Immunomodulation and adult neurogenesis after stroke

2010 Fiscal Year Final Research Report

• Project/Area Number: 21790836
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Neurology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: ISHIBASHI Satoru Tokyo Medical and Dental University, 医学部附属病院, 助教 (30533369)
• Project Period (FY): 2009 – 2010
• Keywords: 脳血管障害 / 制御性T細胞 / E-セレクチン / 神経新生 / 神経幹細胞 / 動物モデル / 再生医療 / 神経保護 / 炎症

Research Abstract

Neuroblasts in the subventricular zone proliferate markedly after stroke, and migrate to the site of injury along with blood vessels. However, a large fraction of stroke-generated neuroblasts die shortly after being born, because of local inflammation.
E-selectin is specifically expressed on endothelial cells, but only when the endothelium activates. Since endothelial activation occurs after stroke, E-selectin can serve as an immunologic tolerization antigen that can focus immunomodulation to regions of the vascular tree. Intranasal instillation of recombinant E-selectin will induce mucosal tolerance to that antigen with the generation of E-selectin-specific regulatory T cells (Tregs). Tregs may protect newly-generated neuroblasts from ischemic damage through'bystander suppression' in which immunomodulatory cytokines such as TGF-β and IL-10 are released locally. In this series of experiments, we have shown that after E-selectin tolerization in permanent middle cerebral artery occlusion (pMCAO) rats Tregs transmigrate to the peri-infarct region of ischemic brain, TNF expression in the local neurovascular niche is reduced, and the survival of newly generated neuroblasts or neurons in the peri-infarct region is increased. Under these conditions, an improvement in sensorimotor function after pMCAO also occurs.
E-selectin-specific Tregs can modulate the efficacy of adult neurogenesis after ischemia and promote repair after brain injury.

Research Products

• [Journal Article] 脳梗塞後の炎症制御と神経再生 (2010)
  • Author(s): 石橋哲
  • Journal Title: 臨床神経 50 Pages: 882-885
  • Peer Reviewed
• [Journal Article] Transplantation of neuronal cells induced from human mesenchymal stem cells improves neurological functions after stroke without cell fusion. (2009)
  • Author(s): Xu H, Miki K, Ishibashi S, Inoue J, Sun L, Endo S, Sekiya I, Muneta T, Inazawa J, Dezawa M, Mizusawa H.
  • Journal Title: J Neurosci Res. 88 Pages: 3598-3609
  • Peer Reviewed
• [Journal Article] Mucosal tolerance to E-selectin promotes the survival of newly generated neuroblasts via regulatory T-cell induction after stroke in spontaneously hypertensive rats. (2009)
  • Author(s): Ishibashi S, Maric D, MouY, Ohtani R, Ruetzler C, Hallenbeck JM.
  • Journal Title: Journal of Cerebral Blood Flow and Metabolism. 29 Pages: 606-620
  • Peer Reviewed
• [Journal Article] Intensity of chronic cerebral hypoperfusion determines white/gray matter injury and cognitive/motor dysfunction in mice. (2009)
  • Author(s): Miki K, Ishibashi S, Sun L, Xu H, Ohashi W, Kuroiwa T, Mizusawa H.
  • Journal Title: J Neurosci Res. 87 Pages: 1270-1281
  • Peer Reviewed
• [Journal Article] Two region-dependent pathways of eosinophilic neuronal death after transient cerebral ischemia. (2009)
  • Author(s): Sun L, Kuroiwa T, Ishibashi S, Miki K, Li S, Xu H, Endo S, Mizusawa H.
  • Journal Title: Neuropathology 29 Pages: 45-54
  • Peer Reviewed
• [Presentation] 脳虚血後の制御性T 細胞誘導による活性型ミクログリアに対する効果の検討 (2010)
  • Author(s): 石橋哲, 水澤英洋, John Hallenbeck.
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-22
• [Presentation] 招待講演脳血管障害治療の次のブレークスルーを目指して:Immunomodulation by inducing tolerance to E-selectin and adult neurogenesis after stroke. (2010)
  • Author(s): 石橋哲
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-21
• [Presentation] ラット中大脳動脈閉塞モデルを使用した制御性T細胞誘導が脳梗塞後のneurovascular nicheに与える効果の検討 (2009)
  • Author(s): 石橋哲、John M.Hallenbeck, 水澤英洋
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-22
• [Presentation] ラット中大脳閉塞モデルを使用した制御性T細胞の誘導が神経新生に与える効果の検討 (2009)
  • Author(s): 石橋哲、John M.Hallenbeck, 水澤英洋
  • Organizer: 第34回日本脳卒中学会総会
  • Place of Presentation: 島根
  • Year and Date: 2009-03-22
• [Book] 学会印象記第19回European Stroke Conference (ESC) 2010 63 (2011)
  • Author(s): 石橋哲
  • Total Pages: 86-87
  • Publisher: Brain & Nerve
• [Book] Clinical Neurosic. 27 (2009)
  • Author(s): 石橋哲 John M.Hallenbeck.
  • Total Pages: 1181
  • Publisher: 中外医学社
• [Remarks] ホームページ等
• [Remarks] 東京医科歯科大学神経内科website
  • URL: http://www.tmd.ac.jp/med/nuro/study.html#5