Treatment of animal model of ALS with anti GM-CSF antibody

• Project/Area Number: 23591244
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Osaka University
• Principal Investigator: OKUNO Tatsusada 大阪大学, 医学(系)研究科(研究院), 助教 (00464248)
• Co-Investigator(Kenkyū-buntansha): 中辻 裕司 大阪大学, 医学系研究科, 講師 (20332744)
• Co-Investigator(Renkei-kenkyūsha): 多田 智 大阪大学, 医学系研究科 (70626530)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ＡＬＳ / GM-CSF / M1/M2 / ミクログリア / 炎症 / ＪＡＫ２阻害剤 / Ｍ１/Ｍ２ / Ｍ１／Ｍ２ / ALS / セマフォリン

Research Abstract

To inhibit GM-CSF-mediated M1 activation in ALS model mice (G93A mSOD1 mice), we used JAK2 inhibitor(R723). Orally adminstered JAK2 inhibitor significantly reduced the number of inflammatory monocytes, as well as the expression level of IFN-gamma and iNOS in the spinal cord tissue of ALS model mice. However, disease progression and survival of mSOD1G93A were not altered by administration of R723.The expression levels of Il-1, Il-6, tumor necrosis factor (TNF), and NADPH oxidase 2 (NOX2) were not altered by R723 treatment.Furthermore, R723 suppressed the expression of Retnla, a marker of neuroprotective M2 microglia.In conclusion,oral administration of JAK2 inhibitor was not effective against ALS symptoms in mSOD1G93A mice, although it suppressed production of several inflammatory molecules. Coincidental suppression of M2 microglia and failure to inhibit critical inflammatory molecules might have contributed to this result.

Research Products

• [Journal Article] Sema4A inhibits the therapeutic effect of IFN-βin EAE (2014)
  • Author(s): Koda T, Okuno T, Takata K, Honorat JA, Kinoshita M, Tada S, Moriya M, Sakoda S, Mochizuki H, Kumanogoh A, Nakatsuji Y
  • Journal Title: J Neur oimmunol Volume: 5728(14) Pages: 2-2
• [Journal Article] Early pathological alterations of lower lumber cords detected by ultrahigh-field MRI in a mouse multiple sclerosis model (2014)
  • Author(s): Mori Y, Murakami M, Arima Y, Zhu D, Terayama Y, Komai Y, Nakatsuji Y, Kamimura D, Yoshioka Y
  • Journal Title: Int Immunol Volume: 26(2) Pages: 93-101
• [Journal Article] Sema4A inhibits the therapeutic effect of IFN-β in EAE. (2014)
  • Author(s): Koda T, Okuno T, Takata K, Honorat JA, Kinoshita M, Tada S, Moriya M, Sakoda S, Mochizuki H, Kumanogoh A, Nakatsuji Y
  • Journal Title: J Neuroimmunol. Volume: 268(1-2) Issue: 1-2 Pages: 43-9
  • DOI: 10.1016/j.jneuroim.2013.12.014
  • Peer Reviewed
• [Journal Article] Roles of Sema4A in Multiple Sclerosis and IFN-βTherapy Efficacy (2013)
  • Author(s): Nakatsuji Y, Okuno T, Koda T, Takata K, Honorat JA, Mochizuki H, Kumanogoh A
  • Journal Title: Clinical Experimental Neur oimmunology Volume: 4 Pages: 274-282
• [Journal Article] A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration (2013)
  • Author(s): Nojima, S., Toyofuku, T., Kamao, H., Ishigami, C., Kaneko, J., Okuno, T., Takamatsu, H., Ito, D., Kang, S., Kimura, T., Yoshida, Y., Morimoto, K., Maeda, Y., Ogata, A., Ikawa, M., Morii, E., Aozasa, K., Takagi, J., Takahashi, M. & Kumanogoh, A
  • Journal Title: Nature communications Volume: 4 Pages: 1406-1406
• [Journal Article] Disease-association analysis of an inflammation-related feedback loop (2013)
  • Author(s): Murakami M, Harada M, Kamimura D, Ogura H, Okuyama Y, Kumai N, Okuyama A, Singh R, Jiang JJ, Atsumi T, Shiraya S, Nakatsuji Y, Kinoshita M, Kohsaka H, Nishida M, Sakoda S, Miyasaka N, Yamauchi-Takihara K, Hirano T
  • Journal Title: Cell Rep Volume: 3(3) Pages: 946-59
• [Journal Article] Xanthine oxidase mediates axonal and myelin loss in a murine model of multiple sclerosis (2013)
  • Author(s): Honorat JA, Kinoshita M, Okuno T, Takata K, Koda T, Mochizuki H, Nakatsuji Y
  • Journal Title: PLoS One Volume: 8(8)
• [Journal Article] BAFF controls neural cell survival through BAFF receptor (2013)
  • Author(s): Tada S, Yasui T, Nakatsuji Y Okuno T, Koda T, Mochizuki H, Sakoda S, Kikutani H
  • Journal Title: PLoS One Volume: 8(7)
• [Journal Article] BAFF controls neural cell survival through BAFF receptor. (2013)
  • Author(s): Tada S, Yasui T, Nakatsuji Y, Okuno T, Koda T, Mochizuki H, Sakoda S, Kikutani H
  • Journal Title: PLoS One. Volume: 29;8(7) Issue: 7 Pages: e70924-e70924
  • DOI: 10.1371/journal.pone.0070924
  • Peer Reviewed
• [Journal Article] Xanthine oxidase mediates axonal and myelin loss in a murine model of multiple sclerosis. (2013)
  • Author(s): Honorat JA, Kinoshita M, Okuno T, Takata K, Koda T, Tada S, Shirakura T, Fujimura H, Mochizuki H, Sakoda S, Nakatsuji Y.
  • Journal Title: PLoS One. Volume: 8;8(8) Issue: 8 Pages: e71329-e71329
  • DOI: 10.1371/journal.pone.0071329
  • Peer Reviewed
• [Journal Article] A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration (2013)
  • Author(s): Nojima S, et al.
  • Journal Title: Nat Commun Volume: 4 Issue: 1 Pages: 1406-1406
  • DOI: 10.1038/ncomms2420
  • Peer Reviewed
• [Journal Article] A case of progressive ataxia and palatal tremor (PAPT) with ear clicks. (2013)
  • Author(s): Sumikura H, Okuno T, Takahashi MP, Araki K, Kitagawa K, Mochizuki H.
  • Journal Title: Clinical Neurology Volume: 53(3) Pages: 224-8
  • NAID: 40019608624
  • Peer Reviewed
• [Journal Article] A case of chronic active Epstein-Barr virus infection associated with recurrent cerebellar ataxia and skin eruptions. (2013)
  • Author(s): Araki K, Okuno T, Honorat JA, Kinoshita M, Takahashi MP, Mizuki M, Kitagawa K, Mochizuki H
  • Journal Title: Clinical Neurology Volume: 53(2) Pages: 119-24
  • NAID: 40019583031
  • Peer Reviewed
• [Journal Article] Elevation of Sema4A implicates Th cell skewing and the efficacy of IFN-βtherapy in multiple sclerosis (2012)
  • Author(s): Nakatsuji Y, Okuno T, Moriya M, Sugimoto T, Kinoshita M, Takamatsu H, i Nojima S, Kimura T, Kang S, Ito D, Nakagawa Y, Toyofuku T, Takata K, Nakano M, Kubo M, Suzuki S, Matsui-Hasumi A, Uto-Konomi A, Ogata A, Mochizuki H, Sakoda S, Kumanogoh A
  • Journal Title: Journal of Immunology Volume: 188 Pages: 4858-65
• [Journal Article] Elevation of Sema4A implicates Th cell skewing and the efficacy of interferon-β therapy in multiple sclerosis. (2012)
  • Author(s): Nakatsuji Y, Okuno T et al.
  • Journal Title: Journal of Immunology. Volume: 188(10) Pages: 4858-6
  • Peer Reviewed
• [Journal Article] Intestinal epithelial cell-derived semaphorin 7A negatively regulates development of colitis via αvβ1 integrin. (2012)
  • Author(s): Kang S, Okuno T, Takegahara N, Takamatsu H, Nojima S, Kimura T, Yoshida Y, Ito D, Ohmae S, You DJ, Toyofuku T, Jang MH, Kumanogoh A
  • Journal Title: Journal of Immunology Volume: 188(3) Pages: 1108-1116
  • Peer Reviewed
• [Journal Article] The role of immune semaphorins in multiple sclerosis (2011)
  • Author(s): Okuno T, Nakatsuji Y, Kumanogoh A
  • Journal Title: FEBS Letter Volume: 585 Pages: 3829-35
• [Journal Article] RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis (2011)
  • Author(s): Muramatsu R, , Kubo T, Mori M, Nakamura Y, Fujita Y, Akutsu T, Okuno T, Taniguchi J, Kumanogoh A, Yoshida M, Mochizuki H, , Kuwabara S, Yamashita T
  • Journal Title: Nature Medicine Volume: 17 Pages: 488-94
• [Journal Article] The role of immune semaphorins in multiple sclerosis. (2011)
  • Author(s): Okuno T, Nakatsuji Y, Kumanogoh A.
  • Journal Title: FEBS Letters. Volume: 585 Pages: 3829-3835
  • Peer Reviewed
• [Presentation] BAFF controls neural cell survival through BAFF receptor (2013)
  • Author(s): Tada S, Yasui T, Nakatsuji Y, Okuno T, Mochizuki H, Sakoda S, Kikutani H
  • Organizer: XXI WORLD CONGRESS OF NEUROLOGY
  • Place of Presentation: Vienna, Austria
• [Presentation] プロスタグランジンI2アゴニストであるONO-1301はALSモデル動物の神経変性を抑制する (2013)
  • Author(s): 多田智、安居輝人、奥野龍禎、中辻裕司、酒井芳紀、宮川繁、澤芳樹、菊谷仁、佐古田三郎、望月秀樹
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京(ポスター)
• [Presentation] BAFF controls neural cell survival through BAFF receptor. (2013)
  • Author(s): Tada S, Yasui T, Nakatsuji Y, Okuno T, Mochizuki H, Sakoda S, Kikutani H
  • Organizer: XXI WORLD CONGRESS OF NEUROLOGY
  • Place of Presentation: Vienna, Austria
• [Presentation] Regulation of microglial axis by T lymphocytes in neurodegenerative disorders
  • Author(s): 奥野龍禎
  • Organizer: 脳内環境若手シンポジウム
  • Place of Presentation: 京都平安ホテル
  • Invited
• [Presentation] ALSモデルマウスにおけるM1/M2活性化とその制御による治療の試み
  • Author(s): 奥野龍禎
  • Organizer: 日本神経学会総会
  • Place of Presentation: 東京
• [Remarks] 本研究も含め大阪大学神経内科の神経免疫グループの業績を公開
  • URL: http://www.med.osaka-u.ac.jp/pub/neurol/myweb6/group03.html