2021 Fiscal Year Final Research Report

Optimizing immunomodulation of hematopoietic stem cell transplantation focusing on allelic polymorphisms of KIRs

Research Project

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Project/Area Number	19K08812
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	Kyoto University
Principal Investigator	Shindo Takero 京都大学, 医学研究科, 助教 (10646706)
Co-Investigator(Kenkyū-buntansha)	高折晃史京都大学, 医学研究科, 教授 (20324626) 伊村明浩京都大学, 医学研究科, 特定病院助教 (60362513)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	同種造血幹細胞移植 / NK細胞受容体 / KIR / GVHD / 抗腫瘍免疫
Outline of Final Research Achievements	Killer cell immunoglobulin-like receptors (KIRs) belong to NK cell receptors and modulate NK cell immunity through binding histocompatibility leukocyte antigens (HLAs). Although the combinations of donor KIRs and recipient HLAs are assumed to be associated with the prognosis of allogeneic hematopoietic stem cell transplantation, clinical significance of KIRs is unclear due to their abundant and undetermined polymorphisms. We established a novel method to determine alleles, copy numbers and haplotypes of 17 KIRs. We then investigated associations between KIR alleles and the prognosis in allogeneic hematopoietic stem cell transplantation. Finally, we confirmed that targeting specific KIR alleles enhances anti-tumor immunity against hematologic malignancies. Based on these results, we aim to propose a novel algorithm to select the best donors to suppress severe GVHD and relapsing malignancies following allogeneic hematopoietic stem cell transplantation.
Free Research Field	移植免疫学
Academic Significance and Societal Importance of the Research Achievements	KIR多型は同種造血幹細胞移植の予後と相関すると考えられるが、その複雑さゆえ正確なタイピング手法は未確立で、臨床的意義も不明であった。今回KIRアレルの自動化タイピング法を新規に開発し、移植症例でその臨床的意義を検証した。さらにKIR3DL1アレルの機能阻害でNK細胞免疫を賦活できることを見出し、KIR多型に基づく免疫療法という概念を確立した。現在移植ドナー選定はHLAにのみ基づいて行われるが、それでは限界があり、重度のGVHDや生着不全、免疫再構築の遅延による感染症死を抑制しきれない。本研究でこれら合併症が克服され予後の改善を見込め、移植合併症による社会資源使用の軽減が期待される。