Crosstalk between gut immunity after hematopoietic stem cell transplantation stem cell transplantation and TLR

• Project/Area Number: 19K16965
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Aichi Medical University
• Principal Investigator: UCHINO KAORI 愛知医科大学, 医学部, 講師 (70714872)
• 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: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: TLR / 造血細胞移植 / UNC93B1 / Toll様受容体 / 遺伝子多型 / 腸内細菌叢 / 同種細胞移植

Outline of Research at the Start

腸内細菌叢と同種移植転帰との関連や、糞便移植の有用性を示唆する報告はあるが、機序の解明は進んでいない。研究代表者は、国内の同種移植約千例の臨床・遺伝学的情報と、実験的検証に基づき、「腸管上皮細胞・ホスト抗原提示細胞・ドナー白血球上のTLRが、腸内細菌叢の存在下で同種移植における腸管免疫を制御し、移植の成否に決定的役割を果たす」との仮説を着想した。本研究はこの仮説を検証するものである。本研究の成果により、移植後の合併症や再発リスクを統合的に減らすことができる。同種造血（幹）細胞移植医療のブレイクスルーにとどまらず、TLRがかかわる自己免疫疾患や感染症、がん、臓器移植診療への波及効果も期待される。

Outline of Final Research Achievements

UNC93B1 is a key regulator of TLRs. We investigated the influence of the UNC93B1 single-nucleotide polymorphism (SNP) rs308328 (T>C) on transplant outcomes in a cohort of 237 patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies. The donor UNC93B1 C/C genotype was associated with a better 3-year overall survival than the donor UNC93B1 C/T or T/T genotype. An analysis of the UNC93B1 rs308328 genotype may therefore be useful for selecting the donor, estimating the prognosis, and creating therapeutic strategies after allogeneic SCT. We also analyzed the variety of guts microbiome with stool of BMT patients. However, there were no significant differences between before and after BMT. One of the reasons why we couldn’t the get the significant difference is that the number of patients who agreed this research was fewer than expected. We continue to collect the samples and analysis of guts microbiome of the BMT patients.

Academic Significance and Societal Importance of the Research Achievements

Unc 93 homolog B1 (Unc93B1)はTLR7とTLR9を核酸認識の場に運搬し、免疫応答バランスに影響する重要なタンパク質であるが、このUNC93B1が造血細胞移植後転帰に関わることを今回初めて証明した。TLR関連遺伝子がTLRの免疫応答バランスに影響している可能性があり、同種移植に適切な免疫応答バランスがそれぞれのTLRごとに存在していると考えられた。TLR関連遺伝子多型の機能や免疫構築における役割が解明できれば、ドナー選定、予後予測、合併症予防に役立つことが期待される。

Research Products

• [Journal Article] Donor UNC-93 Homolog B1 genetic polymorphism predicts survival outcomes after unrelated bone marrow transplantation. (2021)
  • Author(s): Uchino K, Vu Quang L, Mizuno S, Horio T, Yamamoto H, Hanamura I, Kodera Y, Luis Espinoza J, Onizuka M, Kashiwase K, Morishima Y, Fukuda T, Doki N, Miyamura K, Mori T, Morishita E, Nakao S, Takami A
  • Journal Title: Genes and Immunity Volume: 24 Issue: 1 Pages: 1-9
  • DOI: 10.1038/s41435-021-00122-y
  • Peer Reviewed / Open Access
• [Journal Article] Favorable prognostic phenotype in myelodysplastic syndrome with der(1;7)(q10;p10) (2020)
  • Author(s): T. Horio, E. Morishita, S. Mizuno, K. Uchino, I. , J.L. Espinoza, Y. Morishima, Y. Kodera, M. Onizuka, K. Kashiwase, T. Fukuda, N. Doki, K. Miyamura, T. Mori, S. Nakao, A. Takami.
  • Journal Title: eJHaem Volume: 1 Issue: 2 Pages: 558-562
  • DOI: 10.1002/jha2.115
  • Peer Reviewed / Open Access
• [Journal Article] Donor Heme Oxygenase-1 Promoter Gene Polymorphism Predicts Survival after Unrelated Bone Marrow Transplantation for High-Risk Patients (2020)
  • Author(s): Horio Tomohiro、Morishita Eriko、Mizuno Shohei、Uchino Kaori、Hanamura Ichiro、Espinoza J. Luis、Morishima Yasuo、Kodera Yoshihisa、Onizuka Makoto、Kashiwase Koichi、Fukuda Takahiro、Doki Noriko、Miyamura Koichi、Mori Takehiko、Nakao Shinji、Takami Akiyoshi
  • Journal Title: Cancers Volume: 12 Issue: 2 Pages: 424-437
  • DOI: 10.3390/cancers12020424
  • Peer Reviewed / Open Access
• [Journal Article] DONOR UNC-93 HOMOLOG B1 GENETIC VARIATION PREDICTS SURVIVAL OUTCOMES AFTER UNRELATED BONE MARROW TRANSPLANTATION: PF756 (2019)
  • Author(s): Kaori Uchino, Shohei Mizuno, Tomohiro Horio, Motonori Mizutani, Ichiro Hanamura, Lam Vu Quang, Yoshihisa Kodera, J. Luis Espinoza, Makoto Onizuka, Koichi Kashiwase, Yasuo Morishima, Takahiro Fukuda, Noriko Doki, Koichi Miyamura, Takehiko Mori, Eriko Morishita, Shinji Nakao, Akiyoshi Takami
  • Journal Title: HemaSphere Volume: 2 Pages: 332-332
• [Presentation] 当院での銅欠乏症患者の検討 (2020)
  • Author(s): Kaori Uchino , Megumi Enomoto, Ayano Nakamura, Satsuki Murakami, Mineaki Goto3, Shohei Mizuno, Hidesuke Yamamoto, Masao Seto, Ichiro Hanamura, Akiyoshi Takami
  • Organizer: 第21回日本検査血液学会学術集会
• [Presentation] Cytopenia associated with copper deficiency (2020)
  • Author(s): Kaori Uchino , Megumi Enomoto, Ayano Nakamura, Satsuki Murakami, Mineaki Goto3, Shohei Mizuno, Hidesuke Yamamoto, Masao Seto, Ichiro Hanamura, Akiyoshi Takami
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Donor UNC-93 homolog B1 genetic variation predicts survival outcomes after unrelated bone marrow transplantation (2019)
  • Author(s): Kaori Uchino, Shohei Mizuno, Tomohiro Horio, Motonori Mizutani, Ichiro Hanamura, Lam Vu Quang, Yoshihisa Kodera, J. Luis Espinoza, Makoto Onizuka, Koichi Kashiwase, Yasuo Morishima, Takahiro Fukuda, Noriko Doki, Koichi Miyamura, Takehiko Mori, Eriko Morishita, Shinji Nakao, Akiyoshi Takami
  • Organizer: 24th Congress of European Hematology Association
  • Int'l Joint Research
• [Presentation] 造血細胞移植におけるTLR関連遺伝子多型の重要性 (2019)
  • Author(s): 内野かおり、水野昌平、堀尾知弘、水谷元紀、中村文乃、髙杉壮一、花村一朗、Lam Vu Quang、小寺良尚、J. Luis Espinoza、鬼塚真仁、柏瀬貢一、森島泰雄、福田 隆浩、土岐典子、宮村耕一、森毅彦、森下英理子、中尾眞二、高見昭良
  • Organizer: 第28回日本組織適合性学会
• [Presentation] Howell-Jolly body predicts functional hyposplenism: visiting old, learn new (2019)
  • Author(s): Kaori Uchino , Yuuya Nakagami, Megumi Enomoto, Soichi Takasugi, Satsuki Murakami, Hiroki Watanabe, Hiroshige Mikamo, Akiyoshi Takami
  • Organizer: 第81回日本血液学会学術集会