Introduction of precision medicine in renal transplantation: attempt to overcome HLA mismatch by TCR/BCR control
| Project/Area Number |
18K19593
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
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| Research Institution | Aichi Medical University |
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Principal Investigator |
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| 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)
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| Project Period (FY) |
2018-06-29 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| 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)
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| 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 |
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| 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.
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| 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。
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Report
(3 results)
Research Products
(25 results)
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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