Tolerance Induction in Organ Transplantation by Myeloid-Derived Suppressor Cells through Recruitment of Regulatory T and B cells

• Project/Area Number: 19K18066
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: NAKAMURA TSUKASA 京都府立医科大学, 医学(系)研究科(研究院), 講師 (30777959)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 臓器移植 / 骨髄由来免疫抑制細胞 / 免疫寛容 / 制御性T細胞 / 制御性B細胞 / 免疫寛容誘導 / 骨髄由来抑制細胞 / MDSCs

Outline of Research at the Start

臓器移植領域において細胞性拒絶は免疫抑制剤の発展とともに良好に制御が可能となっている。しかし、特に抗体関連拒絶については現在でも制御は不十分であり臨床臓器移植において長期生着を阻む最大の問題となっており、その制御が非常に重要な課題となっている。骨髄由来抑制細胞　Myeloid-derived suppressor cells (MDSCs)は制御性T細胞(Tregs)、制
御性B細胞(Bregs)を誘導する能力を有し、臓器移植において制御不十分な拒絶反応に重要な役割を果たす可能性がある。
本研究ではMDSCsのBregs/Tregs誘導効果による免疫寛容誘導法を考案する。

Outline of Final Research Achievements

Myeloid-derived suppressor cells (MDSCs) are heterogenous myeloid-origin population which potentially suppresses immunological rejection in the field of transplantation.
A recipient C3H mouse received a cardiac graft from a Balb/C mouse. In the untreated group, both class I and II DSA production in serum were confirmed on post-operative days (POD) 10. Upon POD 10, Intra-graft class I DSA deposition was clearly observed, whilst class II DSA started to accumulate. On the other hand, monocytic MDSCs (Ly6G-/Ly6C+/CD11b+) were isolated from the spleens of rapamycin-treated C3H recipient mice on POD 7. These MDSCs were transferred just before reperfusion and on POD 2. As a result, the indices of both class I and II DSA in serum were significantly lower on POD 10. Subsequent intra-graft DSA deposition was also notably suppressed. Taken together, the transfer of MDSCs may postpone DSA production. Consequently, the graft survival was prolonged (8.1±0.9 vs. 24.1±3.8)

Academic Significance and Societal Importance of the Research Achievements

臓器移植において拒絶反応の制御は最重要課題の一つである。免疫調節能を持つ細胞として制御性T細胞が従来から注目されているが、単独効果での免疫寛容誘導は種々の報告からも難しい可能性がある。一方、近年免疫抑制効果を持つ、MDSCsが免疫抑制、寛容誘導に重要な役割を担っている可能性がある。本研究成果はMDCSsが臓器移植において抗体産生を抑制することを明らかにし、その結果、移植臓器生存期間の延長につながることを示唆した。既存報告と併せ、MDSCsは細胞性拒絶反応、抗体関連型拒絶反応共に制御することを示した。今後、臨床での免疫抑制剤の減量、拒絶反応の治療、また免疫寛容誘導への応用が期待される。

Research Products

• [Journal Article] Intra Liver Allograft C3d Binding Donor Specific anti HLA Antibodies Predict Rejection After Liver Transplantation. (2022)
  • Author(s): Nakamura, T., Shirouzu, T., Kawai, S., Sugimoto, R., Harada, S., Yoshikawa, M. et al.
  • Journal Title: Transplantation Proceedings Volume: 54 Issue: 2 Pages: 450-453
  • DOI: 10.1016/j.transproceed.2021.08.065
  • Peer Reviewed
• [Journal Article] Single vs Multiple Artery Reconstruction in Living Donor Liver Transplantation. (2022)
  • Author(s): Nakamura, T., Nobori, S, Harada, S.,Sugimoto, R., Yoshikawa, M., Ushigome, H., et al.
  • Journal Title: Transplantation Proceedings Volume: 54 Issue: 2 Pages: 399-402
  • DOI: 10.1016/j.transproceed.2021.08.069
  • Peer Reviewed
• [Journal Article] The impact of the donors and the recipients age on the outcomes of living-donor liver transplantation. (2022)
  • Author(s): Nakamura, T., Nobori, S, Harada, S.,Sugimoto, R., Yoshikawa, M., Ushigome, H., et al.
  • Journal Title: Transplantation Proceedings Volume: 54 Issue: 2 Pages: 438-442
  • DOI: 10.1016/j.transproceed.2021.08.068
  • Peer Reviewed
• [Journal Article] The Abundance of Anti-Galactose-deficient IgA1 Autoantibodies Results in Glomerular Deposition and IgA Nephropathy Recurrence after Renal Transplantation (2021)
  • Author(s): Nakamura, T., Shirouzu, T., Harada, S., Sugimoto, R., Nobori, S., Yoshikawa, M. et al.
  • Journal Title: Transplantation Volume: 105 Issue: 12 Pages: 407-408
  • DOI: 10.1097/tp.0000000000003879
  • Peer Reviewed
• [Journal Article] 臓器移植における骨髄由来免疫抑制細胞の役割 (2020)
  • Author(s): 中村緑佐
  • Journal Title: BioClinica Volume: 35 Pages: 61-64
  • Peer Reviewed
• [Journal Article] The Role of Major Histocompatibility Complex in Organ Transplantation - Donor Specific Anti-Major Histocompatibility Complex Antibodies Analysis Goes to the Next Stage - (2019)
  • Author(s): Nakamura, T., Shirouzu, T., Nakata, K., Yoshimura, N., Ushigome, H.
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 18 Pages: 4544-4565
  • DOI: 10.3390/ijms20184544
  • Peer Reviewed / Open Access
• [Journal Article] Graft Immunocomplex capture fluorescence analysis can detect intra-graft anti MHC antibodies in mice cardiac transplantation. (2019)
  • Author(s): Nakamura, T., Shirouzu, T., Kawai, S., Matsuyama, T., Harada, S., Nobori, S., et al.
  • Journal Title: Transplant Proceedings Volume: 51 Issue: 5 Pages: 1531-1535
  • DOI: 10.1016/j.transproceed.2019.01.114
  • Peer Reviewed
• [Journal Article] Detection of Intra-Graft Anti-Blood Group A/B Antibodies following Renal Transplantation. (2019)
  • Author(s): Nakamura, T., Shirouzu, T., Kawai, S., Imanishi, Y., Matsuyama, T., Harada, S. et al.
  • Journal Title: Transplant Proceedings Volume: 51 Issue: 5 Pages: 1371-1377
  • DOI: 10.1016/j.transproceed.2019.01.128
  • Peer Reviewed
• [Journal Article] Clearance of Intra-graft Donor Specific Anti-HLA Antibodies in the Early Stage of Antibody-Mediated Rejection following Rituximab and Apheresis Therapy in Renal Transplantation. (2019)
  • Author(s): Nakamura, T., Yoshimura, N., Akioka, K., Shirouzu, T., Kawai, S., Imanishi, Y. et al.
  • Journal Title: Transplant Proceedings Volume: 51 Issue: 5 Pages: 1365-1370
  • DOI: 10.1016/j.transproceed.2019.01.126
  • Peer Reviewed
• [Presentation] Intra Liver Allograft C3d Binding Donor Specific anti HLA Antibodies Predict Rejection After Liver Transplantation. (2021)
  • Author(s): Nakamura, T., Shirouzu, T., Kawai, S., Sugimoto, R., Harada, S., Yoshikawa, M. et al.
  • Organizer: Congress of the Asian Society for Transplantation
  • Int'l Joint Research
• [Presentation] Single vs Multiple Artery Reconstruction in Living Donor Liver Transplantation. (2021)
  • Author(s): Nakamura, T., Nobori, S, Harada, S.,Sugimoto, R., Yoshikawa, M., Ushigome, H.
  • Organizer: Congress of the Asian Society for Transplantation
  • Int'l Joint Research
• [Presentation] The impact of the donors and the recipients age on the outcomes of living-donor liver transplantation. (2021)
  • Author(s): Nakamura, T., Nobori, S, Harada, S.,Sugimoto, R., Yoshikawa, M., Ushigome, H.
  • Organizer: Congress of the Asian Society for Transplantation
  • Int'l Joint Research
• [Presentation] The Index of Intra-graft Donor Specific Anti-HLA Antibodies Predicts Responsiveness to Rejection Therapies. (2020)
  • Author(s): Tsukasa Nakamura
  • Organizer: American Society for Histocompatibility & Immunogenetics
  • Int'l Joint Research
• [Presentation] グラフトICFA法によるグラフト内ドナー特異的抗HLA抗体検出の有用性 (2019)
  • Author(s): 中村緑佐
  • Organizer: 日本移植学会総会
  • Invited
• [Presentation] DSAに対する新たな取り組み～血清DSAからグラフト内DSA検出へ～ (2019)
  • Author(s): 中村緑佐
  • Organizer: 腎移植血管外科研究会
  • Invited