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Elucidation of the NK cell immune escape mechanism using iPS cell-derived platelets and development of treatment

Research Project

Project/Area Number 21K08413
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionKyoto University

Principal Investigator

Sugimoto Naoshi  京都大学, iPS細胞研究所, 特定拠点准教授 (10447956)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsiPS細胞 / 血小板 / HLAクラスI / 遺伝子編集 / NK細胞 / TGF-β / ヒト化マウス / TGFβ / プロテオミック解析 / 免疫抑制分子 / ライブ動態解析 / HLA / 免疫寛容
Outline of Research at the Start

高度の血小板減少症では血小板の輸血が行われるが、HLAクラスI不適合に起因して約5%では拒絶される。ユニバーサルな解決策となるHLA-I欠失血小板を製造したところ、他のHLA-I欠失細胞と異なり血小板はNK細胞に攻撃されないことが判明した。そこで、各種解析によって寄与候補分子を同定し、ヒト化マウスを用いたビボ検証等を行うことにより、血小板のNK細胞に対する免疫逃避メカニズムを解明する。本研究は、多様な免疫病態に関与する血小板の作用メカニズムに新知見をもたらし、新規治療戦略に結びつくと期待される。

Outline of Final Research Achievements

To overcome platelet transfusion refractoriness caused by rejection due to HLA class I incompatibility, we developed HLA class I-deficient iPS cell-derived platelets. In this study, we performed in vitro NK cell co-culture analysis, transplantation verification using NK cell-reconstituted humanized mice, live imaging analysis of cell kinetics, and proteomic analysis using HLA class I-deficient iPS platelets and their source, the HLA class I-deficient megakaryocytic line (imMKCL). These studies confirmed the immune evasiveness of HLA class I-deficient iPS platelets against NK cells, and also suggested that the immunosuppressive molecule TGF-β contributes to this unique characteristic.

Academic Significance and Societal Importance of the Research Achievements

血小板は、赤血球輸血や骨髄移植、臓器移植と異なり、適合性を考慮しなくとも他者に輸血が可能という特異的な免疫性質を有する。そのメカニズムはこれまで不詳であったが、本研究はその一端を解明することに貢献する。この様な血小板の特徴は、血小板増加をしばしば引き起こすことのある、がんが免疫システムの攻撃を逃れていることに関与している可能性も考えうる。
本研究で示された血小板の免疫を逃れる性質とそのメカニズムは、その応用によって輸血や移植医療の免疫的なバリアーの克服を一歩進める一方、抑制的に制御することによってがんに対する新たな治療法の開発につながる可能性がある。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (17 results)

All 2023 2022 2021

All Journal Article (7 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 6 results) Presentation (9 results) (of which Int'l Joint Research: 4 results,  Invited: 1 results) Book (1 results)

  • [Journal Article] Humanized mouse models with endogenously developed human natural killer cells for in?vivo immunogenicity testing of HLA class I-edited iPSC-derived cells2023

    • Author(s)
      Flahou Charlotte、Morishima Tatsuya、Higashi Natsumi、Hayashi Yoshikazu、Xu Huaigeng、Wang Bo、Zhang Chaoqi、Ninomiya Atsushi、Qiu Wei-Yin、Yuzuriha Akinori、Suzuki Daisuke、Nakamura Sou、Manz Markus、Kaneko Shin、Hotta Akitsu、Takizawa Hitoshi、Eto Koji、Sugimoto Naoshi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 662 Pages: 76-83

    • DOI

      10.1016/j.bbrc.2023.04.067

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Fit-For-All iPSC-Derived Cell Therapies and Their Evaluation in Humanized Mice With NK Cell Immunity.2021

    • Author(s)
      Flahou C, Morishima T, Takizawa H, Sugimoto N.
    • Journal Title

      Front Immunol

      Volume: 12 Pages: 662360-662360

    • DOI

      10.3389/fimmu.2021.662360

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Generation and manipulation of human iPSC-derived platelets2021

    • Author(s)
      Sugimoto Naoshi、Eto Koji
    • Journal Title

      Cellular and Molecular Life Sciences

      Volume: 78 Issue: 7 Pages: 3385-3401

    • DOI

      10.1007/s00018-020-03749-8

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] iPS細胞技術を応用した血液疾患およびがんに対する治療戦略2021

    • Author(s)
      杉本直志、江藤浩之
    • Journal Title

      先進医療Navigator

      Volume: 8 Pages: 20-23

    • Related Report
      2021 Research-status Report
  • [Journal Article] Silencing of p53 and CDKN1A establishes sustainable immortalized megakaryocyte progenitor cells from human iPSCs2021

    • Author(s)
      Sone Masamitsu、Nakamura Sou、Umeda Sachiko、Ginya Harumi、Oshima Motohiko、Kanashiro Maria Alejandra、Paul Sudip Kumar、Hashimoto Kanae、Nakamura Emiri、Harada Yasuo、Tsujimura Kyoko、Saraya Atsunori、Yamaguchi Tomoyuki、Sugimoto Naoshi、Sawaguchi Akira、Iwama Atsushi、Eto Koji、Takayama Naoya
    • Journal Title

      Stem Cell Reports

      Volume: 16 Issue: 12 Pages: 2861-2870

    • DOI

      10.1016/j.stemcr.2021.11.001

    • NAID

      120007177810

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Extracellular laminin regulates hematopoietic potential of pluripotent stem cells through integrin β1-ILK-β-catenin-JUN axis2021

    • Author(s)
      Yuzuriha Akinori、Nakamura Sou、Sugimoto Naoshi、Kihara Shunsuke、Nakagawa Masato、Yamamoto Takuya、Sekiguchi Kiyotoshi、Eto Koji
    • Journal Title

      Stem Cell Research

      Volume: 53 Pages: 102287-102287

    • DOI

      10.1016/j.scr.2021.102287

    • NAID

      120007006753

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of platelet replacement therapy using human induced pluripotent stem cells2021

    • Author(s)
      Nakamura Sou、Sugimoto Naoshi、Eto Koji
    • Journal Title

      Development, Growth & Differentiation

      Volume: 63 Issue: 2 Pages: 178-186

    • DOI

      10.1111/dgd.12711

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 再生医療におけるHLA欠失細胞のin vivo免疫原性試験用のNK細胞を含む免疫系ヒト化マウスの確立2023

    • Author(s)
      杉本直志, Charlotte Flahou, 森嶋達也, 東奈津美, 徐淮耕, 王博, 金子新, 堀田秋津, 滝澤仁, 江藤浩之
    • Organizer
      第23回日本再生医療学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Elucidating the immune escape mechanisms of HLA-KO iPSC-platelets from NK cells2022

    • Author(s)
      Charlotte Flahou
    • Organizer
      第19回幹細胞シンポジウム
    • Related Report
      2022 Research-status Report
  • [Presentation] Immune escape of HLA-KO iPSC-platelets from Natural Killer cells2022

    • Author(s)
      Charlotte Flahou
    • Organizer
      30th Congress of the International Society on Thrombosis and Haemostasis (ISTH)
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Developing in vivo preclinical models using human NK cell reconstituted mice for allogeneic regenerative medicine2022

    • Author(s)
      杉本直志
    • Organizer
      6th International Workshop on Humanized Mice
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Mechanisms of HLA-KO iPSC-platelets immune escape from NK cells2022

    • Author(s)
      Charlotte Flahou
    • Organizer
      第84回日本血液学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] Establishment of human immune system mice for evaluation of rejection of HLA-depleted cells in regenerative medicine2022

    • Author(s)
      杉本直志
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] HLA-KO iPSC-platelets immune escape from NK cells2022

    • Author(s)
      杉本直志
    • Organizer
      Cell Symposium: Advances in Therapeutic Applications of Stem Cells
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] iPS細胞技術を用いた血小板製造と動脈硬化研究への応用の可能性2021

    • Author(s)
      杉本直志
    • Organizer
      第53回日本動脈硬化学会学術集会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] The first-in-human clinical trial of iPSC-derived platelets (iPLAT1): Autologous transfusion to an aplastic anemia patient with alloimmune platelet transfusion refractoriness2021

    • Author(s)
      Naoshi Sugimoto
    • Organizer
      63rd Annual Meeting of the American Society of Hematology
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Book] ゲノム編集技術を応用した製品開発とその実用化(9節)2021

    • Author(s)
      執筆者:96名、技術情報協会
    • Total Pages
      602
    • Publisher
      技術情報協会
    • ISBN
      9784861048272
    • Related Report
      2021 Research-status Report

URL: 

Published: 2021-04-28   Modified: 2025-01-30  

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