急性移植片対宿主病における腸内真菌叢の役割の解明

2020 Fiscal Year Research-status Report

• Project/Area Number: 20K08748
• Research Institution: The University of Tokyo
• Principal Investigator: 小沼 貴晶 東京大学, 医科学研究所, 助教 (00709553)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 同種造血細胞移植 / 腸内真菌叢 / 腸内細菌叢 / 移植片対宿主病 / 免疫再構築

Outline of Annual Research Achievements

本研究では、高度免疫抑制状態かつ広域抗菌剤や抗真菌剤の投与を要する同種造血細胞移植において、ダイナミックな腸内真菌叢の変動が全身の免疫担当細胞に与える影響と、それが移植片対宿主病の発症にどのような役割を果たしているのかを解明することで、同種造血細胞移植における腸内真菌叢変容の意義を明らかにすることを目的としている。
初年度は、同種造血細胞移植症例の38例の糞便サンプルを収集して、最初に腸内細菌叢が免疫再構築に及ぼす影響を評価した。臍帯血移植後１ヶ月の腸内細菌叢は、その後の末梢血の単球および樹状細胞の再構築に影響することを明らかにした (Biol Blood Marrow Transplant. 2020 Nov;26(11):e292-e297)。これと並行して、腸内真菌叢を評価する系を確立するための予備検討を行なった。糞便サンプルから全真菌DNAを抽出して、ITS1の保存領域に設計したユニバーサルプライマーを用いて、PCRを行い、それぞれのPCR産物を混合し、次世代シークエンサーを用いて解析を行い、腸内真菌プロファイルを作成した。それらを用いて包括的な腸内真菌叢のクラスター解析を行った。これらのサンプルおよび実験系を用いることで、腸内真菌叢の評価が可能であることが確認できた。同時に、末梢血のCD4+T細胞、CD8+T細胞、FOXP3+制御性T細胞、CD3+TCRVα24Jα18+のiNKT細胞、γδT細胞、自然リンパ球(innate lymphoid cells: ILCs)、粘膜関連T(MAIT)細胞、CD19+B細胞、CD56+NK細胞、単球、樹状細胞の絶対数や白血球における割合を、各々の症例で検討している。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

初年度として、適切に研究が遂行可能であることを確認した。

Strategy for Future Research Activity

今後は、同種造血細胞移植症例の糞便サンプルを蓄積すると同時に、腸内真菌叢と、1) 腸内細菌叢との関連、2) 末梢血各白血球サブセットとの関連、3) 移植後合併症との関連を明らかにするために、さらなる研究を進めていく予定である。

Causes of Carryover

その他、17936円の繰越額が発生したため、次年度使用額として計上した。

Research Products

• [Journal Article] Single cord blood transplantation for acute myeloid leukemia patients aged 60 years or older: a retrospective study in Japan (2021)
  • Author(s): Isobe Masamichi、Konuma Takaaki、Masuko Masayoshi、Uchida Naoyuki、Miyakoshi Shigesaburo、Sugio Yasuhiro、Yoshida Shuro、Tanaka Masatsugu、Matsuhashi Yoshiko、Hattori Norimichi、Onizuka Makoto、Aotsuka Nobuyuki、Kouzai Yasushi、Wake Atsushi、Kimura Takafumi、Ichinohe Tatsuo、Atsuta Yoshiko、Yanada Masamitsu
  • Journal Title: Annals of Hematology Volume: － Pages: －
  • DOI: 10.1007/s00277-021-04464-5.
  • Peer Reviewed
• [Journal Article] Early-Phase Peripheral Blood Eosinophilia Predicts Lower Overall and Non-Relapse Mortality After Single-Unit Cord Blood Transplantation (2021)
  • Author(s): Konuma T, Monna-Oiwa M, Kaito Y, Isobe M, Okabe M, Kato S, Takahashi S, Tojo A.
  • Journal Title: Transplant Cell Ther. Volume: 27(4) Pages: 336e1-336e9
  • DOI: 10.1016/j.jtct.2021.01.027.
  • Peer Reviewed
• [Journal Article] Single Cord Blood Transplantation Versus Unmanipulated Haploidentical Transplantation for Adults with Acute Myeloid Leukemia in Complete Remission. (2021)
  • Author(s): Konuma T, Kanda J, Yamasaki S, Harada K, Shimomura Y, Terakura S, Mizuno S, Uchida N, Tanaka M, Doki N, Ozawa Y, Nakamae H, Sawa M, Matsuoka KI, Morishige S, Maruyama Y, Ikegame K, Kimura T, Kanda Y, Ichinohe T, Atsuta Y, Yanada M.
  • Journal Title: Transplant Cell Ther. Volume: 27(4) Pages: 334.e1-334.e11.
  • DOI: 10.1016/j.jtct.2021.01.023.
  • Peer Reviewed
• [Journal Article] Prognostic Impact of the Fractionation of Total Body Irradiation for Patients with Acute Myeloid Leukemia Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation. (2021)
  • Author(s): Ueda N, Konuma T, Aoki J, Takahashi S, Ozawa Y, Mori T, Ota S, Eto T, Takada S, Yoshioka S, Shiratori S, Kako S, Onizuka M, Fukuda T, Kanda Y, Atsuta Y, Yanada M.
  • Journal Title: Transplant Cell Ther. Volume: 27(2) Pages: 185.e1-185.e6.
  • DOI: 10.1016/j.jtct.2020.10.018.
  • Peer Reviewed
• [Journal Article] Lower vancomycin trough levels in adults undergoing unrelated cord blood transplantation. (2021)
  • Author(s): Yasu T, Konuma T, Oiwa-Monna M, Kato S, Isobe M, Takahashi S, Tojo A.
  • Journal Title: Leuk Lymphoma. Volume: 62(2) Pages: 348-357.
  • DOI: 10.1080/10428194.2020.1834096.
  • Peer Reviewed
• [Journal Article] Predicting non-relapse mortality following allogeneic hematopoietic cell transplantation during first remission of acute myeloid leukemia. (2021)
  • Author(s): Yanada M, Konuma T, Mizuno S, Saburi M, Shinohara A, Tanaka M, Marumo A, Sawa M, Uchida N, Ozawa Y, Onizuka M, Yoshioka S, Nakamae H, Kondo T, Kimura T, Kanda J, Fukuda T, Atsuta Y, Nakasone H, Yano S.
  • Journal Title: Bone Marrow Transplant. Volume: 56(2) Pages: 387-394.
  • DOI: 10.1038/s41409-020-01032-9.
  • Peer Reviewed
• [Journal Article] Effect of polymorphism in base excision repair genes on outcomes in adults following myeloablative single-unit cord blood transplantation. (2021)
  • Author(s): Konuma T, Oiwa-Monna M, Isobe M, Kato S, Yokoyama K, Yusa N, Takahashi S, Tojo A.
  • Journal Title: Leuk Lymphoma. Volume: 62(4) Pages: 1019-1021
  • DOI: 10.1080/10428194.2019.1683738.
  • Peer Reviewed
• [Journal Article] Hematopoietic cell transplantation in adults with acute myeloid leukemia: A review of the results from various nationwide registry studies in Japan (2021)
  • Author(s): Yasuyuki Arai, Takaaki Konuma, Masamitsu Yanada
  • Journal Title: Blood Cell Therapy Volume: In press Pages: In press
  • DOI: 10.31547/bct-2020-023
  • Peer Reviewed
• [Journal Article] Impact of a prior history of cancer on prognosis after myeloablative single-unit cord blood transplantation (2020)
  • Author(s): Okabe Motohito、Konuma Takaaki、Oiwa-Monna Maki、Kato Seiko、Isobe Masamichi、Takahashi Satoshi、Tojo Arinobu
  • Journal Title: Japanese Journal of Clinical Oncology Volume: 51 Pages: 657～660
  • DOI: 10.1093/jjco/hyaa250.
  • Peer Reviewed
• [Journal Article] Relapse of acute myeloid leukemia after allogeneic hematopoietic cell transplantation: clinical features and outcomes. (2020)
  • Author(s): Yanada M, Konuma T, Yamasaki S, Kondo T, Fukuda T, Shingai N, Sawa M, Ozawa Y, Tanaka M, Uchida N, Nakamae H, Katayama Y, Matsuoka KI, Kimura T, Kanda Y, Ichinohe T, Atsuta Y, Yano S.
  • Journal Title: Bone Marrow Transplant. Volume: In press Pages: In press
  • DOI: 10.1038/s41409-020-01163-z.
  • Peer Reviewed
• [Journal Article] Randomised controlled trial of conditioning regimen for cord blood transplantation for adult myeloid malignancies comparing high-dose cytarabine/cyclophosphamide/total body irradiation with versus without G-CSF priming: G-CONCORD study protocol. (2020)
  • Author(s): Terakura S, Konuma T, Tanaka M, Ozawa Y, Onizuka M, Nanno S, Onishi Y, Aotsuka N, Kondo T, Kawakita T, Kato J, Kobayashi T, Nishida T, Yamaguchi T, Kuwatsuka Y, Takahashi S.
  • Journal Title: BMJ Open. Volume: 10(12) Pages: e040467.
  • DOI: 10.1136/bmjopen-2020-040467.
  • Peer Reviewed
• [Journal Article] High Prevalence of Left Ventricular Non-Compaction and Its Effect on Chemotherapy-Related Cardiac Dysfunction in Patients With Hematological Diseases. (2020)
  • Author(s): Hirano M, Kimura K, Ishigaki T, Nojima M, Daimon M, Morita H, Takenaka K, Xu B, Sawada N, Hirokawa M, Komuro I, Morisaki T, Yotsuyanagi H, Kawamata T, Yokoyama K, Konuma T, Kato S, Yasui H, Nagamura-Inoue T, Uchimaru K, Takahashi S, Imai Y, Tojo A.
  • Journal Title: Circ J. Volume: 84(11) Pages: 1957-1964.
  • DOI: 10.1253/circj.CJ-20-0344.
  • Peer Reviewed
• [Journal Article] Effects of Acute and Chronic Graft-versus-myelodysplastic Syndrome on Long-term Outcomes Following Allogeneic Hematopoietic Cell Transplantation. (2020)
  • Author(s): Konuma T, Ishiyama K, Igarashi A, Uchida N, Ozawa Y, Fukuda T, Ueda Y, Matsuoka KI, Mori T, Katayama Y, Onizuka M, Ichinohe T, Atsuta Y
  • Journal Title: Clin Cancer Res. Volume: 26(24) Pages: 6483-6493.
  • DOI: 10.1158/1078-0432.CCR-20-1104.
  • Peer Reviewed
• [Journal Article] Impact of Intestinal Microbiota on Reconstitution of Circulating Monocyte, Dendritic Cell, and Natural Killer Cell Subsets in Adults Undergoing Single-Unit Cord Blood Transplantation. (2020)
  • Author(s): Konuma T, Kohara C, Watanabe E, Takahashi S, Ozawa G, Inomata K, Suzuki K, Mizukami M, Nagai E, Okabe M, Isobe M, Kato S, Oiwa-Monna M, Takahashi S, Tojo A.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 26(11) Pages: e292-e297.
  • DOI: 10.1016/j.bbmt.2020.08.009.
  • Peer Reviewed
• [Journal Article] Updated Comparison of 7/8 HLA Allele-Matched Unrelated Bone Marrow Transplantation and Single-Unit Umbilical Cord Blood Transplantation as Alternative Donors in Adults with Acute Leukemia. (2020)
  • Author(s): Miyao K, Terakura S, Kimura F, Konuma T, Miyamura K, Yanada M, Kako S, Morhishima S, Uchida N, Toya T, Ozawa Y, Fukuda T, Tanaka M, Sawa M, Takada S, Yoshida S, Kimura T, Ichinohe T, Atsuta Y, Kanda J
  • Journal Title: Biol Blood Marrow Transplant. Volume: 26(11) Pages: 2105-2114.
  • DOI: 10.1016/j.bbmt.2020.08.001.
  • Peer Reviewed
• [Journal Article] Disseminated Tuberculosis with Cholecystitis in a Patient after Cord Blood Transplantation. (2020)
  • Author(s): Konuma T, Isobe M, Adachi E, Kato S, Takahashi S, Yotsuyanagi H, Tojo A.
  • Journal Title: Intern Med. Volume: 59(21) Pages: 2769-2771.
  • DOI: 10.2169/internalmedicine.4923-20.
  • Peer Reviewed
• [Journal Article] Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia conducted in Japan during the past quarter century. (2020)
  • Author(s): Yanada M, Takami A, Yamasaki S, Arai Y, Konuma T, Uchida N, Najima Y, Fukuda T, Tanaka M, Ozawa Y, Ikegame K, Takanashi M, Ichinohe T, Okamoto S, Atsuta Y, Yano S.
  • Journal Title: Ann Hematol. Volume: 99(6) Pages: 1351-1360.
  • DOI: 10.1007/s00277-020-04051-0.
  • Peer Reviewed
• [Journal Article] Clinical outcomes of persistent colonization with multidrug-resistant Gram-negative rods in adult patients undergoing single cord blood transplantation. (2020)
  • Author(s): Mizusawa M, Konuma T, Kato S, Isobe M, Shibata H, Suzuki M, Takahashi O, Oiwa-Monna M, Takahashi S, Tojo A.
  • Journal Title: Int J Hematol. Volume: 111(6) Pages: 858-868.
  • DOI: 10.1007/s12185-020-02854-5.
  • Peer Reviewed
• [Journal Article] Telomere length in CD4+ and CD8+ T cells among long-term survivors of adults after single cord blood transplantation. (2020)
  • Author(s): Jimbo K, Konuma T, Mizukami M, Nagai E, Oiwa-Monna M, Isobe M, Kato S, Takahashi S, Tojo A.
  • Journal Title: Eur J Haematol. Volume: 104(5) Pages: 509-511.
  • DOI: 10.1111/ejh.13385.
  • Peer Reviewed
• [Journal Article] Reconstitution of Circulating Mucosal-Associated Invariant T Cells after Allogeneic Hematopoietic Cell Transplantation: Its Association with the Riboflavin Synthetic Pathway of Gut Microbiota in Cord Blood Transplant Recipients. (2020)
  • Author(s): Konuma T, Kohara C, Watanabe E, Takahashi S, Ozawa G, Suzuki K, Mizukami M, Nagai E, Jimbo K, Kaito Y, Isobe M, Kato S, Takahashi S, Chiba A, Miyake S, Tojo A.
  • Journal Title: J Immunol. Volume: 204(6) Pages: 1462-1473.
  • DOI: 10.4049/jimmunol.1900681.
  • Peer Reviewed
• [Journal Article] Improvement of early mortality in single-unit cord blood transplantation for Japanese adults from 1998 to 2017. (2020)
  • Author(s): Konuma T, Kanda J, Inamoto Y, Hayashi H, Kobayashi S, Uchida N, Sugio Y, Tanaka M, Kobayashi H, Kouzai Y, Takahashi S, Eto T, Mukae J, Matsuhashi Y, Fukuda T, Takanashi M, Kanda Y, Atsuta Y, Kimura F.
  • Journal Title: Am J Hematol. Volume: 95(4) Pages: 343-353.
  • DOI: 10.1002/ajh.25705.
  • Peer Reviewed
• [Journal Article] Candida colonization is associated with severe acute GVHD in adult patients undergoing single-unit cord blood transplantation. (2020)
  • Author(s): Konuma T, Mizusawa M, Suzuki M, Kaito Y, Isobe M, Kato S, Shibata H, Takahashi O, Oiwa-Monna M, Takahashi S, Tojo A.
  • Journal Title: Eur J Haematol. Volume: 104(1) Pages: 74-76.
  • DOI: 10.1111/ejh.13341.
  • Peer Reviewed
• [Presentation] 臍帯血移植の適正な移植前処置 (2021)
  • Author(s): 小沼 貴晶
  • Organizer: 第43回日本造血細胞移植学会総会
  • Invited
• [Presentation] 臍帯血移植後の末梢血赤芽球の出現は予後に影響を与えるか? (2021)
  • Author(s): 海渡 裕太、小沼 貴晶、加藤せい子、磯部 優理、岡部 基人、大岩 真希、今井 陽一、 高橋 聡、東條 有伸
  • Organizer: 第43回日本造血細胞移植学会総会
• [Presentation] AML 患者への骨髄破壊的同種造血幹細胞移植における TBI 分割回数の予後への影響 (2021)
  • Author(s): 上田 格弘、小沼 貴晶、青木 淳、高橋 聡、小澤 幸泰、森 毅彦、 太田 秀一、衛藤 徹也、高田 覚、吉岡 聡、白鳥 聡一、賀古 真一、 福田 隆浩、鬼塚 真仁、神田 善伸、熱田 由子、柳田 正光
  • Organizer: 第43回日本造血細胞移植学会総会
• [Presentation] AML 第 1 寛解期移植における非再発死亡予測モデルの構築 (2021)
  • Author(s): 柳田 正光、小沼 貴晶、水野 昌平、佐分利益穂、篠原 明仁、田中 正嗣、 丸毛 敦史、澤 正史、内田 直之、小澤 幸泰、鬼塚 真仁、吉岡 聡、 中前 博久、近藤 忠一、木村 貴文、諫田 淳也、福田 隆浩、熱田 由子、 仲宗根秀樹、矢野 真吾
  • Organizer: 第43回日本造血細胞移植学会総会
• [Presentation] 同種造血細胞移植サバイバーにおけるネット生存率と Conditional Survival:移植レジストリ解析 (2021)
  • Author(s): 鍬塚八千代、伊藤 秀美、田渕 健、小沼 貴晶、内田 直之、土岐 典子、 小澤 幸泰、池亀 和博、福田 隆浩、一戸 辰夫、木村 文彦、諫田 淳也、 熱田 由子、松尾恵太郎
  • Organizer: 第43回日本造血細胞移植学会総会
• [Presentation] 指数関数的増幅モデルを用いた好中球回復の勢いは臍帯血移植の予後を推定する (2021)
  • Author(s): 磯部 優理、小沼 貴晶、加藤せい子、岡部 基人、大岩 真希、高橋 聡、東條 有伸
  • Organizer: 第43回日本造血細胞移植学会総会
• [Presentation] 移植前の悪性腫瘍の既往歴は臍帯血移植後の予後に影響を与えるか？ (2021)
  • Author(s): 岡部 基人、小沼 貴晶、加藤せい子、磯部 優理、大岩 真希、高橋 聡、東條 有伸
  • Organizer: 第43回日本造血細胞移植学会総会
• [Presentation] Immunoglobulin superfamily member 8 is a critical regulator for myeloid leukemia (2020)
  • Author(s): Koji Jimbo，Takaaki Konuma，Takahiro Ito，Yaeko Nakajima， Atsushi Iwama，Arinobu Tojo
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Updated comparison of outcomes of 7/8 allele matched UBMT and UCBT (2020)
  • Author(s): Kotaro Miyao，Seitaro Terakura，Fumihiko Kimura，Takaaki Konuma， Koichi Miyamura，Masamitsu Yanada，Shinichi Kako，Satoko Morishima， Naoyuki Uchida，Noriko Doki，Yukiyasu Ozawa，Takahiro Fukuda， Masatsugu Tanaka，Masashi Sawa，Satoru Takada，Tetsuya Eto， Takafumi Kimura，Tatsuo Ichinohe，Yoshiko Atsuta，Junya Kanda
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Graft-versus-leukemia effects according to donor type (2020)
  • Author(s): Konuma T，Kanda J，Kuwatsuka Y，Yanada M， Kondo T，Hirabayashi S，Kako S，Akahoshi Y， Uchida N，Doki N，Ozawa Y，Tanaka M， Eto T，Sawa M，Yoshioka S，Kimura T， Kanda Y，Fukuda T，Atsuta Y，Kimura F
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Cord blood transplantation for AML of the elderly: a retrospective study of adult AMLWG on JSHCT (2020)
  • Author(s): Isobe M, Konuma T, Masuko M, Uchida N, Miyakoshi S, Sugio Y, Yoshida S, Tanaka M, Matsuhashi Y, Hattori N, Onizuka M, Aotsuka N, Kouzai Y, Wake A, Kimura T, Ichinohe T, Atsuta Y, Yanada M
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Immunoglobulin Superfamily Member 8 Is Indispensable for Myeloid Leukemia Via Wnt/beta-Catenin Signaling Pathway (2020)
  • Author(s): Koji Jimbo, Takaaki Konuma, Takahiro Ito, Yaeko Nakajima-Takagi, Atsushi Iwama, Arinobu Tojo
  • Organizer: 62nd American Society of Hematology Annual Meeting
• [Presentation] SINGLE CORD BLOOD TRANSPLANTATION FOR ACUTE MYELOID LEUKEMIA PATIENTS AGED 60 YEARS OR OLDER: A RETROSPECTIVE STUDY OF THE JAPAN SOCIETY FOR HEMATOPOIETIC CELL TRANSPLANTATION (JSHCT) (2020)
  • Author(s): Isobe M, Konuma T, Masuko M, Uchida N, Miyakoshi S, Sugio Y, Yoshida S, Tanaka M, Matsuhashi Y, Hattori N, Onizuka M, Aotsuka N, Kouzai Y, Wake A, Kimura T, Ichinohe T, Atsuta Y, Yanada M
  • Organizer: 25th Congress of the European Hematology Association