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Introduction of precision medicine in renal transplantation: attempt to overcome HLA mismatch by TCR/BCR control

Research Project

Project/Area Number 18K19593
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
Research InstitutionAichi Medical University

Principal Investigator

Kobayashi Takaaki  愛知医科大学, 医学部, 教授 (70314010)

Co-Investigator(Kenkyū-buntansha) 岩崎 研太  愛知医科大学, 医学部, 准教授 (10508881)
三輪 祐子  愛知医科大学, 医学部, 助教 (90572941)
Project Period (FY) 2018-06-29 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2018: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Keywords移植・再生医療 / 抗体関連型拒絶反応 / T細胞受容体 / ドナー特異的HLA抗体 / レパトア解析 / 個別化医療 / ドナー特異的HLA抗体 / 腎移植
Outline of Final Research Achievements

HLA mismatches cannot be avoided in kidney transplantation. To control chronic antibody-mediated rejection (ABMR) caused by donor specific HLA antibody (DSA) after kidney transplantation, our attention has been directed towards T cell receptor (TCR) and B cell receptor (BCR). Analysis of PBMC mRNA from recipients with de novo DSA showed the specific trend in TCR beta, but not in TCR alpha or BCR. Candidates for TCR beta which might be involved in de novo DSA production have been identified. In vitro assay which can analyze indirect recognition pathway of CD4+ T cells was developed. We detected human CD45+ cells and IgG (IgM) in blood circulation using humanized (NSG) mice model. In silico analysis of T cell epitopes for over 700 renal transplant recipients revealed usefulness in de novo DSA risk prediction.
To develop early diagnosis and effective avoidance of chronic ABMR, theoretical rationale and feasibility of TCR-targeted research have been demonstrated.

Academic Significance and Societal Importance of the Research Achievements

わが国では慢性腎臓病の患者数は1300万人以上と推定され、年間4万人以上が末期腎不全となり、血液透析、腹膜透析、腎移植の腎代替療法を受けている。腎移植は末期腎不全に対する最良の治療とされているが、腎代替療法の中でわずか2-3%程度であり、ドナー不足問題とともに長期成績のさらなる改善が課題となっている。本研究では、次世代シークセンスなどの最新技術を用い、免疫応答の第一歩であるT細胞受容体に着目し、1兆種類以上ある多様性から関連のある受容体を特定することができた。慢性拒絶反応に関わるドナーHLAに対する抗体産生を予防し、効率的に回避するための研究アプローチの妥当性を明らかにした。

Report

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

    (25 results)

All 2020 2019 2018 Other

All Int'l Joint Research (4 results) Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (19 results) (of which Int'l Joint Research: 6 results,  Invited: 1 results)

  • [Int'l Joint Research] Matthias Niemann/PIRCHE AG(ドイツ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Eric Spierings/UMC Utrecht(オランダ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Mattias Niemann/PIRCHE AG(ドイツ)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] Kirsten Geneugelijk, Eric Spierings/UMC Utrecht(オランダ)

    • Related Report
      2018 Research-status Report
  • [Journal Article] Interferon-γ-induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG-CoA reductase2020

    • Author(s)
      Maenaka A, Kenta I, Ota A, Miwa Y, Ohashi W, Horimi K, Matsuoka Y, Ohnishi M, Uchida K, Kobayashi T
    • Journal Title

      FEBS Open Bio

      Volume: - Issue: 5 Pages: 927-936

    • DOI

      10.1002/2211-5463.12854

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Suppressive effect of everolimus on IL-2, IL-10, IL-21, and IFNγ levels: Implication for successful minimization of calcineurin inhibitor use in transplantation2019

    • Author(s)
      Kenta Iwasaki, Nana Kitahata, Yuko Miwa, Kazuharu Uchida, Matsuoka Yutaka, Kosei Horimi, and Takaaki Kobayashi
    • Journal Title

      Therapeutic Drug Monitoring

      Volume: Mar 29 Issue: 3 Pages: 371-375

    • DOI

      10.1097/ftd.0000000000000630

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] 愛知医科大学における抗HLA抗体モニタリングとその対応2020

    • Author(s)
      堀見孔星、岩崎研太、小林孝彰
    • Organizer
      第53回日本臨床腎移植学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 術前ドナーHLA応答性T細胞診断の重要性2020

    • Author(s)
      友杉俊英、岩崎研太、坂本慎一郎、神田亜希子、二村健太、岡田学、平光高久、後藤紀彦、鳴海俊治、渡井至彦、小林孝彰
    • Organizer
      第53回日本臨床腎移植学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ABO Incompatibility in Kidney Transplantation Can Increase a Safety Margin of Epitope Mismatch Levels against De Novo DSA Production.2019

    • Author(s)
      T. Kobayashi K. Iwasaki, M. Okada, K. Horimi, Y. Matsuoka, A. Takeda, N. Goto, S. Narumi, Y. Watarai
    • Organizer
      American Transplant Congress (ATC) 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The number of donor-HLA-derived peptides presented by recipient DRB3/4/5 and DQA1-DQB1 in kidney-transplanted recipients are independent from the number of DRB1-presented peptides.2019

    • Author(s)
      M. Niemann, K. Geneugelijk, E. Spierings, T. Tomosugi, T. Kobayashi
    • Organizer
      33rd European Immunogenetics and Histocompatibility Conference (EFI meeting)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification of immunogenic recipient HLA class II and donor-HLA-derived peptide complexes: clinical relevance to de novoo donor-specific HLA antibody formataion in kidney transplantation.2019

    • Author(s)
      T. Tomosugi, K. Iwasaki, K. Futamura, M. Okada, T. Hiramitsu, M. Tsujita, N. Goto, S. Narumi, Y. Watarai, T. Kobayashi, M. Niemann, E. Spierings
    • Organizer
      19th ESOT (European Society or Organ Transplantation)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Preventive and preemptive therapy for antibody-mediated rejection2019

    • Author(s)
      T. Kobayashi
    • Organizer
      International Symposium of Transplantation 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ドナー特異的抗体(DSA)検出に向けたヒト化マウスの作製2019

    • Author(s)
      野田貴幸、岩﨑研太、三輪祐子、小林孝彰
    • Organizer
      第28回日本組織適合性学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] de novo DSA産生に影響を及ぼす, レシピエントHLA class II・ドナーpeptideの複合体の検討2019

    • Author(s)
      友杉俊英、岩﨑研太、坂本慎太郎、神田亜希子、二村健太、岡田学、 平光高久、後藤憲彦、鳴海俊治、渡井至彦、小林孝彰、Niemann Matthias、Spierings Eric
    • Organizer
      第28回日本組織適合性学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 内皮細胞HLA-class II DRとアロ応答するPD-1+CD25+foxp3+CD4 T細胞の機能解析2019

    • Author(s)
      岩﨑研太、三輪祐子、打田和治、堀見孔星、松岡裕、小林孝彰
    • Organizer
      第28回日本組織適合性学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 抗体関連型拒絶反応抵抗性獲得メカニズムに関する研究2019

    • Author(s)
      岩﨑研太、三輪祐子、平光高久、岡田学、鳴海俊治、渡井至彦、武田朝美、堀見孔星、松岡裕、友杉俊英、奥村真衣、野田貴幸、前仲亮宏、打田和治、小林孝彰
    • Organizer
      第55回日本移植学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] PIRCHE によるドナーHLA 応答性T 細胞の術前診断2019

    • Author(s)
      友杉俊英、岩﨑研太、坂本慎太郎、縄野貴明、神田亜希子、福原宏樹、二村健太、岡田学、平光高久、後藤憲彦、鳴海俊治、渡井至彦、小林孝彰
    • Organizer
      第55回日本移植学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] de novo DSA によるABMR 抑制のためのグラフトHLA 発現制御2019

    • Author(s)
      前仲亮宏、岩崎研太、三輪祐子、堀見孔星、松岡祐、打田和治、大西正文、小林孝彰
    • Organizer
      第55回日本移植学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Searching for Recipient-HLA Class II and Donor-HLA-Derived Peptide Complexes Inducing Protective Effect against De Novo Donor- Specific HLA Antibodies Formation in Kidney Transplantation.2018

    • Author(s)
      T. Tomosugi, K. Iwasaki, M. Okumura, Y. Matsuoka, K. Horimi, M. Okada, Y. Watarai, T. Kobayashi.
    • Organizer
      American Transplant Congress (ATC) 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Beneficial effect of ABO incompatibility on de novo DSA production after kidney transplantation2018

    • Author(s)
      Takaaki Kobayashi, Manabu Okada, Kenta Iwasaki, Kosei Horimi, Yutaka Matsuoka, Yuko Miwa, Kazuharu Uchida, Asami Takeda, Norihiko Goto, Shunji Narumi, Yoshihiko Watarai.
    • Organizer
      TTS (The Transplantation Society) 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] De novo DSA産生を抑制に導く、レシピエント・ドナーHLAの組み合わせの検討2018

    • Author(s)
      友杉俊英、岩崎研太、二村健太、岡田学、平光高久、辻田誠、後藤憲彦、鳴海俊治、渡井至彦、小林孝彰
    • Organizer
      第27回日本組織適合性学会
    • Related Report
      2018 Research-status Report
  • [Presentation] DSA産生B細胞の機能解析に向けた in vitro 培養系の確立とヒト化マウスの作製2018

    • Author(s)
      野田貴幸、岩崎研太、三輪祐子、相原祐子、河野あゆみ、斎藤寛子、小林孝彰
    • Organizer
      第27回日本組織適合性学会
    • Related Report
      2018 Research-status Report
  • [Presentation] De novo DSA 抗体産生抑制に関与し得るHLAアリルの検討2018

    • Author(s)
      友杉俊英、岩崎研太、二村健太、岡田学、辻田誠、平光高久、後藤憲彦、一森敏弘、鳴海俊治、渡井至彦、小林孝彰
    • Organizer
      第54回日本移植学会
    • Related Report
      2018 Research-status Report
  • [Presentation] DSA産生B細胞の機能解析のための in vitro 培養系とヒト化マウスの作製2018

    • Author(s)
      野田貴幸、岩崎研太、三輪祐子、相原祐子、河野あゆみ、斎藤寛子、小林孝彰
    • Organizer
      第54回日本移植学会
    • Related Report
      2018 Research-status Report
  • [Presentation] TCRを標的としたドナー特異的応答性T細胞のモニタリングの構築2018

    • Author(s)
      岩崎研太、三輪祐子、相原祐子、河野あゆみ、堀見孔星、松岡裕、友杉俊英、奥村真衣、打田和治、小林孝彰
    • Organizer
      第54回日本移植学会
    • Related Report
      2018 Research-status Report

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Published: 2018-07-25   Modified: 2021-02-19  

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