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Induction of persistent lung transplant tolerance by IL-2 complex-stimulated regulatory T cells: a study for the clinical application

Research Project

Project/Area Number 18K08778
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 55040:Respiratory surgery-related
Research InstitutionKyoto University

Principal Investigator

Yamada Yoshito  京都大学, 医学研究科, 特定病院助教 (80375691)

Co-Investigator(Kenkyū-buntansha) 吉野 一郎  千葉大学, 大学院医学研究院, 教授 (40281547)
本橋 新一郎  千葉大学, 大学院医学研究院, 教授 (60345022)
鈴木 秀海  千葉大学, 医学部附属病院, 講師 (60422226)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords肺移植術後拒絶反応 / IL-2複合体 / 制御性T細胞 / 三次リンパ構造 / 慢性期肺移植片機能不全 / 肺移植後急性拒絶反応 / 遺伝子導入マウス / マウス肺移植 / 急性拒絶反応 / 慢性拒絶反応
Outline of Final Research Achievements

Using targeted interleukin-2 (IL-2) pre-treatment in fully immunocompetent mice, we here achieved acceptance of fully mismatched lung allografts that remained functional for >90 days. These tolerogenic effects were controlled by graft-homing forkhead box p3 (Foxp3)+ regulatory T (Treg) cells. Thus, although circulating Treg cell counts rapidly returned to baseline following IL-2 pre-treatment, Foxp3+ Treg cells persisted in peribronchial areas of the grafted lung, forming bronchus-associated lymphoid tissues (BALT). Foxp3-transgenic mice with inducible deletion of Foxp3+ cells were unable to form organized BALT containing Foxp3+ Treg cells, as evidenced using microscopy-based calculation of ordered distribution, and these mice acutely rejected their lung allografts. Collectively, we report a high-intensity and biased IL-2 pre-conditioning able to induce Foxp3-controlled BALT to facilitate acceptance of vascularized and ventilated lung allografts without the need of immunosuppression.

Academic Significance and Societal Importance of the Research Achievements

肺移植は末期呼吸器疾患に対する治療手段の一つである。1998年の本邦初症例以来、症例数は増加しており、一般呼吸器外科診療の一つとなった。一方で、肺移植術後慢性期の術後成績は長年停滞傾向となっている。本研究ではIL-2複合体によりマウス肺移植実験で長期に渡ってグラフト保護効果を示した。本法を用いた免疫制御法で、臨床肺移植で課題となっている慢性期免疫抑制治療戦略を改善できると考える。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (6 results)

All 2019 2018

All Journal Article (3 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 3 results) Presentation (3 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] T Helper Cell Subsets in Experimental Lung Allograft Rejection2019

    • Author(s)
      Yamada Yoshito、Br?stle Karina、Jungraithmayr Wolfgang
    • Journal Title

      Journal of Surgical Research

      Volume: 233 Pages: 74-81

    • DOI

      10.1016/j.jss.2018.07.073

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Magnetisation transfer as a biomarker for chronic airway fibrosis in a mouse lung transplantation model2018

    • Author(s)
      Kenkel David、Yamada Yoshito、Weiger Markus、Wurnig Moritz C.、Jungraithmayr Wolfgang、Boss Andreas
    • Journal Title

      European Radiology Experimental

      Volume: 2 Issue: 1

    • DOI

      10.1186/s41747-017-0032-3

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Impact of human leukocyte antigen mismatch on lung transplant outcome†2018

    • Author(s)
      Yamada Yoshito、Langner Tim、Inci Ilhan、Benden Christian、Schuurmans Mac?、Weder Walter、Jungraithmayr Wolfgang
    • Journal Title

      Interactive CardioVascular and Thoracic Surgery

      Volume: 26 Issue: 5 Pages: 859-864

    • DOI

      10.1093/icvts/ivx412

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] IL-2複合体によるマウス肺移植後免疫寛容の誘導における制御性T細胞の役割2018

    • Author(s)
      山田義人、海寳大輔、椎名裕樹、畑敦、坂入祐一、田村創、藤原大樹、和田啓伸、中島崇裕、鈴木秀海、千代雅子、Walter Weder、Onur Boyman、Wolfgang Jungraithmayr、吉野一郎
    • Organizer
      第35回日本呼吸器外科学会
    • Related Report
      2018 Research-status Report
  • [Presentation] 肺移植後拒絶の克服 ―臨床応用への「死の谷」を超えるため2018

    • Author(s)
      山田義人、Wolfgang Jungraithmayr、吉野一郎
    • Organizer
      第35回日本呼吸器外科学会
    • Related Report
      2018 Research-status Report
  • [Presentation] Regulatory T cells on persistent tolerance stimulated by IL-2 complex in mouse lung transplant2018

    • Author(s)
      Yoshito Yamada, Daniela Impellizzieri, Jae-Hwi Jang, Tony Nguyen, Ufuk Karakus, Ilhan Inci, Ichiro Yoshino, Christian Benden, Walter Weder, Wolfgang Jungraithmayr, Onur Boyman
    • Organizer
      The 38th Annual Meeting & Scientific Sessions of the international society for heart and lung transplantation
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2022-01-27  

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