具备内源性人类自然杀伤细胞的人源化小鼠模型，用于HLA I类编辑的iPSC导出细胞的体内免疫原性测试。
Humanized mouse models with endogenously developed human natural killer cells for in vivo immunogenicity testing of HLA class I-edited iPSC-derived cells.
发表日期：2023 Apr 20
作者：
Charlotte Flahou, Tatsuya Morishima, Natsumi Higashi, Yoshikazu Hayashi, Huaigeng Xu, Bo Wang, Chaoqi Zhang, Atsushi Ninomiya, Wei-Yin Qiu, Akinori Yuzuriha, Daisuke Suzuki, Sou Nakamura, Markus Manz, Shin Kaneko, Akitsu Hotta, Hitoshi Takizawa, Koji Eto, Naoshi Sugimoto
来源：
Cellular & Molecular Immunology
摘要：
人类诱导多能干细胞 (hiPSCs) 经基因编辑剔除人类白细胞抗原 (HLA) I 类表达，可以规避 T 细胞异体免疫反应，因此成为细胞治疗的通用来源。然而，由于 HLA I 类分子是自然杀伤 (NK) 细胞的抑制配体，这些治疗可能会引起 NK 细胞的排异反应。在这里，我们专注于使用 MTSRG 和 NSG-SGM3 型人源化小鼠评估自身发育的人源 NK 细胞对 HLA 编辑 iPSC 衍生细胞的耐受性。通过移植脐带血源人类造血干细胞 (hHSCs) 并接受人类白细胞介素-15 (hIL-15) 和 IL-15 受体 alpha (hIL-15Rα) 的注射，我们实现了高度 NK 细胞重建。这种“人源化 NK 小鼠”拒绝了 HLA I 类缺失 hiPSC 衍生的造血祖细胞、巨核细胞和 T 细胞，但未拒绝 HLA-A/B 缺失、表达 HLA-C 的造血祖细胞。据我们所知，这是首次在体内重现非肿瘤 HLA I 类下调细胞对强效自身 NK 细胞应答的研究。我们的“人源化 NK 小鼠”模型适用于 HLA 编辑细胞的非临床评估，并将有助于通用现成再生医学的发展。版权所有 © 2023 Elsevier Inc.
Human induced pluripotent stem cells (hiPSCs) genetically depleted of human leucocyte antigen (HLA) class I expression can bypass T cell alloimmunity and thus serve as a one-for-all source for cell therapies. However, these same therapies may elicit rejection by natural killer (NK) cells, since HLA class I molecules serve as inhibitory ligands of NK cells. Here, we focused on testing the capacity of endogenously developed human NK cells in humanized mice (hu-mice) using MTSRG and NSG-SGM3 strains to assay the tolerance of HLA-edited iPSC-derived cells. High NK cell reconstitution was achieved with the engraftment of cord blood-derived human hematopoietic stem cells (hHSCs) followed by the administration of human interleukin-15 (hIL-15) and IL-15 receptor alpha (hIL-15Rα). Such "hu-NK mice" rejected HLA class I-null hiPSC-derived hematopoietic progenitor cells (HPCs), megakaryocytes and T cells, but not HLA-A/B-knockout, HLA-C expressing HPCs. To our knowledge, this study is the first to recapitulate the potent endogenous NK cell response to non-tumor HLA class I-downregulated cells in vivo. Our hu-NK mouse models are suitable for the non-clinical evaluation of HLA-edited cells and will contribute to the development of universal off-the-shelf regenerative medicine.Copyright © 2023 Elsevier Inc. All rights reserved.