PDF(Pubmed)
Abstract：
The spectrum of background, incidental, and experimentally induced lesions affecting NSG and NOG mice has been the subject of intense investigation. However, comprehensive studies focusing on the spontaneous neuropathological changes of these immunocompromised strains are lacking. This work describes the development of spontaneous early-onset neurodegeneration affecting both juvenile and adult NSG, NOG, and NXG mice. The study cohort consisted of 367 NSG mice of both sexes (including 33 NSG-SGM3), 61 NOG females (including 31 NOG-EXL), and 4 NXG females. These animals were primarily used for preclinical CAR T-cell testing, generation of humanized immune system chimeras, and/or tumor xenograft transplantation. Histopathology of brain and spinal cord and immunohistochemistry (IHC) for AIF-1, GFAP, CD34, and CD45 were performed. Neurodegenerative changes were observed in 57.6% of the examined mice (affected mice age range was 6-36 weeks). The lesions were characterized by foci of vacuolation with neuronal degeneration/death and gliosis distributed throughout the brainstem and spinal cord. IHC confirmed the development of gliosis, overexpression of CD34, and a neuroinflammatory component comprised of CD45-positive monocyte-derived macrophages. Lesions were significantly more frequent and severe in NOG mice. NSG males were considerably more affected than NSG females. Increased lesion frequency and severity in older animals were also identified. These findings suggest that NSG, NOG, and NXG mice are predisposed to the early development of identical neurodegenerative changes. While the cause of these lesions is currently unclear, potential associations with the genetic mutations shared by NSG, NOG, and NXG mice as well as unidentified viral infections are considered.
摘要：
背景的光谱，附带的,影响NSG和NOG小鼠的实验诱导的损伤一直是深入研究的主题。然而,缺乏针对这些免疫受损菌株的自发神经病理学变化的综合研究。这项工作描述了影响青少年和成人NSG的自发性早发性神经变性的发展，NOG,和NXG小鼠。研究队列由367只两性的NSG小鼠（包括33只NSG-SGM3）组成，61名女性（包括31名NOG-EXL），和4名NXG女性。这些动物主要用于临床前CAR-T细胞测试，产生人源化免疫系统嵌合体，和/或肿瘤异种移植。脑和脊髓的组织病理学和AIF-1，GFAP的免疫组织化学（IHC），进行CD34和CD45。在57.6%的受检小鼠中观察到神经变性变化(受影响的小鼠年龄范围为6-36周)。病变的特征是空泡灶，神经元变性/死亡和神经胶质增生分布在整个脑干和脊髓中。IHC证实神经胶质增生的发展，CD34的过表达，以及由CD45阳性单核细胞衍生的巨噬细胞组成的神经炎性成分。NOG小鼠的病变明显更频繁和严重。NSG男性比NSG女性受到的影响更大。还鉴定了老年动物中病变频率和严重程度的增加。这些发现表明，NSG，NOG,和NXG小鼠倾向于早期发展相同的神经退行性变化。虽然这些病变的原因目前尚不清楚，与NSG共有的基因突变的潜在关联，NOG,和NXG小鼠以及未识别的病毒感染被考虑。
