Research for establishment of antigen-specific immunosuppressive therapy in autoimmune diseases

• Project/Area Number: 15K09551
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Ehime University
• Principal Investigator: Hasegawa Hitoshi 愛媛大学, 医学系研究科, 教授 (40164826)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 寛容型樹状細胞 / 自己免疫疾患 / 制御性T細胞

Outline of Final Research Achievements

Tolerogenic dendritic cells (tDCs) are a promising therapeutic tool for specific induction of immunological tolerance. Human tDCs can be generated ex vivo using various compounds. However, the compound(s) most suitable for clinical application remain undefined. We compared the tolerogenic properties of tDCs treated with protein kinase C inhibitor (PKCI), dexamethasone, vitamin D3, rapamycin (Rapa), IL-10, TGF-beta, and a combination of peroxisome proliferator-activated receptor gamma agonist and retinoic acid. PKCI-, TGF-beta-, and Rapa-tDCs showed CCR7 expression and migration to CCL19, but other tDCs showed little or none. PKCI- and IL-10-tDCs induced functional regulatory T cells more strongly than other tDCs. The tolerogenic properties of all tDCs were stable against proinflammatory stimuli. Furthermore, PKCI-tDCs were generated from patients with Sjogren's syndrome. Therefore, PKCI-tDCs showed the characteristics best suited for tolerance-inducing therapy.

Academic Significance and Societal Importance of the Research Achievements

ヒトのtDCsの治療効果については、欧州や米国を中心にI型糖尿病，関節リウマチ, クローン病、多発性硬化症に対して臨床試験が進められている。これらの試験において、いずれも安全性は確認されており、効果もあることが報告されている。これらの臨床研究で用いているtDCsは様々な方法で誘導したtDCsを用いているが、我々はPKCI-tDCsが最も良いことを明らかにした。PKCI-tDCsは自己免疫疾患における抗原特異的免疫抑制療法の有力なツールになることが期待される。

Research Products

• [Journal Article] Mechanisms of tolerance induction by dendritic cells in vivo. (2018)
  • Author(s): Hasegawa H, Matsumoto T
  • Journal Title: Frontiers in Immunology Volume: 9 Pages: 350-350
  • DOI: 10.3389/fimmu.2018.00350
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cキナーゼ阻害剤で誘導されたヒト免疫寛容樹状細胞による自己免疫疾患への展開 (2017)
  • Author(s): 松本卓也，長谷川均
  • Journal Title: アレルギーの臨床 Volume: 37 Pages: 49-54
• [Journal Article] Human tolerogenic dendritic cells generated with protein kinase C inhibitor are optimal for functional regulatory T cell induction (2016)
  • Author(s): Adnan E, Yasukawa M, et al.
  • Journal Title: Clin Immunol. Volume: 173 Pages: 96-108
  • DOI: 10.1016/j.clim.2016.09.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Cキナーゼ阻害剤で誘導されたヒト寛容型樹状細胞の特徴と自己免疫疾患からの誘導 (2018)
  • Author(s): 長谷川均、松本卓也、石崎淳、末盛浩一郎
  • Organizer: 第62回日本リウマチ学会総会・学術集会
• [Presentation] Characterization of human tolerogenic dendritic cells generated with protein kinase C inhibitor and induction from patients with autoimmune diseases. (2017)
  • Author(s): Hasegawa, H., Matsumoto, T., Adnan, E., Ishizaki, J., Suemori, K., Yasukawa, M.
  • Organizer: 2017 ACR/ARHP Annual Meeting.
  • Int'l Joint Research
• [Presentation] 各種誘導物質で誘導された免疫寛容樹状細胞の抑制機能の比較検討 (2015)
  • Author(s): 長谷川均、Endy Adnan、松本卓也、石崎淳、大西佐知子、末盛浩一郎、安川正貴
  • Organizer: 第43回日本臨床免疫学会総会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-10-22