A novel strategy to expand regulatory T cells by topical application of active vitamin D3

• Project/Area Number: 20K23014
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0907:Oral science and related fields
• Research Institution: Tohoku University
• Principal Investigator: Tanaka Yukinori 東北大学, 大学病院, 講師 (60637958)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 制御性 T 細胞 / 樹状細胞 / 活性型ビタミン D3 / 皮膚免疫 / 制御性T細胞 / 活性型ビタミンD3

Outline of Research at the Start

制御性 T 細胞（Treg）は自己に対する免疫応答や、常在細菌叢などの無害な非自己に対する過剰な免疫応答を抑制する重要な働きをもつ。そのため、Treg の機能障害は自己免疫疾患や、外界とのバリア面である皮膚や腸管粘膜の炎症を引き起こす。他方、Treg を増強する治療戦略は自己免疫疾患や炎症性疾患に有効である。本研究では新規 Treg 療法として皮膚へ活性型ビタミン D3 を塗布する方法を開発する。

Outline of Final Research Achievements

Regulatory T cells (Tregs) function to suppress excessive immune responses, and therapeutic strategies to augment Tregs are promising for the treatment of autoimmune and inflammatory diseases. In this study, we aimed to elucidate the mechanism underlying systemic Treg proliferation by topical application of active vitamin D3 to establish this method as a new Treg-based therapy. We found that topical application of active vitamin D3 stimulates skin dendritic cells in a TSLP-dependent manner and they promote Treg proliferation in the skin-draining lymph nodes.

Academic Significance and Societal Importance of the Research Achievements

Treg 増殖を促進し過剰な免疫応答を抑制する治療法としては、慢性移植片対宿主病（GVHD）に対する低用量 IL-2 療法が代表的である。皮膚への活性型ビタミン D3 塗布による Treg 増殖誘導法は、皮膚を利用して全身の免疫バランスを調節するという新しい発想に基づいており、低用量 IL-2 ほど強力ではないものの、簡便かつ安価である。本研究はその臨床応用に向け、マウスモデルで Treg 増殖機構を明らかにしたものである。

Research Products

• [Int'l Joint Research] University of Pennsylvania(米国)
• [Int'l Joint Research] University of Pennsylvania(米国)
• [Journal Article] Differential expression of CD11c defines two types of tissue-resident macrophages with different origins in steady-state salivary glands (2022)
  • Author(s): Lu Lu, Toshinobu Kuroishi, Yukinori Tanaka, Mutsumi Furukawa, Tomonori Nochi, Shunji Sugawara
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 931-931
  • DOI: 10.1038/s41598-022-04941-5
  • Peer Reviewed / Open Access
• [Journal Article] Salt-Sensitive Hypertension Induces Osteoclastogenesis and Bone Resorption via Upregulation of Angiotensin II Type 1 Receptor Expression in Osteoblasts (2022)
  • Author(s): Adya Pramusita, Hideki Kitaura, Fumitoshi Ohori, Takahiro Noguchi, Aseel Marahleh, Yasuhiko Nara, Ria Kinjo, Jinghan Ma, Kayoko Kanou, Yukinori Tanaka and Itaru Mizoguchi
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 10 Pages: 816764-816764
  • DOI: 10.3389/fcell.2022.816764
  • Peer Reviewed / Open Access
• [Journal Article] Nitrogen-containing bisphosphonates and lipopolysaccharide mutually augment inflammation via adenosine triphosphate (ATP)-mediated and interleukin 1β (IL-1β)-mediated production of neutrophil extracellular traps (NETs) (2021)
  • Author(s): Kanan Bando, Toshinobu Kuroishi, Hiroyuki Tada, Takefumi Oizumi, Yukinori Tanaka, Tetsu Takahashi, Itaru Mizoguchi, Shunji Sugawara, Yasuo Endo
  • Journal Title: Journal of Bone and Mineral Research Volume: 36 Issue: 9 Pages: 1866-1878
  • DOI: 10.1002/jbmr.4384
  • Peer Reviewed / Open Access
• [Journal Article] Cellular context of IL-33 expression dictates impact on anti-helminth immunity (2020)
  • Author(s): Hung Li-Yin、Tanaka Yukinori、Herbine Karl、Pastore Christopher、Singh Brenal、Ferguson Annabel、Vora Nisha、Douglas Bonnie、Zullo Kelly、Behrens Edward M.、Li Hui Tan Tiffany、Kohanski Michael A.、Bryce Paul、Lin Cailu、Kambayashi Taku、Reed Danielle R.、Brown Breann L.、Cohen Noam A.、Herbert De’Broski R.
  • Journal Title: Science Immunology Volume: 5 Issue: 53
  • DOI: 10.1126/sciimmunol.abc6259
  • Peer Reviewed / Int'l Joint Research
• [Presentation] ヒスチジン脱炭酸酵素レポーターマウスを用いた新規ヒスタミン産生細胞の同定 (2020)
  • Author(s): 田中志典、水田健太郎
  • Organizer: 第48回日本歯科麻酔学会総会・学術集会