PDF(Pubmed)
Abstract：
Severe combined immunodeficient (SCID) mice serve as a critical model for human xenotransplantation studies, yet they often suffer from low engraftment rates and susceptibility to graft-versus-host disease (GVHD). Moreover, certain SCID strains demonstrate \'immune leakage\', underscoring the need for novel model development. Here, we introduce an SCID mouse model with a targeted disruption of the dclre1c gene, encoding Artemis, which is essential for V(D)J recombination and DNA repair during T cell receptor (TCR) and B cell receptor (BCR) assembly. Artemis deficiency precipitates a profound immunodeficiency syndrome, marked by radiosensitivity and compromised T and B lymphocyte functionality. Utilizing CRISPR/Cas9-mediated gene editing, we generated dclre1c-deficient mice with an NOD genetic background. These mice exhibited a radiosensitive SCID phenotype, with pronounced DNA damage and defective thymic, splenic and lymph node development, culminating in reduced T and B lymphocyte populations. Notably, both cell lines and patient-derived tumor xenografts were successfully engrafted into these mice. Furthermore, the human immune system was effectively rebuilt following peripheral blood mononuclear cells (PBMCs) transplantation. The dclre1c-knockout NOD mice described herein represent a promising addition to the armamentarium of models for xenotransplantation, offering a valuable platform for advancing human immunobiological research.
摘要：
严重的联合免疫缺陷（SCID）小鼠作为人类异种移植研究的关键模型，然而,他们经常遭受低植入率和移植物抗宿主病(GVHD)的易感性.此外，某些SCID菌株显示“免疫渗漏”，强调了开发新模型的必要性。这里,我们引入了一个SCID小鼠模型，对dclre1c基因进行靶向破坏，编码Artemis,这对于T细胞受体（TCR）和B细胞受体（BCR）组装过程中的V（D）J重组和DNA修复至关重要。Artemis缺乏症导致严重的免疫缺陷综合症，以放射敏感性和受损的T和B淋巴细胞功能为标志。利用CRISPR/Cas9介导的基因编辑，我们产生了具有NOD遗传背景的dclre1c缺陷小鼠.这些小鼠表现出放射敏感的SCID表型，有明显的DNA损伤和胸腺缺陷，脾和淋巴结发育，最终导致T和B淋巴细胞数量减少。值得注意的是,细胞系和患者来源的肿瘤异种移植物均成功移植入这些小鼠.此外，外周血单核细胞（PBMC）移植后，人类免疫系统得到了有效重建。本文描述的dclre1c敲除NOD小鼠代表了异种移植模型的有希望的补充。为推进人类免疫生物学研究提供了一个有价值的平台。
