HLA-DR15欠失血球陽性再生不良性貧血における免疫病態の解明

• Project/Area Number: 21K08367
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kanazawa University
• Principal Investigator: 細川 晃平 金沢大学, 附属病院, 講師 (10786239)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 再生不良性貧血 / HLA-DRB1*15:01 / 造血幹前駆細胞 / 造血障害 / 自己免疫 / HLA-DR / HLA-DR15

Outline of Research at the Start

特発性再生不良性貧血(aplastic anemia: AA)は、造血幹前駆細胞に対する細胞傷害性T細胞の攻撃により発症する自己免疫疾患である。HLAクラスIIのDR15はAA患者で保有率が高く、このアレルを持つ患者はシクロスポリン（CsA）が効きやすいことが知られているが、DR15がAAの発症にどのように関与しているかは不明であった。本研究では、HLA-DR15陽性AA患者を対象として、抗原特異的CD4+ T細胞による造血抑制のメカニズムと、HLA-DR15が提示するAAの自己抗原を明らかにする。

Outline of Annual Research Achievements

再生不良性貧血(aplastic anemia : AA)、低リスク骨髄異形成症候群（MDS）、骨髄不全型発作性夜間ヘモグロビン尿症（PNH）では、HLADR15の保有率が高いことが知られている。特にHLA-DRB1*15:01は、シクロスポリン(CsA)依存性のAA患者で特に高頻度にみられる。このDRB1アレルは、自己免疫性造血不全の発症メカニズムに深く関与していると考えられるが、どのようにして造血不全の発症に寄与しているのかは分かっていない。我々は最近の研究により、HLA-DR15を保有するCsA依存性AA患者の末梢血造血幹前駆細胞（HSPC）では、HLA-DRの欠失が高頻度に見られることを見出した。このDR欠失は、インターフェロンγ存在下での培養により完全に回復することから、エピジェネティックな機構によるものであると考えられた。同様の現象は、同種造血幹細胞移植後再発の急性骨髄性白血病細胞においても報告されていることから、DRの欠失は、HSPCがDR15が提示する自己抗原特異的CD4T細胞からの攻撃を免れるための逃避現象である可能性がある。以上のことから、HLA-DR15陽性CsA依存性AA患者では、HLA-DR15拘束性にHSPCを傷害するCD4陽性T細胞が存在している可能性が高い。現在、HLA-DR15陽性CsA依存性AA患者を対象にCD4陽性T細胞のレパトア解析を行い、抗原特異的T細胞クローンの同定を試みている。

Research Products

• [Journal Article] Immune pathophysiology of bone marrow failure (2023)
  • Author(s): 細川 晃平
  • Journal Title: Rinsho Ketsueki Volume: 64 Issue: 9 Pages: 908-915
  • DOI: 10.11406/rinketsu.64.908
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] A longitudinal analysis of paroxysmal nocturnal haemoglobinuria‐type cells in patients with bone marrow failure: Results of a prospective multi‐centre study in Japan (2023)
  • Author(s): Ishiyama Ken、Yonemura Yuji、Kawaguchi Tatsuya、Hosokawa Kohei、Sugimori Chiharu、Ueda Yasutaka、Takamori Hiroyuki、Obara Naoshi、Noji Hideyoshi、Shirasugi Yukari、Ando Kiyoshi、Shichishima Tsutomu、Ninomiya Haruhiko、Chiba Shigeru、Nishimura Jun‐ichi、Kanakura Yuzuru、Nakao Shinji
  • Journal Title: British Journal of Haematology Volume: 203 Issue: 3 Pages: 468-476
  • DOI: 10.1111/bjh.19048
  • Peer Reviewed
• [Journal Article] Correction: Frequent HLA-DR loss on hematopoietic stem progenitor cells in patients with cyclosporine-dependent aplastic anemia carrying HLA-DR15 (2023)
  • Author(s): Tsuji Noriaki、Hosokawa Kohei、Urushihara Ryota、Tanabe Mikoto、Zaimoku Yoshitaka、Katagiri Takamasa、Ozawa Tatsuhiko、Takamatsu Hiroyuki、Ishiyama Ken、Yamazaki Hirohito、Kishi Hiroyuki、Ogawa Seishi、Nakao Shinji
  • Journal Title: Leukemia Volume: 37 Issue: 10 Pages: 2143-2143
  • DOI: 10.1038/s41375-023-02011-x
  • Peer Reviewed
• [Journal Article] GPI(-) granulocyte populations in aplastic anemia and healthy individuals derived from a few PIGA-mutated hematopoietic stem progenitor cells (2023)
  • Author(s): Mizumaki Hiroki、Tran Dung Cao、Hosokawa Kohei、Hosomichi Kazuyoshi、Zaimoku Yoshitaka、 Takamatsu Hiroyuki、Yamazaki Hirohito、Ishiyama Ken、Yamazaki Rena、Fujiwara Hiroshi、Tajima Atsushi、Nakao Shinji
  • Journal Title: Blood Cancer Journal Volume: 13 Issue: 1 Pages: 165-165
  • DOI: 10.1038/s41408-023-00932-5
  • Peer Reviewed / Open Access
• [Journal Article] Frequent HLA-DR loss on hematopoietic stem progenitor cells in patients with cyclosporine-dependent aplastic anemia carrying HLA-DR15 (2022)
  • Author(s): Tsuji Noriaki、Hosokawa Kohei、Urushihara Ryota、Tanabe Mikoto、Katagiri Takamasa、Ozawa Tatsuhiko、Takamatsu Hiroyuki、Ishiyama Ken、Yamazaki Hirohito、Kishi Hiroyuki、Ogawa Seishi、Nakao Shinji
  • Journal Title: Leukemia Volume: 36 Issue: 6 Pages: 1666-1675
  • DOI: 10.1038/s41375-022-01549-6
  • Peer Reviewed
• [Journal Article] Hematopoietic stem progenitor cells with malignancy‐related gene mutations in patients with acquired aplastic anemia are characterized by the increased expression of CXCR4 (2022)
  • Author(s): Katagiri Takamasa,Espinoza Luis,Uemori Mizuho,Ikeda Honoka,Hosokawa Kohei,Ishiyama Ken,Yoroidaka Takeshi,Imi Tatsuya,Takamatsu Hiroyuki,Ozawa Tatsuhiko,Kishi Hiroyuki,Yamamoto Yasuhiko,Elbadry Mahmoud,Yoshida Yoshinori,Chonabayashi Kazuhisa,Takenaka Katsuto,Akashi Koichi,Nannya Yasuhito,Ogawa Seishi,Nakao Shinji
  • Journal Title: eJHaem Volume: 3 Issue: 3 Pages: 669-680
  • DOI: 10.1002/jha2.515
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Somatic mutations and clonal expansions in paroxysmal nocturnal hemoglobinuria (2022)
  • Author(s): Hosokawa Kohei、Nakao Shinji
  • Journal Title: Seminars in Hematology Volume: 59 Issue: 3 Pages: 143-149
  • DOI: 10.1053/j.seminhematol.2022.08.004
  • Peer Reviewed
• [Journal Article] Clinical significance of the increased expression of the WT1 gene in peripheral blood of patients with acquired aplastic anemia (2022)
  • Author(s): Ishiyama Ken、Dung Tran Cao、Imi Tatsuya、Hosokawa Kohei、Nannya Yasuhito、Yamazaki Hirohito、Ogawa Seishi、Nakao Shinji
  • Journal Title: eJHaem Volume: 3 Issue: 4 Pages: 1116-1125
  • DOI: 10.1002/jha2.563
  • Peer Reviewed / Open Access
• [Journal Article] The effectiveness of immunosuppressive therapy in patients with aplastic anaemia secondary to chemoradiotherapy for cancers (2021)
  • Author(s): Nakagawa Noriharu、Ishiyama Ken、Tanabe Mikoto、Yoroidaka Takeshi、Mizumaki Hiroki、Imi Tatsuya、Zaimoku Yoshitaka、Maruyama Hiroyuki、Hosokawa Kohei、Yamazaki Hirohito、Nakao Shinji
  • Journal Title: British Journal of Haematology Volume: 195 Issue: 5 Pages: 770-780
  • DOI: 10.1111/bjh.17802
  • Peer Reviewed
• [Journal Article] The GPI-anchored protein CD109 protects hematopoietic progenitor cells from undergoing erythroid differentiation induced by TGF-β (2021)
  • Author(s): Tanabe Mikoto、Hosokawa Kohei、Nguyen Mai Anh Thi、Nakagawa Noriharu、Maruyama Kana、Tsuji Noriaki、Urushihara Ryota、Espinoza Luis、Elbadry Mahmoud I.、Mohiuddin Md、Katagiri Takamasa、Ono Masanori、Fujiwara Hiroshi、Chonabayashi Kazuhisa、Yoshida Yoshinori、Yamazaki Hirohito、Hirao Atsushi、Nakao Shinji
  • Journal Title: Leukemia Volume: 36 Issue: 3 Pages: 847-855
  • DOI: 10.1038/s41375-021-01463-3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Detection of Antibodies Against Human Leukocyte Antigen Class II in the Sera of Patients Receiving Intravenous Immunoglobulin (2021)
  • Author(s): Takamatsu Hiroyuki、Yamada Shinya、Tsuji Noriaki、Nakagawa Noriharu、Matsuura Erika、Kasada Atsuo、Sato Keijiro、Hosokawa Kohei、Iwaki Noriko、Arahata Masahisa、Tanaka Hidenori、Nakao Shinji
  • Journal Title: Transplantation Direct Volume: 7 Issue: 6 Pages: e697-e697
  • DOI: 10.1097/txd.0000000000001146
  • Peer Reviewed
• [Journal Article] Hematopoietic stem progenitor cells lacking HLA differ from those lacking GPI-anchored proteins in the hierarchical stage and sensitivity to immune attack in patients with acquired aplastic anemia (2021)
  • Author(s): Yoroidaka T, Hosokawa K, Imi T, Mizumaki H, Katagiri T, Ishiyama K, Yamazaki H, Azuma F, Nanya Y, Ogawa S, Nakao S
  • Journal Title: Leukemia Volume: in press Issue: 11 Pages: 3257-3267
  • DOI: 10.1038/s41375-021-01202-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Single-Cell Dissection Reveals a Distinct Origin of Small Paroxysmal Nocturnal Hemoglobinuria Clones in Immune Aplastic Anemia and Healthy Individuals (2023)
  • Author(s): Dung Cao Cao Tran, Yoshitaka Zaimoku, Kazuyoshi Hosomichi, Hiroki Mizumaki, Kohei Hosokawa, Hirohito Yamazaki, Toshihiro Miyamoto, Shinji Nakao
  • Organizer: 2023 ASH annual meeting
  • Int'l Joint Research
• [Presentation] 再生不良性貧血における新たな免疫逃避機構の同定 (2023)
  • Author(s): 辻 紀章, 細川 晃平, 漆原 涼太, 田辺 命, 材木 義隆, 高松 博幸, 石山 謙, 山崎 宏人, 中尾 眞二, 宮本 敏浩
  • Organizer: 第120回日本内科学会講演会
• [Presentation] 再生不良性貧血におけるシクロスポリン非依存性の寛解には造血幹細胞の進化が必要である (2023)
  • Author(s): 細川 晃平, Tran Dung Cao, 水牧 裕希, 鎧高 健志, 井美 達也, 丸山 裕之, 辻 紀章, 漆原 涼太, 田辺 命, 材木 義隆, 片桐 孝和, 高松 博幸, 石山 謙, 山崎 宏人, 宮本 敏浩, 中尾 眞二
  • Organizer: 85回 日本血液学会学術集会
• [Presentation] Recent advances in the pathogenesis and treatment of aplastic anemia (2023)
  • Author(s): Kohei Hosokawa
  • Organizer: 2023 Korean Society of Hematology International Conference ＆ 64rd annual meeting
  • Int'l Joint Research / Invited
• [Presentation] PNH clone expansion: our understanding in 2022 (2022)
  • Author(s): Kohei Hosokawa
  • Organizer: Eighth International Bone Marrow Failure Scientific Symposium
  • Int'l Joint Research / Invited
• [Presentation] Minor GPI(-) Granulocyte Populations in Patients with Acquired Aplastic Anemia and Healthy Individuals Are Derived from a Few Piga-Mutated Hematopoietic Stem Progenitor Cells (2021)
  • Author(s): Hiroki Mizumaki, Dung Cao Tran, Kohei Hosokawa, Kazuyoshi Hosomichi, Hiroyuki Takamatsu, Hirohito Yamazaki, Atsushi Tajima, Ken Ishiyama and Shinji Nakao
  • Organizer: 2021 ASH annual meeting
  • Int'l Joint Research
• [Presentation] The Copy Number of Disease-Associated HLA Alleles Predicts the Response to Immunosuppressive Therapy in Acquired Aplastic Anemia (2021)
  • Author(s): Yoshitaka Zaimoku, Hiroki Mizumaki, Tatsuya Imi, Kohei Hosokawa, Hiroyuki Maruyama, Takamasa Katagiri, Takeshi Yoroidaka, Noriharu Nakagawa, Mikoto Tanabe, Noriaki Tsuji, Ryota Urushihara, Hiroyuki Takamatsu, Hirohito Yamazaki, Ken Ishiyama and Shinji Nakao
  • Organizer: 2021 ASH annual meeting
  • Int'l Joint Research
• [Presentation] Anti-COX-2 Autoantibody Is a Novel Diagnostic Marker of Aplastic Anemia (2021)
  • Author(s): Yasutaka Ueda, Kohei Hosokawa, Ken Ishiyama, Hiroyuki Takamori, Yuji Yonemura, Naoshi Obara, Hideyoshi Noji, Kiyoshi Ando, Tsutomu Shichishima, Takayuki Ikezoe, Shigeru Chiba, Haruhiko Ninomiya, Tatsuya Kawaguchi, Jun-ichi Nishimura, Yuzuru Kanakura and Shinji Nakao
  • Organizer: 2021 ASH annual meeting
  • Int'l Joint Research
• [Presentation] 再生不良性貧血におけるHLAクラスIアレル欠失血球検出の臨床的意義 (2021)
  • Author(s): 細川晃平、中尾眞二
  • Organizer: 第83回日本血液学会学術集会
  • Invited