A research of immune mechanism and treatment in neuromyelitis optica

• Project/Area Number: 15K09332
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Tohoku University
• Principal Investigator: MISU TATSURO 東北大学, 医学系研究科, 講師 (00396491)
• Co-Investigator(Renkei-kenkyūsha): Aoki Masashi 東北大学, 大学院医学系研究科, 教授 (70302148)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: アクアポリン4 / アストロサイト / 視神経脊髄炎 / 多発性硬化症 / 脱髄性疾患 / アストロサイトパチー / アクアポリン４ / 脱髄 / アクアポリン４抗体

Outline of Final Research Achievements

We made a new high-affinity antibody against the extradomain of aquaporin-4(AQP4）and studied about its pathogenic roles in experimental rat models. We revealed that high-affinity IgG could make a diffuse astrocytophaty with extensively diffuse lesion lacking AQP4 compared with human IgG, suggesting the important role of antibody-related affinity in the pathogenesis of neuromyelitis optica (NMO). In addition, a rat model injected with AQP4-specific T cell lines and human-derived AQP4-IgG, we could make a new rat model with typical perivascular loss of AQP4 in cerebrum, periventriculum, spinal cord, retina, and optic chiasm　with secondary demyelination and diffuse axonal damage, which is close to the pathological findings of tiffuse injury in NMO patients in post-mortem.

Research Products

• [Journal Article] Bilateral frontal cortex encephalitis and paraparesis in a patient with anti-MOG antibodies (2017)
  • Author(s): Fujimori J, Takai Y, Nakashima I, Sato DK, Takahashi T, Kaneko K, Nishiyama S, Watanabe M, Tanji H, Kobayashi M, Misu T, Aoki M, Fujihara K
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 印刷中 Issue: 6 Pages: 534-536
  • DOI: 10.1136/jnnp-2016-315094
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Impact of the Great East Japan Earthquake in 2011 on MS and NMOSD: a study in Sendai, Japan (2017)
  • Author(s): Kanamori Y, Nakashima I, Takai Y, Misu T, Kuroda H, Nishiyama S, Takahashi T, Sato S, Fujimori J, Higuchi J, Itoyama Y, Aoki M, Fujihara K
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 88 Issue: 4 Pages: 362-364
  • DOI: 10.1136/jnnp-2016-313890
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] MOG-antibody-positive, benign, unilateral, cerebral cortical encephalitis with epilepsy (2017)
  • Author(s): Ogawa R, Nakashima I, Takahashi T, Kaneko K, Akaishi T, Takai Y, Sato DK, Nishiyama S, Misu T, Kuroda H, Aoki M, Fujihara K
  • Journal Title: Neurol Neuroimmunol Neuroinflamm Volume: 16 Issue: 2
  • DOI: 10.1212/nxi.0000000000000322
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fingolimod-associated PML with mild IRIS in MS (2017)
  • Author(s): Nishiyama Shuhei、Misu Tatsuro、Shishido-Hara Yukiko、Nakamichi Kazuo、Saijo Masayuki、Takai Yoshiki、Takei Kentarou、Yamamoto Naoki、Kuroda Hiroshi、Saito Ryuta、Watanabe Mika、Tominaga Teiji、Nakashima Ichiro、Fujihara Kazuo、Aoki Masashi
  • Journal Title: Neurology - Neuroimmunology Neuroinflammation Volume: 5 Issue: 1
  • DOI: 10.1212/nxi.0000000000000415
  • Peer Reviewed / Open Access
• [Journal Article] Aquaporin 4-specific T cells and NMO-IgG cause primary retinal damage in experimental NMO/SD (2016)
  • Author(s): Zeka B, Hastermann M, Kaufmann N, Schanda K, Pende M, Misu T, Rommer P, Fujihara K, Nakashima I, Dahle C, Leutmezer F, Reindl M, Lassmann H, Bradl M
  • Journal Title: Acta Neuropathol Commun Volume: 4 Issue: 1 Pages: 82-82
  • DOI: 10.1186/s40478-016-0355-y
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Lesion length of optic neuritis impacts visual prognosi in neuromyelitis optica (2016)
  • Author(s): Akaishi T, Ichiro Nakashima, Takeshita T, Mugikura S, Sato DK, Takahashi T, Nishiyama S, Kurosawa K, Misu T, Nakazawa T, Aoki M, Fujihara K
  • Journal Title: J Neuroimmunol Volume: 293 Pages: 28-33
  • DOI: 10.1016/j.jneuroim.2016.02.004
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hypoxia-like tissue injury and glial response contribute to Balo concentric lesion development. (2016)
  • Author(s): Takai Y, Misu T, Nishiyama S, Ono H, Kuroda H, Nakashima I, Saito R, Kanamori M, Sonoda Y, Kumabe T, Mugikura S, Watanabe M, Aoki M, Fujihara K.
  • Journal Title: Neurology Volume: 87 Pages: 2000-2005
  • Peer Reviewed / Open Access
• [Journal Article] High avidity chimeric monoclonal antibodies against the extracellular domains of human aquaporin-4 competing with the neuromyelitis optica autoantibody, NMO-IgG. (2015)
  • Author(s): Miyazaki-Komine K, Takai Y, Huang P, Kusano-Arai O, Iwanari H, Misu T, Koda K, Mitomo K, Sakihama T, Toyama Y, Fujihara K, Hamakubo T, Yasui M, Abe Y.
  • Journal Title: Br J Pharmacol Volume: 173 Issue: 1 Pages: 103-103
  • DOI: 10.1111/bph.13340
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS. (2015)
  • Author(s): Zeka B, Hastermann M, Hochmeister S, Kögl N, Kaufmann N, Schanda K, Mader S, Misu T, Rommer P, Fujihara K, Illes Z, Leutmezer F, Sato DK, Nakashima I, Reindl M, Lassmann H, Bradl M.
  • Journal Title: Acta Neuropathol Volume: 130 Issue: 6 Pages: 783-783
  • DOI: 10.1007/s00401-015-1501-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Severely exacerbated neuromyelitis optica rat model with extensive astrocytopathy by high affinity anti-aquaporin-4 monoclonal antibody. (2015)
  • Author(s): Kurosawa K, Misu T, Takai Y, Sato DK, Takahashi T, Abe Y, Iwanari H, Ogawa R, Nakashima I, Fujihara K, Hamakubo T, Yasui M, Aoki M.
  • Journal Title: Acta Neuropathol Commun Volume: 4 Issue: 1 Pages: 783-783
  • DOI: 10.1186/s40478-015-0259-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 抗MOG抗体関連疾患の病理学的特徴 (2018)
  • Author(s): 三須 建郎
  • Organizer: 第37回日本画像学会
  • Invited
• [Presentation] 抗MOG抗体関連疾患の病理学的特徴 (2018)
  • Author(s): 三須建郎
  • Organizer: 難治性疾患実用化研究事業「多発性硬化症に対する新規免疫修飾薬の実用」（OCH班会議）
• [Presentation] Scientific program M02C: MS and other inflammatory disease-emerging therapeutics strategy of MS subtypes and NMOSD. New insight into the pathogenesis of anti-MOG and other disseminated demyelinating diseases. (2017)
  • Author(s): Tatsuro Misu
  • Organizer: World Congress of Neurology
  • Int'l Joint Research / Invited
• [Presentation] Cerebrospilnal fluid-Actin related protein 2/3 complex subunit 4 as an astrocytic foot process damage marker of aquaporin-4-IgG positive neuromyelitis optica spectrum disorders. (2017)
  • Author(s): Ryo Ogawa, Hirohiko Ono, Kazuhiro Kurosawa, Yoshiki Takai, Toshiyuki Takahashi, Hiroshi Kuroda, Kazuo Fujihara, Masashi Aoki
  • Organizer: World Congress of Neurology
  • Int'l Joint Research
• [Presentation] The Staging of astrocytopathy in aquaporin 4‐Igg‐positive neuromyelitis optica spectrum disorders. (2017)
  • Author(s): Takai Y, Misu T, Nishiyama S, Kuroda H, Ogawa R, Kaneko K, Takahashi T, Nakashima I, Suzuki H, Fujihara K, Aoki M
  • Organizer: XXIII World Congress of Neurology, Kyoto
  • Int'l Joint Research
• [Presentation] Efficacy of interferon-β for myelin oligodendrocyte glycoprotein antibody-positive demyelinating disorder (2017)
  • Author(s): Kaneko K, Sato DK, Ogawa R, Akaishi T, Takai Y, Nishiyama S, Takahashi T, Misu T, Kuroda H, Nakshima I, Fujihara K, Aoki M
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Cerebrospilnal fluid-Actin related protein 2/3 complex subunit 4 as an astrocytic foot process damage marker of aquaporin-4-IgG positive neuromyelitis optica spectrum disorders. (2017)
  • Author(s): Nishiyama S, Misu T, Nakashima I, Sato DS, Kaneko K, Ogawa R, Ono H, Kurosawa K, Takai Y, Takahashi T, Kuroda H, Fujihara K, Aoki M
  • Organizer: 33rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis
  • Int'l Joint Research
• [Presentation] 初期の病理像を呈したFingolimod関連進行性多巣性白質脳症の１例 (2017)
  • Author(s): 西山修平、三須建郎、宍戸-原由紀子、中道一生、武井健太郎、山本尚輝、中島一郎、藤原一男、青木正志
  • Organizer: 第58回日本神経病理学会
• [Presentation] 視神経脊髄炎の一剖検例 (2017)
  • Author(s): 岡直美、突田健一、田野大人、鈴木靖士、三須建郎、高井良樹、渡辺源也、栗原紀子、櫻田潤子、鈴木博義
  • Organizer: 第58回日本神経病理学会
• [Presentation] 抗 MOG 抗体陽性脱髄疾患における IFNβの有効性 (2017)
  • Author(s): 金子仁彦，佐藤ダグラス，小川諒，赤石哲也，高井良樹，西山修平，高橋利幸，三須建郎，黒田宙，中島一郎，藤原一男，青木正志
  • Organizer: 第59回日本小児神経学会総会
• [Presentation] 視神経脊髄炎関連疾患病変におけるアストロサイトパチーによる病期分類 (2017)
  • Author(s): 高井良樹, 三須建郎, 鈴木博義, 高橋利幸, 西山修平, 黒田宙, 中島一郎, 藤原一男, 青木正志
  • Organizer: 第29回日本神経免疫学会学術集会
• [Presentation] 抗MOG抗体陽性自己免疫性脳炎の検討 (2017)
  • Author(s): 小川 諒, 中島一郎, 高橋利幸, 金子仁彦, 高井良樹, 藤盛寿一, 三須建郎, 黒田 宙,藤原一男, 青木正志
  • Organizer: 第29回日本神経免疫学会学術集会
• [Presentation] Hypoxia-like tissue injury and glial response contribute to the development of Balo's concentric demyelination (2016)
  • Author(s): Takai Y, Misu T, Nishiyama S, Ono H, Kuroda H, Nakashima I, Saito R, Kanamori M, Mugikura S, Watanabe M, Aoki M, Fujihara K.
  • Organizer: Pan-Asian Comittee of Treatment and Research in Multiple Sclerosis
  • Place of Presentation: バンコク(タイ）
  • Year and Date: 2016-10-27
  • Int'l Joint Research
• [Presentation] Balo病における同心円状脱髄病巣形成に対する虚血性組織障害とグリア細胞の関与 (2016)
  • Author(s): 高井良樹、三須建郎、西山修平、黒田宙、中島一郎、渡辺みか、斎藤竜太、金森正之、藤原一男、青木正志．
  • Organizer: 日本神経免疫学会
  • Place of Presentation: 長崎（長崎ブリックホール）
  • Year and Date: 2016-09-29
• [Presentation] 抗MOG抗体陽性ADEMの一生検例 (2016)
  • Author(s): 高井良樹、三須建郎、金子仁彦、黒田宙、成川孝一、及川崇紀、石川修一、板倉裕子、小川諒、西山修平、高橋利幸、中島一郎、藤原一男、青木正志
  • Organizer: 日本神経病理学会
  • Place of Presentation: 弘前（弘前ニューキャッスル）
  • Year and Date: 2016-06-01
• [Presentation] Severely exacerbated neuromyelitis optica rat model with extensive astrocytopathy in the acute phase. (2016)
  • Author(s): Kurosawa K, Misu T, Abe Y, Takai Y, Takahashi T, Sato D, Nakashima I, Fujihara K, Yasui M, Aoki M.
  • Organizer: 日本神経学会
  • Place of Presentation: 神戸（神戸コンベンションセンター）
  • Year and Date: 2016-05-18
• [Presentation] Chronological change is the main cause of histopathological diversity in neuromyelitis optica with anti-AQP4 antibody. (2016)
  • Author(s): Takai Y, Misu T, Nakashima I, Kuroda H, Takahashi T, Nishiyama S, Kaneko K, Akaishi T, Ogawa R, Fujihara K, Aoki M.
  • Organizer: 日本神経学会
  • Place of Presentation: 神戸（神戸コンベンションセンター）
  • Year and Date: 2016-05-18
• [Presentation] 抗AQP4モノクローナル抗体を用量段階的に投与したpassive IgG transfer NMO rat modelの病理組織学的検討 (2015)
  • Author(s): 黒澤和広、三須 建郎, 阿部 陽一郎, 高井 良樹, 高橋 利幸, 佐藤 ダグラス, 中島 一郎, 藤原 一男, 安井 正人, 青木 正志
  • Organizer: 日本神経免疫学会
  • Place of Presentation: 岐阜（長良川国際会議場）
  • Year and Date: 2015-09-15
• [Presentation] MS基礎 NMOモデルマウスにおけるアストロサイト障害に伴う二次性脱髄機序の解明 (2015)
  • Author(s): 高井 良樹, 三須 建郎, 黒沢 和大, 高橋 利幸, 中島 一郎, 黒田 宙, 西山 修平, 藤原 一男, 青木 正志
  • Organizer: 日本神経免疫学会
  • Place of Presentation: 岐阜（長良川国際会議場）
  • Year and Date: 2015-09-15
• [Presentation] Passive transferred NMO rat model with high affinity mouse anti-AQP4+ antibody (2015)
  • Author(s): 黒澤和広、三須建郎、阿部陽一郎、高井良樹、高橋利幸、佐藤ダグラス、中島一郎、藤原一男、安井正人、青木正志
  • Organizer: 日本神経学会
  • Place of Presentation: 新潟(朱鷺メッセ）
  • Year and Date: 2015-05-20
• [Book] 【免疫性神経疾患-基礎・臨床研究の最新知見-】 免疫性中枢神経疾患 視神経脊髄炎(NMO) 視神経脊髄炎の検査・診断・鑑別診断 視神経脊髄炎の画像所見・髄液所見 (2015)
  • Author(s): 三須建郎
  • Total Pages: 6
  • Publisher: 日本臨床