Development of a novel therapy for endotoxic shock using a humanized mouse model

• Project/Area Number: 15K15659
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Emergency medicine
• Research Institution: University of Tsukuba
• Principal Investigator: Shibuya Akira 筑波大学, 医学医療系, 教授 (80216027)
• Project Period (FY): 2015-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: ヒト化マウス / 敗血症 / CD300a

Outline of Final Research Achievements

We established a humanized mouse model, in which the immune responses in human endotoxic shock in vivo can be analyzed. By using this model, we examine the effect of anti-human CD300a monoclonal antibody on the endotoxic shock. First, we established a humanized mouse by transfer of human hematopoietic cells into severe immunodeficiency mouse (NOG mouse) and induced sepsis by cecal puncture and ligation. We analyzed survival, ALT, AST, and proinflammatory cytokines and chemokines such as IFNγ, TNF-a, IL-6, and IL-8 by ELISA and immune-beads analyses. These analyses suggest that anti-human CD300a monoclonal antibody is useful for the treatment of human endotoxic shock.

Research Products

• [Journal Article] Increased soluble CD155 in the serum of cancer patients (2016)
  • Author(s): Iguchi-Manaka A, Okumura G, Kojima H, Cho Y, Hirochika R, Bando H, Sato T, Yoshikawa H, Hara H, Shibuya A, Shibuya K.
  • Journal Title: PLoS One Volume: 11(4) Issue: 4 Pages: 1-12
  • DOI: 10.1371/journal.pone.0152982
  • NAID: 120007135543
  • Peer Reviewed / Open Access
• [Journal Article] Apoptotic epithelial cells control the abundance of Treg cells at barrier surfaces (2016)
  • Author(s): Nakahashi-Oda C, Udayanga KGS, Nakamura Y, Nakazawa Y, Miki H, Iino S, Tahara-Hanaoka S, Shibuya K, Shibuya A.
  • Journal Title: Nature Immunol, 17(4):441-453, 2016 Volume: 17 Issue: 4 Pages: 441-453
  • DOI: 10.1038/ni.3345
  • Peer Reviewed / Open Access
• [Journal Article] CD155/CD226-interaction impacts on the generation of innate CD8+ thymocytes by regulating iNKT-cell differentiation (2015)
  • Author(s): Georgiev H, Ravens I, Shibuya A, Förster R, Bernhardt G.
  • Journal Title: Eur J Immunol Volume: 1 Issue: 4 Pages: 1-11
  • DOI: 10.1002/eji.201546073
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of DNAM-1 (CD226) on inflammatory monocytes (2015)
  • Author(s): Vo AV, Takenaka E, Shibuya A, Shibuya K.
  • Journal Title: Mol Immunol Volume: 69 Pages: 70-76
  • DOI: 10.1016/j.molimm.2015.11.009
  • NAID: 120007129692
  • Peer Reviewed / Open Access
• [Journal Article] Tie2 Signaling Enhances Mast Cell Progenitor Adhesion to Vascular Cell Adhesion Molecule-1 (VCAM-1) through α4β1 Integrin. (2015)
  • Author(s): Kanemaru K, Noguchi E, Tokunaga T, Nagai K, Hiroyama T, Nakamura Y, Tahara-Hanaoka S, Shibuya A.
  • Journal Title: PLoS One, 10(12), 2015 Volume: 10 Issue: 12 Pages: 1-16
  • DOI: 10.1371/journal.pone.0144436
  • NAID: 120007130029
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IgM-Dependent Phagocytosis in Microglia Is Mediated by Complement Receptor 3, Not Fcα/μ Receptor (2015)
  • Author(s): Weinstein JR, Quan Y, Hanson JF, Colonna L, Iorga M, Honda S, Shibuya K, Shibuya A, Elkon KB, Möller T.
  • Journal Title: J Immunol Volume: 195(11) Issue: 11 Pages: 5309-5317
  • DOI: 10.4049/jimmunol.1401195
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification and Characterization of CD300H, a New Member of the Human CD300 Immunoreceptor Family (2015)
  • Author(s): Niizuma K, Tahara-Hanaoka S, Noguchi E, Shibuya A.
  • Journal Title: J. Biol. Chem, 290(36):22298-22308, 2015 Volume: 290 Issue: 36 Pages: 22298-22308
  • DOI: 10.1074/jbc.m115.643361
  • NAID: 120007136146
  • Peer Reviewed / Open Access
• [Journal Article] CD155 (PVR/Necl5) Mediates a Costimulatory Signal in CD4+ T Cells and Regulates Allergic Inflammation (2015)
  • Author(s): 4.Yamashita--Kanemaru Y, Takahashi Y, Wang Y, Tahara-Hanaoka S, Honda S, Bernhardt G, Shibuya A, Shibuya K.
  • Journal Title: J Immunol, 194(12):5644-5653, 2015 Volume: 194 Issue: 12 Pages: 5644-5653
  • DOI: 10.4049/jimmunol.1401942
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of CD300a Phosphatidylserine Immunoreceptor in Aluminum Salt Adjuvant–Induced Th2 Responses (2015)
  • Author(s): Miki H, Nakahashi-Oda C, Sumida T, Shibuya A.
  • Journal Title: J Immunol Volume: 194(11) Issue: 11 Pages: 5069-5076
  • DOI: 10.4049/jimmunol.1402915
  • Peer Reviewed / Open Access
• [Presentation] 免疫グロブリン様受容体と疾患 (2016)
  • Author(s): 渋谷 彰
  • Organizer: 第35回神戸ラボ全体研究会議
  • Place of Presentation: 神戸バイオテクノロジー研究・人材育成センター（兵庫）
  • Year and Date: 2016-03-25
  • Invited
• [Presentation] アトピー性皮膚炎におけるClec10a(Mgl1/CD301a)の機能解析 (2016)
  • Author(s): 金丸 和正、田原 聡子、伝田 香里、入村 達郎、野口 恵美子、渋谷 彰
  • Organizer: 第4回筑波大学・東京理科大学生命医科学研究所合同リトリート
  • Place of Presentation: オークラフロンティアホテルつくば（茨城）
  • Year and Date: 2016-03-19
• [Presentation] 樹状細胞上のAllergin-1はHDMにより誘導される好酸球性気道炎症を抑制する (2016)
  • Author(s): 三木 春香、人見 香織、田原 聡子、久保 允人、渋谷 彰
  • Organizer: 第4回筑波大学・東京理科大学生命医科学研究所合同リトリート
  • Place of Presentation: オークラフロンティアホテルつくば（茨城）
  • Year and Date: 2016-03-19
• [Presentation] Expression of DNAM-1 (CD226) on inflammatory monocytes (2016)
  • Author(s): Vo AV, Takenaka E, Shibuya A, Shibuya K.
  • Organizer: The 55th Midwinter Conference of Immunologists
  • Place of Presentation: Asilomar Conference Grounds, Pacific Grove California, USA
  • Year and Date: 2016-01-24
  • Int'l Joint Research
• [Presentation] 難治疾患の克服を目指した免疫受容体の研究 (2015)
  • Author(s): 渋谷 彰
  • Organizer: （財）茨城県科学技術振興財団 つくば賞受賞記念 特別講演会
  • Place of Presentation: 筑波大学総合研究棟D（つくば）
  • Year and Date: 2015-11-25
  • Invited
• [Presentation] Increased soluble CD155 in patients with various cancers (2015)
  • Author(s): Iguchi-Manaka A, Shibuya A, Shibuya K.
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-20
• [Presentation] CD300a on mast cells and dendritic cells control the pathogenesis of experimental sepsis (2015)
  • Author(s): Udayanga K G S, Nakahashi-Oda C, Shibuya A.
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-20
• [Presentation] Allergin-1 suppresses Toll-like receptor 2 ligand-induced dermatitis in mice (2015)
  • Author(s): Tsurusaki S, Tahara-Hanaoka S, Shibayama S, Shibuya A.
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-20
• [Presentation] Functional analysis of CD300a in atopi c dermatitis and colitis (2015)
  • Author(s): Nakamura Y, Nakahashi-Oda C, Shibuya A.
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-19
• [Presentation] Involvement of DNAM-1 (CD226) expressed on small peritoneal macrophages in antigen presentation (2015)
  • Author(s): Takenaka E, Vo AV, Shibuya A, Shibuya K.
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-19
• [Presentation] MAIR-II exacerbates bleomycin-induced pulmonary fibrosis through neutrophilic inflammation (2015)
  • Author(s): Ohtsuka S, Totsuka N, Nakahashi-Oda C, Shibuya A.
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-19
• [Presentation] Development of a novel method for isolation of follicular dendritic cells (2015)
  • Author(s): Sato K, Honda S, Shibuya K, Shibuya A.
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-19
• [Presentation] The analysis of autoimmune-like phenotypes in Allergy inhibitory receptor-1 deficient mice (2015)
  • Author(s): Iizuka A, Segawa S, Tahara M, Kaneko S, Yokosawa M, Kondo Y, Tahara-Hanaoka S, Shibayama S, Goto D, Matsumoto I, Shibuya A, Sumida T.
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-18
• [Presentation] Tie2 Signaling Enhances Mast Cell Progenitor Adhesion to VCAM-1 through β1 Integrin (2015)
  • Author(s): Kanemaru K, Noguchi E, Nagai K, Tahara-Hanaoka S, Shibuya A.
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-18
• [Presentation] Eolvl6 attenuates OVA-induced atopic dermatitis by reducing the response to mechanical stress (2015)
  • Author(s): Nakamura Y, Nakahashi-Oda C, Shibuya A.
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-18
• [Presentation] Eolvl6 attenuates OVA-induced atopic dermatitis by reducing the response to mechanical stress (2015)
  • Author(s): Nakamura Y, Oda C, Matsuzaka T, Shimano H, Shibuya A.
  • Organizer: 14th International Workshop on Langerhans Cells
  • Place of Presentation: Kyoto International Community House, Kyoto
  • Year and Date: 2015-11-06
  • Int'l Joint Research
• [Presentation] The role of DNAM-1 and CD155 in tumor immunity and escape (2015)
  • Author(s): Shibuya K, Iguchi-Manaka A, Kojima H, Cho Y, Hirochika R, Shibuya A.
  • Organizer: International Symposium on Immune Regulation
  • Place of Presentation: Oarai Park Hotel, Ibaraki
  • Year and Date: 2015-10-30
  • Int'l Joint Research / Invited
• [Presentation] Allergin-1 in House Dust Mite-induced Allergic Asthma Model (2015)
  • Author(s): Tahara-Hanaoka S, Hitomi K, Niizuma K, Shibagaki S, Miki H, Kubo M, Shibuya A.
  • Organizer: International Symposium on Immune Regulation
  • Place of Presentation: Oarai Park Hotel, Ibaraki
  • Year and Date: 2015-10-30
  • Int'l Joint Research / Invited
• [Presentation] Apoptotic epithelial cells control regulatory T cell expansion (2015)
  • Author(s): Nakahashi-Oda C, Udayanga K G S, Nakamura Y, Nakazawa Y, Totsuka N, Miki H, Iino S, Tahara-Hanaoka S, Honda S, Shibuya K, Shibuya A.
  • Organizer: International Symposium on Immune Regulation
  • Place of Presentation: Oarai Park Hotel, Ibaraki
  • Year and Date: 2015-10-29
  • Int'l Joint Research / Invited
• [Presentation] Marginal zone B cells exacerbate endotoxic shock via interleukin-6 secretion induced by Fcα/µR-coupled TLR4 signaling (2015)
  • Author(s): Honda S, Sato K, Totsuka N, Fujiyama S, Fujimoto M, Miyake K, Nakahashi-Oda C, Tahara-Hanaoka S, Shibuya K, Shibuya A.
  • Organizer: International Symposium on Immune Regulation
  • Place of Presentation: Oarai Park Hotel, Ibaraki
  • Year and Date: 2015-10-29
  • Int'l Joint Research / Invited
• [Presentation] Increased soluble CD155 in the serum of cancer patients (2015)
  • Author(s): Iguchi-Manaka A, Kojima H, Cho Y, Shibuya A, Shibuya K.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2015-10-08
• [Presentation] 癌患者血清における可溶型CD155の上昇 (2015)
  • Author(s): 井口 研子、渋谷 彰、渋谷 和子
  • Organizer: 第7回血液疾患免疫療法研究会学術集会
  • Place of Presentation: 東京大学 伊藤国際学術研究センター（東京）
  • Year and Date: 2015-09-26
• [Presentation] Regulation of immune responses by apoptotic cells (2015)
  • Author(s): Shibuya A.
  • Organizer: The 4th CSI/JSI/KAI Joint Symposium
  • Place of Presentation: Jinling Guanyuan International Hotel, Suzhou Industrial Park, Suzhou, China
  • Year and Date: 2015-09-20
  • Int'l Joint Research / Invited
• [Presentation] 抗生物質による腸内細菌バランスの乱れと喘息 (2015)
  • Author(s): 渋谷 彰
  • Organizer: 免疫ふしぎ未来
  • Place of Presentation: 日本科学未来館（東京）
  • Year and Date: 2015-08-09
  • Invited
• [Presentation] 上皮アポトーシス細胞による免疫恒常性の維持機構 (2015)
  • Author(s): 渋谷 彰、Kankanam Gamage Sanath Udayanga、中村 貴之、中澤 優太、三木 春香、小田 ちぐさ
  • Organizer: 第24回日本Cell Death学会
  • Place of Presentation: 大阪大学会館（大阪）
  • Year and Date: 2015-07-12
  • Invited
• [Presentation] 免疫受容体を標的とした疾患制御 (2015)
  • Author(s): 渋谷 彰
  • Organizer: つくば臨床医学研究開発機構開設記念講演会
  • Place of Presentation: 筑波大学 臨床講義室（つくば）
  • Year and Date: 2015-07-06
  • Invited
• [Presentation] CD226阻害による自己免疫性筋炎モデルの治療 (2015)
  • Author(s): 建石 奈緒、木村 直樹、平田 真哉、渋谷 和子、渋谷 彰、上阪 等
  • Organizer: 第1回日本骨免疫学会
  • Place of Presentation: ホテルブリーズベイマリーナ（宮古島）
  • Year and Date: 2015-07-01
• [Presentation] Promotion of allergic airway inflammation by gut fungal overgrowth (2015)
  • Author(s): 渋谷 彰
  • Organizer: Annual International Workshop on Mucosal Immunology and Vaccine for Young Investigators
  • Place of Presentation: 伊豆今井浜東急リゾート（静岡）
  • Year and Date: 2015-05-20
  • Invited
• [Presentation] 免疫受容体を標的とした疾患制御 (2015)
  • Author(s): 渋谷 彰
  • Organizer: セミナー
  • Place of Presentation: 株式会社ペルセウス プロテオミクス（東京）
  • Year and Date: 2015-04-22
  • Invited
• [Remarks] 免疫学研究室ホームページ
  • URL: http://immuno-tsukuba.com/index.html
• [Remarks] TRIOS
  • URL: http://trios.tsukuba.ac.jp/researcher/0000001643
• [Remarks] つくばリポジトリ
  • URL: https://tsukuba.repo.nii.ac.jp/index.php?action=pages_view_main&active_action=repository_view_main_item_snippet&index_id=543&pn=1&count=20&order=7&lang=japanese&page_id=13&block_id=83