita, Birgit Obermeier, Thomas J. Kryzer, Yasuteru Sano, Takashi Kanda, Vanda A. Lennon, Richard M. Ransohoff, Jeffrey L. Bennett
  • Journal Title: SciTransl Med Volume: 9 Issue: 397 Pages: 49-53
  • DOI: 10.1126/scitranslmed.aai9111
  • Peer Reviewed / Int'l Joint Research
• [Presentation] シンポジウム：「神経免疫疾患の病態解明への多面的アプローチ」血液脳関門からのアプローチ (2019)
  • Author(s): 神田 隆
  • Organizer: 第60回日本神経学会学術集会
  • Invited
• [Presentation] 血液脳関門の人為的操作：中枢神経疾患の新しい治療へ (2019)
  • Author(s): 神田 隆
  • Organizer: 第60回日本神経学会学術集会
  • Invited
• [Presentation] 神経免疫疾患治療の進歩．シンポジウム１ 「自己免疫疾患治療の進歩 平成から令和へ」 (2019)
  • Author(s): 神田 隆
  • Organizer: 第47回日本臨床免疫学会総会
  • Invited
• [Presentation] 教育講演：神経系を侵す自己免疫疾患 (2019)
  • Author(s): 神田 隆
  • Organizer: 第47回日本臨床免疫学会総会
  • Invited
• [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 2019
• [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] The effect of Neuromyelitis Optica (NMO)-IgG and anti-IL-6 receptor monoclonal antibody (SA237;satralizumab) for barrier function at the Blood-Brain Barrier in vitro (2019)
  • Author(s): Yukio Takeshita, Kenichi Serizawa, Susumu Fujikawa, Fumitaka Shimizu, Toshihiko Maeda, Yasuteru Sano, Michiaki Koga, Takashi Kanda
  • Organizer: 第60回日本神経学会学術集会
• [Presentation] The effect of Neuromyelitis Optica (NMO)-IgG and anti-IL-6 receptor monoclonal antibody (SA237;satralizumab) for barrier function at the Blood-Brain Barrier in vitro (2019)
  • Author(s): Yukio Takeshita, Kenichi Serizawa, Susumu Fujikawa, Fumitaka Shimizu, Toshihiko Maeda, Yasuteru Sano, Michiaki Koga, Takashi Kanda
  • Organizer: ECTRIMS 2019
  • Int'l Joint Research
• [Presentation] Identification of targeted membrane antigens of human brain microvascular endothelial cells in relapsing-remitting multiple sclerosis． (2019)
  • Author(s): Yukio Takeshita, Susumu Fujikawa, Tomohiro Makino, Masato Hoshino, Takeshi Hanada, Makoto Masumura, Hideaki Nishihara, Toshihiko Maeda, Fumitaka Shimizu, Yasuteru Sano, Michiaki Koga, Takashi Kanda
  • Organizer: XXIV World Congress of Neurology
  • Int'l Joint Research
• [Presentation] BBB構成細胞による継時的バリア評価モデルの開発とIL-6受容体阻害が視神経脊髄炎のBBB破綻に与える効果検証 (2019)
  • Author(s): 竹下幸男, 芹澤賢一, 藤川 晋, 清水文崇, 藤澤美和子, 古賀道明, 神田 隆
  • Organizer: 第31回日本神経免疫学会学術集会
• [Presentation] The barrier effect of the components of the blood-brain barrier and the blood-nerve barrier in vitro. (2018)
  • Author(s): Takeshita Y, Fujikawa S, Shimizu F, Maeda T, Sano Y, Koga M, Kanda T.
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] Construction of the new multi-cultured in vitro blood-brain barrier model under shear forces. (2018)
  • Author(s): Fujikawa S, Takeshita Y, Maeda T, Shimizu F, Sano Y, Kanda T.
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] 再発寛解型多発性硬化症における微小脳血管膜蛋白に対する標的抗原分子の同定法の確立 (2018)
  • Author(s): 竹下幸男，藤川 晋，牧野智宏，星野将人，花田雄志，升村 誠，西原秀昭，前田敏彦，清水文崇，佐野泰照，古賀道明，神田 隆
  • Organizer: 第30回神経免疫学会学術集会
• [Presentation] The new in vitro blood-brain barrier (BBB) model under shear forces with multi-culture of BBB components in multiple sclerosis. (2018)
  • Author(s): Takeshita Y, Fujikawa S, Maeda T, Shimizu F, Sano Y, Kanda T.
  • Organizer: 34th Congress of ECTRIMS 2018
  • Int'l Joint Research
• [Presentation] Destruction and repair of blood-brain barrier in neuroimmunological disoders (2018)
  • Author(s): Kanda T
  • Organizer: 第41回日本神経科学会
  • Invited
• [Presentation] 神経系のバリアー機能とその分子構造 (2018)
  • Author(s): 神田 隆
  • Organizer: 第３０回日本神経免疫学会学術集会
  • Invited
• [Presentation] 血液脳関門・血液末梢神経関門モデルからの創薬 (2018)
  • Author(s): 神田 隆
  • Organizer: 第59回日本神経学会学術大会
  • Invited
• [Presentation] The effect of blood-brain barrier (BBB)-specific laminins for barrier function with a new in vitro BBB model incorporating multi-culturing system of BBB components. (2017)
  • Author(s): Takeshita Y, Fujikawa S, Shimizu F, Sano Y, Maeda T, Kanda T
  • Organizer: 23rd World Congress of Neurology
  • Int'l Joint Research