Identification of autoantigens recognized by cytotoxic T-cells and responsible for the pathogenesis of aplastic anemia.

• Project/Area Number: 15K09512
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Fujita Health University
• Principal Investigator: Akatsuka Yoshiki 藤田保健衛生大学, 医学部, 教授 (70333391)
• Co-Investigator(Kenkyū-buntansha): 葛島 清隆 愛知県がんセンター(研究所), その他部局等, 部長 (30311442)
• Co-Investigator(Renkei-kenkyūsha): NAKAO Shiji 金沢大学, 医薬保健研究域医学系・細胞移植学, 教授 (70217660)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 再生不良性貧血 / 細胞傷害性T細胞 / 自己抗原 / 細胞障害性T細胞 / 抗原遺伝子

Outline of Final Research Achievements

We attempted to identify antigens recognized by HLA-B*40:02-restricted cytotoxic T lymphocytes (CTLs) that might be related to the pathogenesis of aplastic anemia. Because the CTLs exerted cytotoxic activity on K562 cells transduced with HLA-B*40:02, we prepared cDNA libraries from messenger RNA extracted from K562. After extensive screening, a cDNA clone that stimulated interferon-gamma release from one of the CTLs was found. The cDNA was encoded by OS9 whose protein is known to be located in the endoplasmic reticulum and also involved in the hypoxic stress, implicating the potential involvement in the pathogenesis of aplastic anemia. The minimum epitope sequence was composed of 11 amino acids: MAAETLLSSLL. Using the peptide, functional analyses are ongoing. An antigen recognized by another CTL with suppressive function in hematopoietic cells has not been identified, even after screening more than 100,000 cDNA clones.

Research Products

• [Journal Article] Hematopoiesis by iPSC-derived hematopoietic stem cells of aplastic anemia that escape cytotoxic T-cell attack (2018)
  • Author(s): Espinoza J. Luis、Elbadry Mahmoud I.、Chonabayashi Kazuhisa、Yoshida Yoshinori、Katagiri Takamasa、Harada Kenichi、Nakagawa Noriharu、Zaimoku Yoshitaka、Imi Tatsuya、Hassanein Hassan A.、Khalifa A. Noreldin Amal、Takenaka Katsuto、Akashi Koichi、Hamana Hiroshi、Kishi Hiroyuki、Akatsuka Yoshiki、Nakao Shinji
  • Journal Title: Blood Adv Volume: 2 Issue: 4 Pages: 390-400
  • DOI: 10.1182/bloodadvances.2017013342
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Induction of HLA-B*40:02-restricted T cells possessing cytotoxic and suppressive functions against haematopoietic progenitor cells from a patient with severe aplastic anaemia. (2015)
  • Author(s): Inaguma Y, Akatsuka Y, Hosokawa K, Maruyama H, Okamoto A, Katagiri T, Shiraishi K, Murayama Y, Tsuzuki-Iba S, Mizutani Y, Nishii C, Yamamoto N, Demachi-Okamura A, Kuzushima K, Ogawa S, Emi N, Nakao S.
  • Journal Title: Br J Haematol. Volume: in press Issue: 1 Pages: 131-134
  • DOI: 10.1111/bjh.13464
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 再生不良性貧血発症に関わる抗原遺伝子同定の試み (2017)
  • Author(s): 赤塚美樹、岡本晃直、岡村文子、楫屋良子、稲熊容子、白石圭子、葛島清隆、恵美宣彦
  • Organizer: 第9回血液疾患免疫療法学会
• [Presentation] 再生不良性貧血患者のKIR リガンド欠失自己造血幹細胞に対するNK 細胞の寛容 (2017)
  • Author(s): 鎧高健志、丸山裕之、Luis Espinoza、Nguyenthi Maianh、佐治博夫、赤塚美樹、中尾慎二
  • Organizer: 第79回日本血液学会総会,
• [Presentation] 遺伝子導入TCR/CARへの刺激でインターフェロンγを産生する人工T細胞株の作成 (2016)
  • Author(s): 赤塚美樹、白石圭子、楫屋良子、岡村文子、太田里永子、藤原 弘、葛島清隆、恵美宣彦.
  • Organizer: 第8回血液疾患免疫療法学会
  • Place of Presentation: 北海道大学医学部学友会館「フラテ」 （札幌市）
• [Presentation] がん細胞では異常なTAP分子によりエピトープを提示する. (2016)
  • Author(s): 岡村文子、赤塚美樹、葛島清隆.
  • Organizer: 第8回血液疾患免疫療法学会
  • Place of Presentation: 北海道大学医学部学友会館「フラテ」 （札幌市）