Regulation of the immunological function by the CD47-SIRP alpha signaling system

• Project/Area Number: 15K08532
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Kobe University
• Principal Investigator: Saito Yasuyuki 神戸大学, 医学研究科, 講師 (40508842)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 樹状細胞 / ストローマ細胞 / SIRPα / CD47 / 免疫学

Outline of Final Research Achievements

We have here investigated the regulatory mechanism of the immune system, especially of dendritic cell function by the CD47-SIRPα signaling system. We have shown that both SIRPα and CD47 on dendritic cells regulate homeostasis of SIRPα+ dendritic cells in lymphoid organs. Moreover, these molecules regulate homeostasis of stromal cells in the spleen through the production of TNF receptor ligands by dendritic cells. Furthermore, we have established a mouse model to characterize human dendritic cells in vivo using humanized mice in the immune system.

Research Products

• [Int'l Joint Research] チューリッヒ大学病院(スイス)
• [Int'l Joint Research] Sanquin研究所(オランダ)
• [Int'l Joint Research] チューリッヒ大学病院(スイス)
• [Journal Article] Regulation by commensal bacteria of neurogenesis in the subventricular zone of adult mouse brain (2018)
  • Author(s): Sawada Naoki、Kotani Takenori、Konno Tasuku、Setiawan Jajar、Nishigaito Yuka、Saito Yasuyuki、Murata Yoji、Nibu Ken-ichi、Matozaki Takashi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 498 Issue: 4 Pages: 824-829
  • DOI: 10.1016/j.bbrc.2018.03.064
  • NAID: 120006733123
  • Peer Reviewed
• [Journal Article] Anti-human SIRPα antibody is a new tool for cancer immunotherapy (2018)
  • Author(s): Murata Yoji、Tanaka Daisuke、Hazama Daisuke、Yanagita Tadahiko、Saito Yasuyuki、Kotani Takenori、Oldenborg Per-Arne、Matozaki Takashi
  • Journal Title: Cancer Science Volume: 印刷中 Issue: 5 Pages: 1300-1308
  • DOI: 10.1111/cas.13548
  • NAID: 120006482611
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] SIRPα+dendritic cells regulate homeostasis of fibroblastic reticular cells via TNF receptor ligands in the adult spleen (2017)
  • Author(s): Saito Yasuyuki、Respatika Datu、Komori Satomi、Washio Ken、Nishimura Taichi、Kotani Takenori、Murata Yoji、Okazawa Hideki、Ohnishi Hiroshi、Kaneko Yoriaki、Yui Katsuyuki、Yasutomo Koji、Nishigori Chikako、Nojima Yoshihisa、Matozaki Takashi
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 114 Issue: 47
  • DOI: 10.1073/pnas.1711345114
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Role of SIRPα in homeostatic regulation of T cells and fibroblastic reticular cells in the spleen. (2017)
  • Author(s): Respatika Datu, Saito Yasuyuki, Washio Ken, Komori Satomi, Kotani Takenori, Okazawa Hideki, Murata Yoji, Matozaki Takashi
  • Journal Title: Kobe Journal of Medical Sciences Volume: 63
  • NAID: 120006335579
• [Journal Article] Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness. (2017)
  • Author(s): Takizawa H, Fritsch K, Kovtonyuk LV, Saito Y, Yakkala C, Jacobs K, Ahuja AK, Lopes M, Hausmann A, Hardt WD, Gomariz A, Nombela-Arrieta C, Manz MG.
  • Journal Title: Cell Stem Cell Volume: 21 Issue: 2 Pages: 225-240
  • DOI: 10.1016/j.stem.2017.06.013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy. (2017)
  • Author(s): Yanagita T, Murata Y, Tanaka D, Motegi S, Arai E, Daniwijaya EW, Hazama D, Washio K, Saito Y, Kotani T, Ohnishi H, Oldenborg PA, Verjan Garcia N, Miyasaka M, Ishikawa O, Kanai Y, Komori T, Matozaki T.
  • Journal Title: JCI Insight Volume: 2 Issue: 1
  • DOI: 10.1172/jci.insight.89140
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ellegast JM, Rauch PJ, Kovtonyuk LV, Muller R, Wagner U, Saito Y, Wildner-Verhey van Wijk N, Fritz C, Rafiei A, Lysenko V, Dudkiewicz E, Theocharides AP, Soldini D, Goede JS, Flavell RA, Manz MG. (2016)
  • Author(s): inv(16) and NPM1mut AMLs engraft human cytokine knock-in mice.
  • Journal Title: Blood Volume: 128 Issue: 17 Pages: 2130-2134
  • DOI: 10.1182/blood-2015-12-689356
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Peripheral blood CD34+ cells efficiently engraft human cytokine knock-in mice. (2016)
  • Author(s): Saito Y, Ellegast JM, Rafiei A, Song Y, Kull D, Heikenwalder M, Rongvaux A, Halene S, Flavell RA, Manz MG.
  • Journal Title: Blood Volume: 128 Issue: 14 Pages: 1829-1833
  • DOI: 10.1182/blood-2015-10-676452
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Generation of Humanized Mice for Analysis of Human Dendritic Cells. (2016)
  • Author(s): Saito Y, Ellegast JM, Manz MG.
  • Journal Title: Methods Mol Biol Volume: 1423 Pages: 309-320
  • DOI: 10.1007/978-1-4939-3606-9_22
  • ISBN: 9781493936045, 9781493936069
  • Int'l Joint Research
• [Journal Article] Dendritic cell SIRPα regulates homeostasis of dendritic cells in lymphoid organs (2015)
  • Author(s): Washio K, Kotani T, Saito Y, Respatika D, Murata Y, Kaneko Y, Okazawa H, Ohnishi H, Fukunaga A, Nishigori C, Matozaki T.
  • Journal Title: Genes Cells Volume: - Issue: 6 Pages: 00-00
  • DOI: 10.1111/gtc.12238
  • Peer Reviewed / Open Access
• [Journal Article] Protein tyrosine phosphatase SAP-1 protects against colitis through regulation of CEACAM20 in the intestinal epithelium (2015)
  • Author(s): Y Murata, T Kotani, Y Supriatna, Y Kitamura, S Imada, K Kawahara, M Nishio, EW Daniwijaya, H Sadakata, S Kusakari, M Mori, Y Kanazawa, Y Saito, K Okawa, M Takeda-Morishita, H Okazawa, H Ohnishi, T Azuma, A Suzuki, T Matozaki
  • Journal Title: Proc Natl Acad Sci U S A Volume: 112 Issue: 31
  • DOI: 10.1073/pnas.1510167112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] SIRPα+ dendritic cells regulate homeostasis of fibroblastic reticular cells via TNF receptor ligands in the adult spleen (2018)
  • Author(s): Satomi Komori, Yasuyuki Saito, Datu Respatika, Takenori Kotani, Yoji Murata, Takashi Matozaki
  • Organizer: 第２回UW・UO・KUシンポジウム
  • Int'l Joint Research
• [Presentation] Establishment of a potential new PDX mouse model for personalized cancer immunotherapy (2017)
  • Author(s): Yasuyuki Saito, Yoji Murata, Takenori Kotani, Richard A. Flavell, Markus G. Manz, Takashi Matozaki
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] SIRPα+ dendritic cells regulate homeostasis of fibroblastic reticular cells via TNF receptor ligands in the adult spleen (2017)
  • Author(s): Yasuyuki Saito, Satomi Komori, Datu Respatika, Ken Washio, Takenori Kotani, Yoji Murata, Hiroshi Ohnishi, Katsuyuki Yui, Koji Yasutomo, Takashi Matozaki
  • Organizer: The 5th annual meeting of the international cytokine and interferon society, ICIS 2017
  • Int'l Joint Research
• [Presentation] SIRPα+ dendritic cells regulate homeostasis of fibroblastic reticular cells via TNF receptor ligands in the adult spleen (2017)
  • Author(s): Yasuyuki Saito, Satomi Komori, Datu Respatika, Ken Washio, Takenori Kotani, Yoji Murata, Hiroshi Ohnishi, Katsuyuki Yui, Koji Yasutomo, Takashi Matozaki
  • Organizer: The 46th annual meeting of the japanese society for immunology
• [Presentation] 免疫系ヒト化マウスを用いた新規がん異種移植マウスモデルの作成 (2017)
  • Author(s): 齊藤 泰之、羽間 大祐、小谷 武徳、村田 陽二、 的崎 尚
  • Organizer: 第16回生体機能研究会
• [Presentation] Blockage of CD47-SIRPαsignaling provide a novel cancer immunotherapy (2017)
  • Author(s): Takashi Matozaki, Yoji Murata, Tadahiko Yanagita, Yasuyuki Saito, Takenori Kotani,
  • Organizer: Europhosphatase 2017:Phosphatases in cell fates and decisions
  • Int'l Joint Research
• [Presentation] 二次リンパ組織ストローマ細胞の新規初代培養系の樹立と増殖・制御機構の解明 (2017)
  • Author(s): 小森 里美、齊藤 泰之、Datu Respatika、小谷 武徳、村田 陽二、的崎 尚
  • Organizer: 第16回生体機能研究会
• [Presentation] Anti-SIRPalpha antibodies provide a basis for new approaches to canser immunotherapy (2017)
  • Author(s): Takashi Matozaki,Yoji Murata, Tadahiro Yanagita, Yasuyuki Saito, Takenori Kotani
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Development of a novel primary culture system for lymphoid organ fibroblastic reticular cells (2017)
  • Author(s): Komori Satomi, Yasuyuki Saito, Datu Respatika, Takenori Kotani, Yoji Murata, Takashi Matozaki
  • Organizer: The 46th annual meeting of the japanese society for immunology
• [Presentation] Role of SIRPα on dendritic cells in homeostatic regulation of fibroblastic reticular cells in the spleen (2016)
  • Author(s): Datu Respatika, Yasuyuki Saito, Ken Washio, Satomi Komori, Takenori Kotani, Yoji Murata, Takashi Matozaki
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター
  • Year and Date: 2016-12-05
• [Presentation] Human hemato-lymphoid system development in human cytokine knock-in mice engrafted with adult donor-derived CD34+ cells (2016)
  • Author(s): Yasuyuki Saito, Takashi Matozaki, Richard A. Flavell, Markus G. Manz
  • Organizer: 第12回プロテインホスファターゼ国際カンファレンス ＆ 革新がんゲノム国際シンポジウム
  • Place of Presentation: 近畿大学東大阪キャンパス
  • Year and Date: 2016-10-27
  • Int'l Joint Research
• [Presentation] Role of SIRPαin the homeostasis of fibroblastic reticular cells by dendritic cells in the spleen (2016)
  • Author(s): Datu Respatika, Yasuyuki Saito, Ken Washio, Satomi Komori, Takenori Kotani, Yoji Murata, Takashi Matozaki
  • Organizer: 第12回プロテインホスファターゼ国際カンファレンス ＆ 革新がんゲノム国際シンポジウム
  • Place of Presentation: 近畿大学東大阪キャンパス
  • Year and Date: 2016-10-27
  • Int'l Joint Research
• [Presentation] Peripheral blood CD34+ cells efficiently engraft human cytokine knock-in immunodeficient mice (2016)
  • Author(s): Yasuyuki Saito, Jana M. Ellegast, Yuanbin Song, Daniel Kull, Mathias Heikenwalder, Anthony Rongvaux, Stephanie Helene, Richard A. Flavell, Markus G. Manz
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-13
• [Presentation] Role of SIRPαon dendritic cells in homeostatic regulation of fibroblastic reticular cells in the spleen (2016)
  • Author(s): Datu Respatika, Yasuyuki Saito, Ken Washio, Satomi Komori, Takenori Kotani, Yoji Murata, Takashi Matozaki
  • Organizer: 第15回生体機能研究会
  • Place of Presentation: 淡路夢舞台国際会議場
  • Year and Date: 2016-07-01
• [Presentation] Essential Role of SIRPA on Dendritic Cells in Homeostatic Regulation of Spleen Stromal Cells (2016)
  • Author(s): Datu Respatika, Yasuyuki Saito, Ken Washio, Satomi Komori, Takenori Kotani, Yoji Murata, Takashi Matozaki
  • Organizer: 第7回日本プロテインホスファターゼ研究会学術集会
  • Place of Presentation: 基礎生物学研究所（愛知県・岡崎市）
  • Year and Date: 2016-01-29
• [Presentation] Human cytokine knock-in hSIRPα-Tg Rag2-/-Il2rg-/- mice efficiently support engraftment of peripheral blood human CD34+ cells in vivo (2016)
  • Author(s): Yasuyuki Saito, Jana Ellegast, Daniel Kull, Mathias Heikenwaelder, Richard Flavell, Markus Manz
  • Organizer: 5th International Workshop on Humanized Mice (IWHM5)
  • Place of Presentation: Zurich, Switzerland (University of Zurich)
  • Year and Date: 2016-01-28
  • Int'l Joint Research
• [Presentation] Development of a human hemato-lymphoid system in human cytokine knock-in Rag2-/-Il2rg-/- mice engrafted with peripheral blood mobilized CD34+ cells (2015)
  • Author(s): Yasuyuki Saito, Jana Ellegast, Daniel Kull, Mathias Heikenwaelder, Richard Flavell, Markus Manz
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 北海道札幌市(札幌コンベンションセンター)
  • Year and Date: 2015-11-18
• [Presentation] Regulation of dendritic cell and stromal-cell homeostasis by dendritic cell-SIRPα in the spleen (2015)
  • Author(s): Yasuyuki Saito
  • Organizer: 2015University of Washington and Kobe University joint symposium 2015神戸大学・ワシントン大学国際合同シンポジウム
  • Place of Presentation: Seattle, USA(University of Washington)
  • Year and Date: 2015-09-11
  • Int'l Joint Research
• [Presentation] Essential role of SIRPα on dendritic cells in Homeostatic regulation of the secondary lymphoid organ (2015)
  • Author(s): Datu Respatika, Yasuyuki Saito, Ken Washio, Satomi Komori, Takenori Kotani, Yoji Murata, Yoriaki Kaneko, Hideki Okazawa, Hiroshi Ohnishi, Atsushi Fukunaga, Chikako Nishigori, Takashi Matozaki
  • Organizer: 2015University of Washington and Kobe University joint symposium 2015神戸大学・ワシントン大学国際合同シンポジウム
  • Place of Presentation: Seattle, USA(University of Washington)
  • Year and Date: 2015-09-11
  • Int'l Joint Research
• [Presentation] 異種間移植におけるCD47-SIRPα系の役割とその応用 (2015)
  • Author(s): 齊藤 泰之、的崎 尚
  • Organizer: 第14回生体機能研究会
  • Place of Presentation: 神奈川県足柄下郡(ザ・プリンス箱根)
  • Year and Date: 2015-07-26
• [Book] Encyclopedia of Signaling Molecules: Sirpa (2017)
  • Author(s): Yasuyuki Saito, Yoji Murata, Takenori Kotani, Takashi Matozaki
  • Total Pages: 7
  • Publisher: Springer
• [Book] Encyclopedia of Signaling Molecules: PTPRH (2017)
  • Author(s): Yoji Murata, Takenori Kotani, Yasuyuki Saito, Takashi Matozaki
  • Total Pages: 8
  • Publisher: Springer
• [Book] Encyclopedia of Signaling Molecules: Tyrosine-Protein Phosphatase Nonreceptor Type 11 (PTPN11) (2017)
  • Author(s): Takenori Kotani, Yoji Murata, Yasuyuki Saito, Takashi Matozaki
  • Total Pages: 9
  • Publisher: Springer
• [Remarks] 神戸大学大学院医学研究科 生化学・分子生物学講座 シグナル統合学分野
  • URL: http://www.med.kobe-u.ac.jp/tougou/signal/Home.html