Development of innovative treatment targeted for CD40 ligand for patients with multiple sclerosis

• Project/Area Number: 17K16109
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Chiba University
• Principal Investigator: Masuda Hiroki 千葉大学, 医学部附属病院, 特任助教 (10722936)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 血液脳関門 / 多発性硬化症 / 可溶型CD40リガンド / 実験的アレルギー性脳脊髄炎 / 脳神経疾患

Outline of Final Research Achievements

To elucidate the potential role of soluble CD40 ligand (sCD40L) in blood brain barrier (BBB) disruption in patients with multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) mice. Serum sCD40L levels, which was higher in patients with MS than in disease controls (DCs), was positively correlated with Qalb, a marker of BBB breakdown [median, 2480 versus 786 pg/mL; interquartile range (IQR), 2590 vs 1379; P = 0.046]. EAE scores of mice receiving high-dose sCD40L were worse than those receiving low-dose sCD40L and controls. Permeability coefficient was increased by sCD40L treatment in the human brain microvascular endothelial cell based BBB model (median, 2.43 vs 1.78 10-3cm/min; IQR, 0.85 vs 0.64; P = 0.032). As conclusion, sCD40L may facilitate inflammation in MS and EAE by BBB disruption.

Academic Significance and Societal Importance of the Research Achievements

多発性硬化症（MS）患者は再発寛解を繰り返しながら神経学的後遺症が蓄積していき、認知機能障害をきたしたり、車椅子や寝たきりになるなど日常生活動作の低下をきたすことが知られている。今回の研究によって、sCD40L がMS の急性期に上昇して血液脳関門破綻を促進し、重症化につながっているということが示唆された。そのため、今後、sCD40L をターゲットとしたMS 急性期の新規治療を確立することで、MS 患者の神経学的後遺症を軽症化することが可能になると予想される。すなわち、本研究の成果は世界で250 万人いるMS 患者の大きな福音になりうる。

Research Products

• [Journal Article] Soluble CD40 ligand disrupts the blood?brain barrier and exacerbates inflammation in experimental autoimmune encephalomyelitis (2018)
  • Author(s): Masuda Hiroki、Mori Masahiro、Umehara Kenta、Furihata Tomomi、Uchida Tomohiko、Uzawa Akiyuki、Kuwabara Satoshi
  • Journal Title: J Neuroimmunol Volume: 316 Pages: 117-120
  • DOI: 10.1016/j.jneuroim.2018.01.001
  • Peer Reviewed
• [Journal Article] Soluble CD40 ligand contributes to blood brain barrier breakdown and central nervous system inflammation in multiple sclerosis and neuromyelitis optica spectrum disorder (2017)
  • Author(s): Masuda H, Mori M, Uchida T, Uzawa A, Ohtani R, Kuwabara S.
  • Journal Title: J Neuroimmnol Volume: 305 Pages: 102-107
  • DOI: 10.1016/j.jneuroim.2017.01.024
  • Peer Reviewed
• [Presentation] Soluble CD40 ligand contributes to blood-brain barrier breakdown in patients with multiple sclerosis and mice with experimental autoimmune encephalomyelitis (2018)
  • Author(s): Hiroki Masuda, Masahiro Mori, Tomohiko Uchida, Akiyuki Uzawa, Ryohei Ohtani, and Satoshi Kuwabara
  • Organizer: ECTRIMS2018
  • Int'l Joint Research
• [Presentation] Soluble CD40 ligand contributes to blood–brain barrier breakdown and central nervous system inflammation (2017)
  • Author(s): Hiroki Masuda, Masahiro Mori, Tomohiko Uchida, Akiyuki Uzawa, Ryohei Otani, Satoshi Kuwabara
  • Organizer: Sendai Conference 2017
• [Presentation] Soluble CD40 ligand contributes to blood–brain barrier breakdown and central nervous system inflammation (2017)
  • Author(s): Hiroki Masuda; Masahiro Mori; Tomohiko Uchida; Akiyuki Uzawa; Ryohei Ohtani; and Satoshi Kuwabara
  • Organizer: XXIII World Congress of Neurology
• [Presentation] 可溶性CD40リガンドは血液脳関門破綻を介して中枢神経の炎症に寄与する (2017)
  • Author(s): 枡田大生、森 雅裕、鵜沢顕之、内田智彦、大谷龍平、桑原 聡
  • Organizer: 第29回日本神経免疫学会学術集会