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HLAの異常に基づく成人T細胞白血病リンパ腫の個別化免疫療法を目指した基礎的研究

Research Project

Project/Area Number 20K08737
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionUniversity of the Ryukyus

Principal Investigator

森島 聡子  琉球大学, 医学(系)研究科(研究院), 准教授 (40463195)

Co-Investigator(Kenkyū-buntansha) 益崎 裕章  琉球大学, 医学(系)研究科(研究院), 教授 (00291899)
椎名 隆  東海大学, 医学部, 教授 (00317744)
Project Period (FY) 2020-04-01 – 2025-03-31
Project Status Granted (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords成人T細胞白血病リンパ腫 / HLA / 個別化免疫療法
Outline of Research at the Start

難治性の血液がんである成人ヒトT細胞白血病リンパ腫(ATLL)の治癒を目指して同種造血幹細胞移植や免疫療法が行われるが、その効果は限定的である。HLAは免疫応答に重要な分子であり、がん細胞に生じるHLA遺伝子異常は免疫回避と関連する。ATLLに生じるHLA遺伝子異常が同種造血幹細胞移植や免疫療法に影響を及ぼすことが推測されるが、明らかにされていない。
本研究はHLAに焦点を当て、高精度のHLA解析法でHLA遺伝子全領域のDNA解析、RNA発現解析を実施する。臨床情報を統合して予後層別化を行い、ATLLのHLA遺伝子異常に基づいた個別化免疫療法の可能性を探る。

Outline of Annual Research Achievements

成人T細胞白血病リンパ腫(ATLL)は、最も難治の血液がんの一つであり、同種造血幹細胞移植が治癒を目指せる唯一の治療法と期待されている。
患者ごとに生じる遺伝子異常は異なり、特にHLA領域の遺伝子異常を正確に把握することは難しい。本研究は個々の患者の腫瘍細胞でのHLA遺伝子異常に基づき、HLA拘束性T細胞による免疫効果で層別化し、最も有効な治療を選択する個別化免疫療法の可能性を探ることを目的とした。
ATLLの末梢血より腫瘍細胞と非腫瘍細胞の各分画からDNAを抽出し、long-range PCR法を用いてHLA-A, -B, -C, -DRB1, -DQA1, -DQB1, -DPA1, -DPB1遺伝子全領域の解析を行い、ATLL細胞に生じるHLA遺伝子異常の概要を明らかにした。急性型ATLでは高率にHLA遺伝子のloss of heterozygosity (LOH)もしくは非同義置換・挿入/欠失などタンパク質の構造に影響を及ぼす変異の存在を認めた。ゲノムでHLA class I遺伝子に異常を認めた症例のHTLV-1感染CD4+ T細胞におけるHLA class I分子の発現は、異常を認めない症例と比較して有意に低下していた。
HLA class II (HLD-DR)の発現は、HTLV-1キャリア、インドレントATL、アグレッシブATL で解析を行なった。HTLV-1感染CD4+ T細胞は非感染CD4+ T細胞に比べてHLA-class IIの発現は高かった。アグレッシブATLは、HTLV-1キャリアとインドレントATLに比べて発現は有意に低いことが判明し、病期進行に伴い、HLA class II遺伝子発現が低下すると考えられた。

Current Status of Research Progress
Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

ATLに生じるHLA遺伝子異常を詳細に解析し、HLA class I遺伝子異常が高頻度に起きること、HLA class I遺伝子異常が生じた症例では細胞表面上でのHLA class I分子の発現が低下していることを明らかにして英文論文として報告したが、HLA class IIの遺伝子解析やRNAの発現解析が予定よりも遅れている。

Strategy for Future Research Activity

多数例でのHLAの遺伝子異常及びRNAの発現解析を実施し、移植成績など臨床情報との関連性を検討し、HLAの情報のバイオマーカーとしての有用性を検討し、英文論文として報告する。

Report

(4 results)
  • 2023 Research-status Report
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (25 results)

All 2023 2022 2021 2020

All Journal Article (15 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 14 results,  Open Access: 14 results) Presentation (10 results) (of which Invited: 3 results)

  • [Journal Article] An open-label, single-arm phase 2 trial of valemetostat for relapsed or refractory adult T-cell leukemia/lymphoma.2023

    • Author(s)
      Izutsu K, Makita S, Nosaka K, Yoshimitsu M, Utsunomiya A, Kusumoto S, Morishima S, Tsukasaki K, Kawamata T, Ono T, Rai S, Katsuya H, Ishikawa J, Yamada H, Kato K, Tachibana M, Kakurai Y, Adachi N, Tobinai K, Yonekura K, Ishitsuka K.
    • Journal Title

      Blood.

      Volume: 141 Issue: 10 Pages: 1159-1168

    • DOI

      10.1182/blood.2022016862

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fatal acquired coagulation factor V deficiency after hepatectomy for advanced hepatocellular carcinoma as a possible immune checkpoint inhibitor-related adverse event: a case report2023

    • Author(s)
      Arakaki Shintaro、Ono Shinichiro、Kawamata Futoshi、Ishino Shinichiro、Uesato Yasunori、Nakajima Tomo、Nishi Yukiko、Morishima Satoko、Arakaki Shingo、Maeshiro Tatsuji、Souri Masayoshi、Ichinose Akitada、Masuzaki Hiroaki、Takatsuki Mitsuhisa
    • Journal Title

      Surgical Case Reports

      Volume: 9 Issue: 1 Pages: 1-7

    • DOI

      10.1186/s40792-023-01601-2

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The clinical benefit of acute GVHD depends on the age at transplantation in patients with adult T-cell leukemia-lymphoma on behalf of the ATL Working Group of the Japan Society for Transplantation and Cellular Therapy.2023

    • Author(s)
      Fuji S, Inoue Y, Makiyama J, Nakano N, Ito A, Kawakita T, Eto T, Suehiro Y, Itonaga H, Sawayama Y, Mori Y, Uchida N, Morishima S, Onizuka M, Ishitsuka K, Fukuda T, Atsuta Y, Yoshimitsu M.
    • Journal Title

      Bone Marrow Transplant.

      Volume: 58 Issue: 6 Pages: 729-731

    • DOI

      10.1038/s41409-023-01969-7

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of HLA disparity on overall mortality risk in patients with extensive chronic GVHD: The HLA Working Group of Japanese Society for Transplantation and Cellular Therapy.2023

    • Author(s)
      Fuji S, Hakoda A, Kanda J, Fukuda T, Doki N, Katayama Y, Uchida N, Ozawa Y, Kanda Y, Tanaka M, Kataoka K, Ara T, Sawa M, Onizuka M, Onishi Y, Kimura T, Ichinohe T, Atsuta Y, Shintani A, Morishima S.
    • Journal Title

      Bone Marrow Transplant.

      Volume: 58 Issue: 11 Pages: 1257-1259

    • DOI

      10.1038/s41409-023-02076-3

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of HLA-mismatched unrelated transplantation in patients with adult T-cell leukemia/lymphoma.2023

    • Author(s)
      Inoue Y, Morishima S, Kato K, Ito A, Nakano N, Kuriyama T, Kawakita T, Mori Y, Suehiro Y, Itonaga H, Miyazaki Y, Imada K, Tomori S, Kanda J, Ichinohe T, Atsuta Y, Fukuda T, Yoshimitsu M.
    • Journal Title

      Bone Marrow Transplant.

      Volume: 58 Issue: 9 Pages: 980-990

    • DOI

      10.1038/s41409-023-02002-7

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Antibody-mediated pathogenesis of chronic GVHD through DBY/HLA class II complexes and induction of a GVL effect.2023

    • Author(s)
      Umino K, Morita K, Ikeda T, Kawaguchi SI, Nagayama T, Ito S, Minakata D, Ashizawa M, Yamamoto C, Hatano K, Sato K, Ohmine K, Fujiwara SI, Kimura SI, Kako S, Doki N, Ozawa Y, Mori Y, Eto T, Hiramoto N, Nakamae H, Kanda J, Ichinohe T, Atsuta Y, Nakasone H, Morishima S, Kanda Y.
    • Journal Title

      Blood.

      Volume: 142 Issue: 11 Pages: 1008-1021

    • DOI

      10.1182/blood.2023019799

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sequence Variations Within HLA-G and HLA-F Genomic Segments at the Human Leukocyte Antigen Telomeric End Associated With Acute Graft-Versus-Host Disease in Unrelated Bone Marrow Transplantation.2022

    • Author(s)
      Suzuki S, Morishima S, Murata M, Tanaka M, Shigenari A, Ito S, Kanga U, Kulski JK, Morishima Y, Shiina T.
    • Journal Title

      Front Immunol.

      Volume: 13 Pages: 938206-938206

    • DOI

      10.3389/fimmu.2022.938206

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Impact of HLA Epitope Matching on Outcomes After Unrelated Bone Marrow Transplantation2022

    • Author(s)
      Iwasaki Makoto、Kanda Junya、Tanaka Hidenori、Shindo Takero、Sato Takahiko、Doki Noriko、Fukuda Takahiro、Ozawa Yukiyasu、Eto Tetsuya、Uchida Naoyuki、Katayama Yuta、Kataoka Keisuke、Ara Takahide、Ota Shuichi、Onizuka Makoto、Kanda Yoshinobu、Ichinohe Tatsuo、Atsuta Yoshiko、Morishima Satoko
    • Journal Title

      Frontiers in Immunology

      Volume: 13 Pages: 811733-811733

    • DOI

      10.3389/fimmu.2022.811733

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Race and Survival in Unrelated Hematopoietic Cell Transplantation.2022

    • Author(s)
      Morishima Y, Morishima S, Stevenson P, Kodera Y, Horowitz M, McKallor C, Malkki M, Spellman SR, Gooley T, Petersdorf EW.
    • Journal Title

      Transplant Cell Ther.

      Volume: 28 Issue: 7 Pages: 357-357

    • DOI

      10.1016/j.jtct.2022.03.026

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Improved outcomes of single-unit cord blood transplantation for acute myeloid leukemia by killer immunoglobulin-like receptor 2DL1-ligand mismatch.2022

    • Author(s)
      Yokoyama H, Kanaya M, Iemura T, Hirayama M, Yamasaki S, Kondo T, Uchida N, Takahashi S, Tanaka M, Onizuka M, Ozawa Y, Kozai Y, Eto T, Sugio Y, Hamamura A, Kawakita T, Aotsuka N, Takada S, Wake A, Kimura T, Ichinohe T, Atsuta Y, Yanada M, Morishima S.
    • Journal Title

      Bone Marrow Transplant.

      Volume: 57 Issue: 7 Pages: 1171-1179

    • DOI

      10.1038/s41409-022-01700-y

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effect of Multiple HLA Locus Mismatches on Outcomes after Single Cord Blood Transplantation.2022

    • Author(s)
      Kanda J, Hirabayashi S, Yokoyama H, Kawase T, Tanaka H, Uchida N, Taniguchi S, Takahashi S, Onizuka M, Tanaka M, Sugio Y, Eto T, Kanda Y, Kimura T, Ichinohe T, Atsuta Y, Morishima S.
    • Journal Title

      Transplant Cell Ther.

      Volume: 28 Issue: 7 Pages: 398-398

    • DOI

      10.1016/j.jtct.2022.05.005

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of human leukocyte antigen mismatch on outcomes after unrelated bone marrow transplantation in paediatric patients: A retrospective analysis by the JSTCT HLA working group.2022

    • Author(s)
      Kato I, Sakaguchi H, Kato S, Sato M, Noguchi M, Yoshida N, Koh K, Koike T, Yanagimachi M, Kato K, Takahashi Y, Fujita N, Sato A, Hashii Y, Tabuchi K, Atsuta Y, Morishima S, Kanda J.
    • Journal Title

      Br J Haematol.

      Volume: 199 Issue: 3 Pages: 392-400

    • DOI

      10.1111/bjh.18425

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Full-length HLA sequencing in adult T cell leukemia-lymphoma uncovers multiple gene alterations.2021

    • Author(s)
      Tamaki K, Morishima S, Suzuki S, Shigenari A, Nomura I, Yokota Y, Morichika K, Nishi Y, Nakachi S, Okamoto S, Fukushima T, Shiina T, Masuzaki H.
    • Journal Title

      Leukemia

      Volume: 35 Issue: 10 Pages: 2998-3001

    • DOI

      10.1038/s41375-021-01403-1

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Individual HLAs influence immunological events in allogeneic stem cell transplantation from HLA-identical sibling donors. Bone Marrow Transplant.2021

    • Author(s)
      Morishima S, Fukuda T, Doki N, Mori T, Onizuka M, Kawakita T, Kato C, Ozawa Y, Tanaka M, Kurokawa M, Kamimura T, Inoue M, Tanaka J, Ichinohe T, Atsuta Y, Morishima Y.
    • Journal Title

      Bone Marrow Transplant.

      Volume: 56 Issue: 3 Pages: 646-654

    • DOI

      10.1038/s41409-020-01070-3

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 造血細胞移植を成功に導くHLA研究2020

    • Author(s)
      森島聡子
    • Journal Title

      臨床免疫・アレルギー科

      Volume: 74 Pages: 456-461

    • Related Report
      2020 Research-status Report
  • [Presentation] 同種造血細胞移植におけるHLA発現量の意義2023

    • Author(s)
      森島聡子
    • Organizer
      第45回 日本造血・免疫細胞療法学会総会
    • Related Report
      2023 Research-status Report
    • Invited
  • [Presentation] HLAの基礎知識と近年明らかになったHLA class Ⅱの意義2023

    • Author(s)
      森島聡子
    • Organizer
      第45回 日本造血・免疫細胞療法学会総会
    • Related Report
      2023 Research-status Report
    • Invited
  • [Presentation] 非血縁者間造血細胞移植におけるHLA発現量と移植成績との関連2023

    • Author(s)
      森島聡子, 椎名隆, 森島泰雄, 東史啓, 村田誠
    • Organizer
      第31回日本組織適合性学会大会
    • Related Report
      2023 Research-status Report
  • [Presentation] 遺伝子異常を伴わないPAI-1欠乏症が疑われた1例2023

    • Author(s)
      森島聡子, 岩城孝行, 浦野哲盟, 宮城理子, 中島知, 北村紗希子, 花城多恵子, 西由希子, 玉城啓太, 森近一穂, 仲地佐和子, 益崎裕章
    • Organizer
      第85回日本血液学会学術集会
    • Related Report
      2023 Research-status Report
  • [Presentation] がんの免疫回避とHLA2022

    • Author(s)
      森島聡子
    • Organizer
      第30回日本組織適合性学会大会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] Expression of HLA class II on HTLV-1 infected cells in patients with ATL and HTLV-1 carriers.2022

    • Author(s)
      森島聡子, 椎名隆, 玉城啓太, 島袋康貴, 鈴木慎吾, 重成敦子, 宮城理子, 中島知, 北村紗希子, 友利昌平, 花城多恵子, 森近一穂, 西由希子, 仲地佐和子, 福島卓也,益崎裕章
    • Organizer
      第84回日本血液学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] The impact of HLA expression level on transplant outcomes in HLA-matched UR-SCT.2022

    • Author(s)
      森島聡子, 椎名隆, 森島泰雄, 東史啓, 友利昌平, 土岐典子, 小澤幸泰, 福田隆浩, 田中正嗣, 衛藤徹也, 河北敏郎, 荒隆英, 平本展大, 内田直之, 神田善伸, 諫田淳也, 鬼塚真仁, 一戸辰夫, 熱田由子, 村田誠
    • Organizer
      第84回日本血液学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] 遺伝子全領域の解析により明らかとなったATLに生じる多彩なHLA遺伝子異常2021

    • Author(s)
      森島聡子、玉城啓太、鈴木進悟、重成敦子、野村育美、横田雄太郎、森近一穂、西由希子、仲地佐和子、岡本士毅、福島卓也、椎名隆、益崎裕章
    • Organizer
      第7回日本HTLV-1学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] A NGS-based high resolution typing elucidates novel perspectives on the HLA gene mutations in ATL.2021

    • Author(s)
      Tamaki K, Morishima S, Suzuki S, Shigenari A, Nomura I, Yokota Y, Morichika K, Nishi Y, Nakachi S, Okamoto S, Fukushima T, Shiina T, Masuzaki H.
    • Organizer
      第83回日本血液学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] The impact of individual HLAs on survival after allo-HSCT from HLA-matched donors for ATL patients.2020

    • Author(s)
      Morishima S, Shindo T, Utsunomiya A, Ishida T, Fukuda T, Nakano N, Sawayama Y, Miyamoto T, Ichinohe T, Atsuta Y, Yoshimitsu M, Kato K. Kawakita T, Eto T, Suehiro Y, Sawayama Y, Miyamoto T, Ichinohe T, Atsuta Y, Yoshimitsu M, Kato K.
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-12-25  

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