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Improved engraftment of human peripheral blood mononuclear cells in NOG MHC double knockout mice generated using CRISPR/Cas9
Immunology Letters ( IF 3.3 ) Pub Date : 2020-11-27 , DOI: 10.1016/j.imlet.2020.11.011
Yuyo Ka 1 , Ikumi Katano 1 , Eiko Nishinaka 1 , Jochen Welcker 2 , Misa Mochizuki 1 , Kenji Kawai 1 , Motohito Goto 1 , Kayo Tomiyama 1 , Tomoyuki Ogura 1 , Taichi Yamamoto 1 , Mamoru Ito 1 , Ryoji Ito 1 , Riichi Takahashi 1
Affiliation  

Humanized mice are widely used to study the human immune system in vivo and develop therapies for various human diseases. Human peripheral blood mononuclear cells (PBMC)-engrafted NOD/Shi-scid IL2rγnull (NOG) mice are useful models for characterization of human T cells. However, the development of graft-versus-host disease (GVHD) limits the use of NOG PBMC models. We previously established a NOG-major histocompatibility complex class I/II double knockout (dKO) mouse model. Although humanized dKO mice do not develop severe GVHD, they have impaired reproductive performance and reduced chimerism of human cells. In this study, we established a novel beta-2 microglobulin (B2m) KO mouse model using CRISPR/Cas9. By crossing B2m KO mice with I-Ab KO mice, we established a modified dKO (dKO-em) mouse model. Reproductivity was slightly improved in dKO-em mice, compared with conventional dKO (dKO-tm) mice. dKO-em mice showed no signs of GVHD after the transfer of human PBMCs; they also exhibited high engraftment efficiency. Engrafted human PBMCs survived significantly longer in the peripheral blood and spleens of dKO-em mice, compared with dKO-tm mice. In conclusion, dKO-em mice might constitute a promising PBMC-based humanized mouse model for the development and preclinical testing of novel therapeutics for human diseases.



中文翻译:

在使用 CRISPR/Cas9 生成的 NOG MHC 双敲除小鼠中改进人外周血单个核细胞的植入

人源化小鼠广泛用于研究体内人体免疫系统并开发针对各种人类疾病的疗法。人外周血单核细胞(PBMC)-engrafted NOD /仕SCID IL2rγ(NOG) 小鼠是表征人类 T 细胞的有用模型。然而,移植物抗宿主病 (GVHD) 的发展限制了 NOG PBMC 模型的使用。我们之前建立了 NOG 主要组织相容性复合物 I/II 类双敲除 (dKO) 小鼠模型。尽管人源化 dKO 小鼠不会发展为严重的 GVHD,但它们的生殖能力受损并减少了人类细胞的嵌合。在这项研究中,我们使用 CRISPR/Cas9 建立了一种新型的 beta-2 微球蛋白 (B2m) KO 小鼠模型。通过将 B2m KO 小鼠与 I-Ab KO 小鼠杂交,我们建立了改良的 dKO (dKO-em) 小鼠模型。与传统的 dKO (dKO-tm) 小鼠相比,dKO-em 小鼠的生殖能力略有提高。dKO-em 小鼠在转移人 PBMC 后未显示 GVHD 迹象;它们还表现出很高的植入效率。与 dKO-tm 小鼠相比,移植的人类 PBMC 在 dKO-em 小鼠的外周血和脾脏中存活的时间明显更长。总之,dKO-em 小鼠可能构成一个有前途的基于 PBMC 的人源化小鼠模型,用于人类疾病新疗法的开发和临床前测试。

更新日期:2020-12-11
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