急性移植片対宿主病における腸内真菌叢の役割の解明

2021 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, 准教授 (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

真菌の網羅的解析方法の発展に伴い、ヒト腸内真菌叢の全貌が少しずつ解明されており、腸内真菌叢の変容(dysbiosis)が炎症性腸疾患や肥満など様々な疾病で認められることが明らかとなりつつある。同種造血細胞移植の特有の合併症である移植片対宿主病では、腸内細菌叢の撹乱が関与していることが示されているが、腸内真菌叢との関連は不明である。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。
今年度も、同種造血細胞移植症例の糞便サンプルを収集して、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、次世代シークエンサーを用いて解析を行った。同時に、糞便をサンプリングした同種造血細胞移植症例の末梢血単核球を、経時的に移植後1、3、6、9、及び12か月の複数の時点でフローサイトメトリーで解析した。来年度も引き続き、症例を蓄積して、末梢血各白血球サブセット、抗菌剤や抗真菌剤投与、腸内細菌叢や移植後合併症である急性移植片対宿主病や菌血症や真菌血症と腸内真菌叢との関連を明らかにして、ヒトを対象とした前臨床試験として、マウスモデルを用いたGVHDに対する真菌プロバイオティクスや糞便真菌移植による治療法の可能性について検証する予定である。

Current Status of Research Progress

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

Reason

今年度も、適切に研究が進展している。

Strategy for Future Research Activity

同種造血細胞移植症例の糞便サンプルを蓄積し、腸内真菌叢と、腸内細菌叢との関連、末梢血各白血球サブセットとの関連、抗菌剤や抗真菌剤投与との関連、移植後合併症との関連を明らかにする予定である。

Research Products

• [Journal Article] Early prediction of neutrophil engraftment using manual leukocyte differential count after cord blood transplantation (2022)
  • Author(s): Mizukami Motoko、Konuma Takaaki、Nagai Etsuko、Monna‐Oiwa Maki、Isobe Masamichi、Kato Seiko、Takahashi Satoshi、Tojo Arinobu、Nannya Yasuhito
  • Journal Title: International Journal of Laboratory Hematology Volume: 44 Pages: e156-e159
  • DOI: 10.1111/ijlh.13803
  • Peer Reviewed
• [Journal Article] Immunoglobulin superfamily member 8 maintains myeloid leukemia stem cells through inhibition of β-catenin degradation (2022)
  • Author(s): Jimbo K, Nakajima-Takagi Y, Ito T, Koide S, Nannya Y, Iwama A, Tojo A, Konuma T
  • Journal Title: Leukemia Volume: In press Pages: In press
  • DOI: 10.1038/s41375-022-01564-7
  • Peer Reviewed
• [Journal Article] Anti-spike protein antibody titer at the time of breakthrough infection of SARS-CoV-2 omicron (2022)
  • Author(s): Adachi E, Nagai E, Saito M, Isobe M, Konuma T, Koga M, Tsutsumi T, Nannya Y, Yotsuyanagi H
  • Journal Title: J Infect Chemother Volume: In press Pages: In press
  • DOI: 10.1016/j.jiac.2022.03.021
  • Peer Reviewed
• [Journal Article] Long-term incidence of varicella zoster virus disease in adults receiving single-unit cord blood transplantation (2022)
  • Author(s): Fukushi K, Konuma T, Monna-Oiwa M, Isobe M, Kato S, Kuroda S, Takahashi S, Nannya Y
  • Journal Title: Transplant Cell Ther Volume: In press Pages: In press
  • DOI: 10.1016/j.jtct.2022.03.022
  • Peer Reviewed
• [Journal Article] HLA 1-3 antigen-mismatched related peripheral blood stem cells transplantation using low-dose antithymocyte globulin versus unrelated cord blood transplantation (2022)
  • Author(s): Wada F, Watanabe M, Konuma T, Okabe M, Kobayashi S, Uchida N, Ikegame K, Tanaka M, Sugio Y, Mukae J, Onizuka M, Kawakita T, Kuriyama T, Takahashi S, Fukuda T, Nakano N, Sawa M, Kimura T, Ichinohe T, Atsuta Y, Kanda J
  • Journal Title: Am J Hematol Volume: 97 Pages: 311-321
  • DOI: 10.1002/ajh.26446
  • Peer Reviewed
• [Journal Article] Outcomes of third allogeneic hematopoietic stem cell transplantation in relapsed/refractory acute leukemia after a second transplantation (2022)
  • Author(s): Kobayashi S, Kanda Y, Konuma T, Inamoto Y, Matsumoto K, Uchida N, Ikegame K, Miyamoto T, Doki N, Nakamae H, Katayama Y, Takahashi S, Shiratori S, Saito S, Kawakita T, Kanda J, Fukuda T, Atsuta Y, Kimura F
  • Journal Title: Bone Marrow Transplant Volume: 57 Pages: 43-50
  • DOI: 10.1038/s41409-021-01485-6
  • Peer Reviewed
• [Journal Article] Long-term outcomes following the addition of granulocyte colony-stimulating factor-combined high-dose cytarabine to total body irradiation and cyclophosphamide conditioning in single-unit cord blood transplantation for myeloid malignancies (2022)
  • Author(s): Konuma T, Ooi J, Nagayama H, Tomonari A, Tsukada N, Kato S, Kawakita T, Isobe M, Monna-Oiwa M, Tojo A, Iseki T, Takahashi S
  • Journal Title: Ann Hematol Volume: 101 Pages: 177-189
  • DOI: 10.1007/s00277-021-04676-9
  • Peer Reviewed
• [Journal Article] Respiratory syncytial virus pneumonia in an adult cord blood transplant recipient during the SARS-CoV-2 outbreak (2021)
  • Author(s): Konuma T, Isobe M, Kato S, Takahashi S, Nannya Y.
  • Journal Title: EJHaem Volume: 3 Pages: 261-262
  • DOI: 10.1002/jha2.351
  • Peer Reviewed / Open Access
• [Journal Article] Total body irradiation-based versus busulfan-based myeloablative conditioning for single-unit cord blood transplantation in adults (2021)
  • Author(s): Konuma T, Ooi J, Monna-Oiwa M, Isobe M, Tomonari A, Kato S, Iseki T, Nannya Y, Tojo A, Takahashi S
  • Journal Title: Leuk Lymphoma Volume: In press Pages: In press
  • DOI: 10.1080/10428194.2021.2018583
  • Peer Reviewed
• [Journal Article] Molecular characterization of healthcare and community-associated methicillin-resistant Staphylococcus aureus using phage open-reading frame typing (2021)
  • Author(s): Konuma T, Takahashi S, Suzuki M, Tojo A
  • Journal Title: Iran J Microbiol Volume: 13 Pages: 560-564
  • DOI: 10.18502/ijm.v13i4.6985
  • Peer Reviewed / Open Access
• [Journal Article] Allogeneic Hematopoietic Cell Transplantation from Alternative Donors in Acute Myelogenous Leukemia: A Comparative Analysis (2021)
  • Author(s): Yanada M, Konuma T, Yamasaki S, Harada K, Iwasaki M, Kobayashi A, Nishijima A, Tanaka M, Uchida N, Nakamae H, Fukuda T, Onizuka M, Ozawa Y, Sawa M, Katayama Y, Yoshioka S, Kimura T, Ichinohe T, Atsuta Y, Kanda J, Yano S
  • Journal Title: Transplant Cell Ther Volume: 27 Pages: 1005.e1-e8
  • DOI: 10.1016/j.jtct.2021.08.027
  • Peer Reviewed
• [Journal Article] The differential effect of disease status at allogeneic hematopoietic cell transplantation on outcomes in acute myeloid and lymphoblastic leukemia (2021)
  • Author(s): Yanada M, Konuma T, Yamasaki S, Mizuno S, Hirabayashi S, Nishiwaki S, Uchida N, Doki N, Tanaka M, Ozawa Y, Sawa M, Eto T, Kawakita T, Ota S, Fukuda T, Onizuka M, Kimura T, Atsuta Y, Kako S, Yano S
  • Journal Title: Ann Hematol Volume: 100 Pages: 3017-3027
  • DOI: 10.1007/s00277-021-04661-2
  • Peer Reviewed
• [Journal Article] Hematological effects on peri-transplant use of linezolid in adults undergoing single-unit cord blood transplantation (2021)
  • Author(s): Yasu T, Konuma T, Oiwa-Monna M, Takahashi S, Nannya Y, Tojo A
  • Journal Title: Ann Hematol Volume: 100 Pages: 2867-2869
  • DOI: 10.1007/s00277-021-04597-7
  • Peer Reviewed
• [Journal Article] Prognostic value of measurable residual disease at allogeneic transplantation for adults with core binding factor acute myeloid leukemia in complete remission (2021)
  • Author(s): Konuma T, Kondo T, Masuko M, Shimizu H, Shiratori S, Fukuda T, Kato J, Sawa M, Ozawa Y, Ota S, Uchida N, Kanda Y, Kako S, Fujisawa S, Fukushima K, Ichinohe T, Atsuta Y, Yanada M
  • Journal Title: Bone Marrow Transplant Volume: 56 Pages: 2779-2787
  • DOI: 10.1038/s41409-021-01409-4
  • Peer Reviewed
• [Journal Article] Cord blood index predicts engraftment and early non-relapse mortality in adult patients with single-unit cord blood transplantation (2021)
  • Author(s): Kondo G, Ishimaru F, Konuma T, Takahashi S, Atsuta Y, Ogawa A, Minemoto M, Kashiwase K, Azuma F, Ito M, Isoyama K, Kobayashi T, Ohashi K, Nakajima F, Hiruma K, Makino S, Mugishima H, Namba N, Tsuno H, Nagai T, Muroi K, Nakajima K
  • Journal Title: Bone Marrow Transplant Volume: 56 Pages: 2771-2778
  • DOI: 10.1038/s41409-021-01406-7
  • Peer Reviewed
• [Journal Article] Momentum of neutrophil recovery using an exponential growth model predicts the prognosis of single cord blood transplantation (2021)
  • Author(s): Isobe M, Konuma T, Monna-Oiwa M, Okabe M, Kato S, Takahashi S, Tojo A
  • Journal Title: Int J Lab Hematol Volume: 43 Pages: 1465-1471
  • DOI: 10.1111/ijlh.13636
  • Peer Reviewed
• [Journal Article] Differential Effect of Graft-versus-Host Disease on Survival in Acute Leukemia according to Donor Type (2021)
  • 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
  • Journal Title: Clin Cancer Res Volume: 27 Pages: 4825-4835
  • DOI: 10.1158/1078-0432.CCR-20-4856
  • Peer Reviewed
• [Journal Article] Prognostic impacts of peripheral blood erythroblasts after single-unit cord blood transplantation (2021)
  • Author(s): Kaito Y, Konuma T, Monna-Oiwa M, Kato S, Isobe M, Okabe M, Imai Y, Takahashi S, Tojo A
  • Journal Title: Int J Lab Hematol Volume: 43 Pages: 1437-1442
  • DOI: 10.1111/ijlh.13622
  • Peer Reviewed
• [Journal Article] Radiation-free myeloablative conditioning consisting of fludarabine added to full-dose busulfan and cyclophosphamide in single-unit cord blood transplantation for adults (2021)
  • Author(s): Konuma T, Monna-Oiwa M, Isobe M, Okabe M, Takahashi S, Tojo A
  • Journal Title: Eur J Haematol Volume: 107 Pages: 374-376
  • DOI: 10.1111/ejh.13669
  • Peer Reviewed
• [Journal Article] Allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome in adolescent and young adult patients (2021)
  • Author(s): Shimomura Y, Hara M, Konuma T, Itonaga H, Doki N, Ozawa Y, Eto T, Uchida N, Aoki J, Kato J, Onishi Y, Takahashi S, Fukushima K, Nakamae H, Kawakita T, Tanaka J, Fukuda T, Atsuta Y, Ishikawa T, Ishiyama K
  • Journal Title: Bone Marrow Transplant Volume: 56 Pages: 2510-2517
  • DOI: 10.1038/s41409-021-01324-8
  • Peer Reviewed
• [Journal Article] Pretransplantation Red Blood Cell and Platelet Transfusion Burden in De Novo Myelodysplastic Syndrome Undergoing Allogeneic Transplantation (2021)
  • Author(s): Konuma T, Aoki J, Ozawa Y, Uchida N, Kobayashi T, Onizuka M, Katayama Y, Ohta T, Nakano N, Ota S, Onishi Y, Kobayashi H, Fukuda T, Kanda Y, Atsuta Y
  • Journal Title: Transplant Cell Ther Volume: 27 Pages: 671-678
  • DOI: 10.1016/j.jtct.2021.05.003
  • 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 Pages: 336.e1-e9
  • DOI: 10.1016/j.jtct.2021.01.027
  • Peer Reviewed
• [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 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
  • Journal Title: Ann Hematol Volume: 100 Pages: 1849-1861
  • DOI: 10.1007/s00277-021-04464-5
  • Peer Reviewed
• [Journal Article] Impact of a prior history of cancer on prognosis after myeloablative single-unit cord blood transplantation (2021)
  • Author(s): Okabe M, Konuma T, Oiwa-Monna M, Kato S, Isobe M, Takahashi S, Tojo A
  • Journal Title: Jpn J Clin Oncol 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 (2021)
  • 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: 56 Pages: 1126-1133
  • DOI: 10.1038/s41409-020-01163-z
  • 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] Long-term outcomes of G-CSF-combined conditioning in single cord blood transplantation (2021)
  • Author(s): 小沼貴晶、大井淳,長山人三,塚田信弘,加藤せい子,河北敏郎,磯部優理,大岩真希,東條 有伸, 井関 徹, 高橋 聡
  • Organizer: 第 83 回日本血液学会学術集会