2021 Fiscal Year Final Research Report

Identification of autoantigens presented by specific HLA class I alleles in aplastic anemia

Research Project

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Project/Area Number	19H03686
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 54010:Hematology and medical oncology-related
Research Institution	Kanazawa University
Principal Investigator	NAKAO Shinji 金沢大学, 医学系, 協力研究員 (70217660)
Co-Investigator(Kenkyū-buntansha)	橋本真一和歌山県立医科大学, 先端医学研究所, 教授 (00313099) 細道一善金沢大学, 医学系, 准教授 (50420948) 岸裕幸富山大学, 学術研究部医学系, 教授 (60186210)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	再生不良性貧血 / 自己抗原 / HLA-B*40:02 / T細胞レセプター / 発作性夜間ヘモグロビン尿症 / HLA-DR15
Outline of Final Research Achievements	To identify an autoantigen presented by HLA-B4002 on hematopoietic stem progenitor cells (HSPCs) of patients with acquired aplastic anemia (AA), we established T-cell receptor (TCR) transfectants using T cells from healthy individuals and TCR cDNA derived from T cells that predominantly proliferated in the bone marrow of an AA patient carrying HLA-B40:02, and examined specific response to peptides bound to HLA-B4002 on a leukemia cell line K562 that were transfected with HLA-B40:02. Two kinds of TCR transfectants specifically recognized one of the HLA-B4002-bound peptides that are derived from a cytoplasmic protein (protein X), which is abundantly expressed by HSPCs. We prepared a peptide-HLA-B4002 tetramer and are now screening peripheral blood T cells of AA patients with HLA-B*40:02 for the presence of the peptide-specific CD8+ T cells. In a separate experiment, we found that HSPCs of AA patients possessing HLA-DR15 frequently lacked HLA-DR through epigenetic mechanisms.
Free Research Field	血液内科学
Academic Significance and Societal Importance of the Research Achievements	AAは、HSPCに対する細胞傷害性T細胞の攻撃がきっかけとなって発症する自己免疫疾患である。しかし、細胞傷害性T細胞の標的となるHSPC上の自己抗原は不明であった。今回同定したX蛋白由来ペプチドに特異的なCD8+ T細胞が、HLA-B*40:02陽性AA患者の末梢血に検出され、さらにそのCD8+ T細胞の自己HSPCに対する細胞傷害性が証明されれば、X蛋白はAAにおける自己抗原であると考えられる。それが証明されれば、HLA-B4002-ペプチドテトラマーを用いたAAの特異的診断や、テトラマー陽性T細胞を標的とする選択的な治療法の開発などが可能となることが期待される。