Development of targeted therapy against sepsis

• Project/Area Number: 17H04362
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Emergency medicine
• Research Institution: University of Tsukuba
• Principal Investigator: Honda Shin-ichiro 筑波大学, 生存ダイナミクス研究センター, 客員研究員 (60360640)
• Co-Investigator(Kenkyū-buntansha): 田原 聡子 筑波大学, 生存ダイナミクス研究センター, 講師 (20360589)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2019: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2017: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: 敗血症 / TLR4 / IL-10 / アラジン－1 / アラジンー1 / TLR / SHP-1 / Toll-like receptor / 感染症 / Allergin-1

Outline of Final Research Achievements

It is important to establish the therapeutic strategy against sepsis by inhibiting hyperactivation of infllammation with controlling infection. An immunoinhibitory receptor, Allergin-1, is expressed on myeloid cells, transmit an inhibitory signal via ITIM sequence in its cytoplasmic region, and function as immune-checkpoint receptor. We found that Allergin-1-deficiency protects the mice from death by cecal ligation puncture (CLP)-induced sepsis. Further analyses demonstrated that Allergin-1-deficiency promotes IL-10 production by peritoneal macrophages via TLR4 signaling. These observations suggest that Allergin-1 may be a therapeutic targeting molecule in sepsis.

Academic Significance and Societal Importance of the Research Achievements

敗血症の治療法は確立しておらず、新たな治療法を開発することが重要である。アラジン－1は免疫応答を制御する免疫チェックポイント分子の１つであるがアラジン－1遺伝子が欠損したマウスでは敗血症誘導後の生存率が亢進することを見出した。アラジン－1は炎症反応を抑制すると仮説を立てたが、予想外に、アラジン－1遺伝子が欠損すると腹腔マクロファージからIL-10産生が亢進し、炎症反応を抑制した。しかし、腹腔内の細菌量には変化がなかった。このことから、アラジン－1を治療標的とすることで、細菌の排除には影響せずに炎症反応だけ抑制できる可能性が示唆された。

Research Products

• [Journal Article] Allergin-1 immunoreceptor suppresses house dust mite-induced allergic airway inflammation. (2020)
  • Author(s): Miki H, Tahara-Hanaoka S, Almeida MS, Hitomi K, Shibagaki S, Kanemaru K, Lin YH, Iwata K, Miyake S, Shibayama S, Sumida T, Shibuya K, Shibuya A
  • Journal Title: Journal of Immunology Volume: 204(4) Issue: 4 Pages: 753-762
  • DOI: 10.4049/jimmunol.1900180
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clec10a regulates mite-induced dermatitis (2019)
  • Author(s): Kanemaru K, Noguchi E, Tahara-Hanaoka S, Mizuno S, Tateno H, Denda-Nagai K, Irimura T, Matsuda H, Sugiyama F, Takahashi S, Shibuya K, Shibuya A
  • Journal Title: Science Immunology, Volume: 4(42) Issue: 42 Pages: 6908-6908
  • DOI: 10.1126/sciimmunol.aax6908
  • Peer Reviewed
• [Journal Article] Selective suppression of oral allergen-induced anaphylaxis by Allergin-1 on basophils in mice (2019)
  • Author(s): Lin Yu-Hsien、Tahara-Hanaoka Satoko、Nagai Kei、Yoshikawa Soichiro、Kubo Masato、Shibayama Shiro、Karasuyama Hajime、Shibuya Akira
  • Journal Title: International Immunology Volume: 32 Issue: 3 Pages: 213-219
  • DOI: 10.1093/intimm/dxz075
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Expression and function of DNAM-1 on human B-lineage cells (2019)
  • Author(s): Nagayama-Hasegawa Y., Honda S, Shibuya A., Shibuya K.
  • Journal Title: Clinical Cytometry Volume: - Issue: 4 Pages: 1-7
  • DOI: 10.1002/cyto.b.21859
  • Peer Reviewed / Open Access
• [Journal Article] Allergy inhibitory receptor‐1 inhibits autoantibody production via upregulation of apoptotic debris clearance by macrophages (2018)
  • Author(s): Iizuka Akira、Segawa Seiji、Kondo Yuya、Kaneko Shunta、Yokosawa Masahiro、Furuyama Kotona、Miki Haruka、Tahara‐Hanaoka Satoko、Shibuya Akira、Tsuboi Hiroto、Goto Daisuke、Matsumoto Isao、Shibayama Shiro、Sumida Takayuki
  • Journal Title: International Journal of Rheumatic Diseases Volume: 21 Issue: 12 Pages: 2071-2078
  • DOI: 10.1111/1756-185x.13381
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Elovl6 regulates mechanical damage-induced keratinocyte death and skin inflammation. (2018)
  • Author(s): Nakamura Y, Matsuzaka T, Tahara-Hanaoka S, Shibuya K, Shimano H, Nakahashi-Oda C, Shibuya A.
  • Journal Title: Cell Death Dis. Volume: 9(12) Issue: 12 Pages: 1181-1181
  • DOI: 10.1038/s41419-018-1226-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Allergin-1 on mast cells suppresses house dust mite-induced airway hyperresponsiveness in mice (2018)
  • Author(s): Hitomi K, Tahara-Hanaoka S, Miki H, Iwata K, Shibayama S, Kubo M, Shibuya A
  • Journal Title: Int Immunol Volume: 30(9) Issue: 9 Pages: 429-434
  • DOI: 10.1093/intimm/dxy025
  • NAID: 120007133761
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cutting Edge: Identification of Marginal Reticular Cells as Phagocytes of Apoptotic B Cells in Germinal Centers (2018)
  • Author(s): Sato Kazuki、Honda Shin-ichiro、Shibuya Akira、Shibuya Kazuko
  • Journal Title: The Journal of Immunology Volume: 200 Issue: 11 Pages: 3691-3696
  • DOI: 10.4049/jimmunol.1701293
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long-term survival of the mouse ES cell-derived mast cell, MEDMC-BRC6, in mast cell-deficient KitW-sh/W-sh mice (2017)
  • Author(s): Shibagaki Shohei、Tahara-Hanaoka Satoko、Hiroyama Takashi、Nakamura Yukio、Shibuya Akira
  • Journal Title: International Immunology Volume: 29 Issue: 5 Pages: 235-242
  • DOI: 10.1093/intimm/dxx022
  • NAID: 120007134419
  • Peer Reviewed
• [Presentation] Allergin-1 immunoreceptor suppresses house dust mite-induced allergic Th2 responses (2018)
  • Author(s): 28.田原 聡子、三木 春香、人見 香織、Almeida Mariana、柴垣 翔平、金丸 和正、岩田 佳奈子、柴山 史朗、住田 孝之、渋谷 和子、渋谷 彰
  • Organizer: 第83回日本インターフェロン・サイトカイン学会
• [Presentation] Inhibition of house dust mite-induced Th2 responses by Allergin-1 immunoreceptor on dendritic cells. (2017)
  • Author(s): Tahara-Hanaoka S, Miki H, Hitomi K, Almeida MS, Iwata K, Kanemaru K, Shibayama S, Kubo M, Sumida T, Shibuya A
  • Organizer: 第46回日本免疫学会総会・学術集会
• [Presentation] Inhibition of house dust mite-induced Th2 responses by Allergin-1 immunoreceptor on dendritic cells. (2017)
  • Author(s): Tahara-Hanaoka S, Miki H, Hitomi K, Almeida MS, Iwata K, Kanemaru K, Shibayama S, Kubo M, Sumida T, Shibuya A
  • Organizer: The 5th Annual Meeting of the International Cytokine and Interferon Society.
  • Int'l Joint Research
• [Remarks] 筑波大学 免疫学研究室
  • URL: http://immuno-tsukuba.com/index.html