Regulation of dendritic cells and lymphoid tissues by CD47-SIRPalpha signaling

• Project/Area Number: 18K15190
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Kobe University
• Principal Investigator: Saito Yasuyuki 神戸大学, 医学研究科, 講師 (40508842)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 樹状細胞 / ストローマ細胞 / 自己免疫疾患 / SIRPα / CD47 / 自己免疫性疾患

Outline of Final Research Achievements

We investigated the regulatory mechanism how dendritic cells (DCs) mediates lymphoid tissue reconstitution, as well as regulates the pathogenesis of autoimmune diseases, by the CD47-SIRPα signaling. We found that SIRPα signaling is important for DC-induced maintenance of stromal cells in vivo, as wll as for the reconstitution of lymphoid tissue. Furthermore, we found that SIRPα and CD47 on DCs regulate the priming of self-reactive T cells in the peripheral lymphoid tissue and the subsequent infiltration or reactivation of inflammatory cells into the central nervous system in an experimental autoimmune encephalomyelitis model.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果により、自己免疫疾患の発症やリンパ組織ストローマ細胞の再構築において新たな作用機序の解明をもたらすことから、各種免疫疾患（自己免疫疾患、感染症、移植免疫）や腫瘍免疫応答に対する革新的な診断や治療技術開発などの新たな創造をもたらすことが期待される。

Research Products

• [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)
• [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)
• [Journal Article] Importance of methodology in the evaluation of renal mononuclear phagocytes and analysis of a model of experimental nephritis with Shp1 conditional knockout mice (2020)
  • Author(s): Watanabe Mitsuharu、Kaneko Yoriaki、Ohishi Yuko、Kinoshita Masato、Sakairi Toru、Ikeuchi Hidekazu、Maeshima Akito、Saito Yasuyuki、Ohnishi Hiroshi、Nojima Yoshihisa、Matozaki Takashi、Hiromura Keiju
  • Journal Title: Biochemistry and Biophysics Reports Volume: 22 Pages: 100741-100741
  • DOI: 10.1016/j.bbrep.2020.100741
  • Peer Reviewed / Open Access
• [Journal Article] An animal model that mimics human herpesvirus 6B pathogenesis (2019)
  • Author(s): Wang B, Saito Y, Nishimura M, Ren Z, Tjan LH, Refaat A, Iida-Norita R, Tsukamoto R, Komatsu M, Itoh T, Matozaki T, Mori Y
  • Journal Title: Journal of Virology Volume: 94 Issue: 6
  • DOI: 10.1128/jvi.01851-19
  • Peer Reviewed / Open Access
• [Journal Article] SIRPα+ dendritic cells promote the development of fibroblastic reticular cells in murine peripheral lymph nodes (2019)
  • Author(s): Komori S, Saito Y, Respatika D, Nishimura T, Kotani T, Murata Y, Matozaki T
  • Journal Title: European Journal of Immunology Volume: 49 Issue: 9 Pages: 1364-1371
  • DOI: 10.1002/eji.201948103
  • NAID: 120006778280
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Role of lysophosphatidic acid in proliferation and differentiation of intestinal epithelial cells (2019)
  • Author(s): Konno T, Kotani T, Setiawan J, Nishigaito Y, Sawada N, Imada S, Saito Y, Murata Y, Matozaki T
  • Journal Title: PLOS ONE Volume: 14 Issue: 4 Pages: e0215255-e0215255
  • DOI: 10.1371/journal.pone.0215255
  • NAID: 120006634675
  • Peer Reviewed / Open Access
• [Journal Article] Microglial SIRPα regulates the emergence of CD11c+ microglia and demyelination damage in white matter. (2019)
  • Author(s): Sato-Hashimoto M, Nozu T, Toriba R, Horikoshi A, Akaike M, Kawamoto K, Hirose A, Hayashi H, Nagai H, Shimizu W, Saiki A., Ishikawa T, Elhanbaly R, Kotani T, Murata Y, Saito Y, Naruse M, Shibasaki K, Oldenborg P.-A, Jung S, Matozaki T, Fukazawa Y, Ohnishi H.
  • Journal Title: eLife Volume: - Pages: 1-29
  • DOI: 10.7554/elife.42025
  • NAID: 120006604638
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An mTORC1/2 kinase inhibitor enhances the cytotoxicity of gemtuzumab ozogamicin by activation of lysosomal function (2018)
  • Author(s): Maimaitili Yimamu、Inase Aki、Miyata Yoshiharu、Kitao Akihito、Mizutani Yu、Kakiuchi Seiji、Shimono Yohei、Saito Yasuyuki、Sonoki Takashi、Minami Hironobu、Matsuoka Hiroshi
  • Journal Title: Leukemia Research Volume: 74 Pages: 68-74
  • DOI: 10.1016/j.leukres.2018.09.017
  • Peer Reviewed
• [Journal Article] Role of Csk in intestinal epithelial barrier function and protection against colitis (2018)
  • Author(s): Sun Chunxiao、Murata Yoji、Imada Shinya、Konno Tasuku、Kotani Takenori、Saito Yasuyuki、Yamada Hideto、Matozaki Takashi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 504 Issue: 1 Pages: 109-114
  • DOI: 10.1016/j.bbrc.2018.08.140
  • NAID: 120006775950
  • Peer Reviewed
• [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] CD47-signal regulatory protein α signaling system and its application to cancer immunotherapy (2018)
  • Author(s): Murata Yoji、Saito Yasuyuki、Kotani Takenori、Matozaki Takashi
  • Journal Title: Cancer Science Volume: 109 Issue: 8 Pages: 2349-2357
  • DOI: 10.1111/cas.13663
  • NAID: 120006517719
  • Peer Reviewed
• [Presentation] A nobel macrocycle peptide targets CD47-SIRPalpha axis and enhances the macrophage-mediated tumor killing (2019)
  • Author(s): Hazama D, Murata Y, Tanaka D, Okamoto T, Saito Y, Kotani T, Nishimura Y, Matozaki T
  • Organizer: 78回日本癌学会総会
• [Presentation] Role of Tsc2-mTORC1 signaling in regulation of colonic epithelial homeostasis (2019)
  • Author(s): Kotani T, Setiawan J, Ihara N, Okamoto S, Murata Y, Saito Y, Matozaki T
  • Organizer: 第78回日本癌学会総会
• [Presentation] SIRPα抗体を用いた新規のがん免疫療法:CD20及びPD-1抗体との併用による有効性 (2019)
  • Author(s): 的崎 尚、村田 陽二、齊藤 泰之、小谷 武徳
  • Organizer: 第78回日本癌学会総会
• [Presentation] Importance of SIRPα+ dendric cells for the development of fibroblastic reticular cells of peripheral lymph nodes (2019)
  • Author(s): Komori S, Saito Y, Respatika D, Nishimura T, Kotani T, Murata Y, Matozaki T
  • Organizer: 第92回日本生化学会大会
• [Presentation] チロシンホスファターゼ SHP-1/2 結合タンパク質 SIRPαによる自然免疫細胞の機能制御 (2019)
  • Author(s): 村田 陽二、齊藤 泰之、小谷 武徳、的崎 尚
  • Organizer: 第92回日本生化学会大会
• [Presentation] 細胞間シグナルCD47-SIRPα系による血球寿命制御とその臨床応用 (2019)
  • Author(s): 的崎 尚、齊藤 泰之、小谷 武徳、村田 陽二
  • Organizer: 第92回日本生化学会大会
  • Invited
• [Presentation] 新規SIRPα阻害剤の開発とその抗腫瘍効果 (2019)
  • Author(s): 村田 陽二、羽間 大祐、田中 大介、岡本 武士、齊藤 泰之、小谷 武徳、的崎 尚
  • Organizer: 第18回生体機能研究会
• [Presentation] SIRPα陽性樹状細胞による末梢リンパ節ストローマ細胞の発達制御 (2019)
  • Author(s): 小森 里美、齊藤 泰之、ダトゥ レスパティカ、西村 太一、小谷 武徳、村田 陽二、的崎 尚
  • Organizer: 第9回ホスファターゼ研究会学術集会
• [Presentation] 膜型分子SIRPαを標的とする新たな免疫チェックポイント阻害剤の開発 (2019)
  • Author(s): 羽間 大祐、村田 陽二、田中 大介、岡本 武士、齊藤 泰之、小谷 武徳、西村 善博、的崎 尚
  • Organizer: 第9回ホスファターゼ研究会学術集会
• [Presentation] 大腸上皮の恒常性制御におけるTsc2-mTORC1シグナルの役割 (2019)
  • Author(s): 小谷 武徳、ジャジャル セティアワン、井原 紀子、岡本 沙樹、村田 陽二、齊藤 泰之、的崎 尚
  • Organizer: 第9回ホスファターゼ研究会学術集会
• [Presentation] SIRPα＋Dendritic Cells regulate organization of lymph node stromal sells in vivo (2018)
  • Author(s): Komori S, Saito Y, Respatika D, Kotani T, Murata Y, Matozaki T
  • Organizer: 第47回日本免疫学学術集会
• [Presentation] Importance of SIRPα on dendritic cells for the development of exprerimental autoimmune encephalomyelitis (2018)
  • Author(s): Nishimura T, Saito Y, Komori S, Respatika D, Washio K, Kotani T, Murata Y, Mizobushi S, Matozaki T
  • Organizer: 第47回日本免疫学学術集会
• [Presentation] Xenograft mouse models for in vivo evaluation of cancer immunotherapy targeting human macrophages (2018)
  • Author(s): Saito Y, Hazama D, Murata Y, Manz MG, Matozaki
  • Organizer: Regeneron HIS Mice Workshop
  • 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): Saito Y
  • Organizer: Workshop on Frontiers in Phosphatase Research and Drug Discovery
  • Int'l Joint Research
• [Presentation] Critical role of SIRPαon dendritic cells for the development of experimental autoimmune encephalomyelitis (2018)
  • Author(s): Nishimura T, Saito Y, Washio K, Komori S, Respatika D, Kotani T, Murata Y, Mizobuchi S, Matozaki T
  • Organizer: Workshop on Frontiers in Phosphatase Research and Drug Discovery
  • 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): Saito Y, Komori S, Respatika D, Washio K, Kotani T, Murata Y, Matozaki T
  • Organizer: 15th International Symposium on Dendritic Cells
  • Int'l Joint Research
• [Presentation] SIRPα陽性樹状細胞による脾臓細網線維芽細胞の恒常性の制御 (2018)
  • Author(s): 齊藤 泰之、小森 里美、Datu Respatika、鷲尾 健、西村 太一、小谷 武徳、村田 陽二、的崎 尚
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 実験的自己免疫性脳脊髄炎の発症制御におけるCD47-SIRPα系の役割について (2018)
  • Author(s): 西村 太一、齊藤 泰之、鷲尾 健、小森 里美、小谷 武徳、村田 陽二、溝渕 知司、的崎 尚
  • Organizer: 第17回生体機能研究会
• [Remarks] シグナル統合学分野ホームページ
  • URL: http://www.med.kobe-u.ac.jp/tougou/signal/Home.html