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

2013 Fiscal Year Final Research Report

• 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
• Keywords: ＡＬＳ / GM-CSF / M1/M2 / ミクログリア / 炎症

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: 00002-2
• [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] 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
• [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) Pages: e71329
• [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) Pages: e70924
• [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] 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
• [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
  • Year and Date: 20130921-26
• [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)
  • Year and Date: 20130529-0601
• [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