M-NSG

NOD背景下Prkdc纯合突变：Prkdc（protein kinase, DNA-activated, catalytic polypeptide）基因主要编码DNA依赖性蛋白激酶（DNA-PK）的催化亚基，是参与双链DNA断裂修复、免疫球蛋白和T细胞受体可变(V)、多样性(D)、连接(J)区段重组的重要基因。Prkdcscid突变代表严重的联合免疫缺陷，表现为缺失T、B细胞，无法介导细胞和体液免疫，不排斥同种和异种移植。无功能T细胞和B细胞，NK细胞活性低，没有溶血补体活性，骨髓发育缺陷。血清免疫球蛋白（Ig）泄漏率非常低，非常适合同种和异种肿瘤移植。 IL2rgnull突变：Interleukin-2受体gamma链（IL-2Rγc，又称CD132)是具有重要免疫功能的细胞因子Il2、Il-4、Il-7、Il-9、Il-15和Il-21的共同受体亚基，该基因敲除后的小鼠机体免疫功能严重降低，通过多种受体阻断细胞因子信号传导，导致功能性NK细胞缺陷。 M-NSG严重免疫缺陷小鼠，缺失成熟T、B、NK细胞，可高效地植入人CD34+造血干细胞（HSC）、外周血单核细胞（PBMC）、病人来源异种移植物（PDX）或成体干细胞和组织，基本上可以植入人体免疫系统，是研究人体免疫功能，传染病，糖尿病，肿瘤学和干细胞生物学的重要免疫缺陷小鼠，是目前国际公认的免疫缺陷程度较高、较适合人源细胞或组织移植的工具小鼠。

表型分析

T、B、NK 细胞 FACS 检测

图 1.M-NSG 小鼠脾脏中 T、B 和 NK 细胞缺失。取 BALB/c、NOD-scid 和 M-NSG 小鼠的脾脏细胞，通过 FACS 对其中 T、B 和 NK 细胞的组成进行分析 (A) 并进行统计对比 (B)。

图 2.M-NSG 小鼠血液中 T、B 和 NK 细胞缺失。取 BALB/c、NOD-scid 和 M-NSG 小鼠的外周血，通过 FACS 对其中 T、B 和 NK 细胞的组成进行分析 (A) 并进行统计对比 (B)。

M、MΦ、DC 细胞 FACS 检测

图 3.M-NSG 小鼠脾脏中单核细胞、巨噬细胞和 DC 细胞比例。取 BALB/c、NOD-scid 和 M-NSG 小鼠的脾脏细胞，通过 FACS 对其中单核细胞、巨噬细胞和 DC 细胞的组成进行分析 (A) 并进行统计对比 (B)。

图 4.M-NSG 小鼠外周血中单核细胞、巨噬细胞和 DC 细胞比例。取 BALB/c、NOD-scid 和 M-NSG 小鼠的外周血，通过 FACS 对其中单核细胞、巨噬细胞和 DC 细胞的组成进行分析 (A) 并进行统计对比 (B)。

图5. M-NSG小鼠生长曲线（n=720）

图6. M-NSG小鼠血清抗体亚类检测（雄性，8周龄）。

图7. M-NSG 各组织病理学检测。A:除脾脏和胸腺外，其他组织未见明显异常，包括：脑、视网膜、脊髓、心脏、肝、肺、肾、小肠、大肠、胃、唾液腺、胰腺、卵巢、子宫、睾丸、附睾、骨骼肌、皮肤和棕色脂肪（雌性，6周龄）；B,C: M-NSG小鼠的脾脏缺乏白髓，淋巴细胞减少（6周龄）。

表1. M-NSG小鼠血常规检测

表2. M-NSG小鼠血生化检测

CDX/PDX成瘤及药效验证

图8. A549 肺肿瘤细胞（A）或 Raji 淋巴瘤细胞（B）在 M-NSG 小鼠上的成瘤验证。

基于 M-NSG 小鼠成功建立的 CDX 模型

图9.利用淋巴癌（Raji）CDX模型进行抗人CD47抗体药效验证实验。

图10. 利用肺癌（A549）CDX模型进行CAR-T药效验证实验。

图11. 移植CAR-T的M-NSG小鼠体内的GVHD研究。

图12. 肝癌PDX在 M-NSG 小鼠上的成瘤验证。

人源免疫系统重建模型 

利用重度免疫缺陷M-NSG小鼠可以通过移植人源外周血细胞、造血干细胞等，实现在小鼠体内重塑人源免疫系统，为免疫学、肿瘤学及人类传染疾病等研究提供有力工具。

PBMC人源化小鼠

Hu-PBMC模型，或者被称为Hu-PBL（perihperal blood lymphocyte, PBL）模型，是一种构建较为简单和经济的免疫系统人源化小鼠模型。Hu-PBMC模型的移植方式主要有腹腔注射与尾静脉注射，通常以4-6周龄的M-NSG小鼠作为移植受体，PBMC移植/接种量通常在5~10*10^6/小鼠。该模型常被用于研究人效应T细胞的活化以及评估免疫抑制药物。

Hu-PBMC模型的供体筛选

图13.  M-NSG小鼠中进行Hu-PBMC重建的供体筛选。

图14.流式分析Hu-PBMC模型外周血淋巴细胞亚群。将人PBMCs(5E6)静脉注射M-NSG小鼠（雌性，6-8周龄，n=4）。植入human PBMCs后取不同时间点的小鼠血液进行流式细胞分析。

图15. 利用骨髓瘤（H929）Hu-PBMC模型进行体内药效研究。

图16. 利用乳腺癌（MDA-MB-231）Hu-PBMC模型进行体内药效研究。

HSC人源化小鼠

Hu-HSC模型，也叫hu-CD34+，或叫hu-SRC（scid-repopulatingcell），已经被广泛应用于研究人类造血发育、细胞介导的免疫反应以及HIV和EBV等病毒感染性疾病中。 其构建方式是将来自人脐带血、骨髓、G-CSF激活的外周血或胎肝的人CD34+ HSCs通过静脉内（i.v.）或股骨内（i.f.）注射到成年免疫缺陷小鼠M-NSG中，得到的小鼠可以产生多种造血干细胞。

图17. M-NSG小鼠中进行Hu-HSC重建的供体筛选。

图18. 流式分析Hu-HSC模型外周血淋巴细胞亚群。

图19. 利用乳腺癌（MDA-MB-231）Hu-HSC模型进行体内药效研究。

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