NOD背景下Prkdc純合突變：Prkdc（protein kinase, DNA-activated, catalytic polypeptide）基因主要編碼DNA依賴性蛋白激酶（DNA-PK）的催化亞基，是參與雙鏈DNA斷裂修復(fù)、免疫球蛋白和T細胞受體可變(V)、多樣性(D)、連接(J)區(qū)段重組的重要基因。Prkdcscid突變代表嚴重的聯(lián)合免疫缺陷，表現(xiàn)為缺失T、B細胞，無法介導(dǎo)細胞和體液免疫，不排斥同種和異種移植。無功能T細胞和B細胞，NK細胞活性低，沒有溶血補體活性，骨髓發(fā)育缺陷。血清免疫球蛋白（Ig）泄漏率非常低，非常適合同種和異種腫瘤移植。 IL2rgnull突變：Interleukin-2受體gamma鏈（IL-2Rγc，又稱CD132)是具有重要免疫功能的細胞因子Il2、Il-4、Il-7、Il-9、Il-15和Il-21的共同受體亞基，該基因敲除后的小鼠機體免疫功能嚴重降低，通過多種受體阻斷細胞因子信號傳導(dǎo)，導(dǎo)致功能性NK細胞缺陷。 M-NSG嚴重免疫缺陷小鼠，缺失成熟T、B、NK細胞，可高效地植入人CD34+造血干細胞（HSC）、外周血單核細胞（PBMC）、病人來源異種移植物（PDX）或成體干細胞和組織，基本上可以植入人體免疫系統(tǒng)，是研究人體免疫功能，傳染病，糖尿病，腫瘤學(xué)和干細胞生物學(xué)的重要免疫缺陷小鼠，是目前國際公認的免疫缺陷程度較高、較適合人源細胞或組織移植的工具小鼠。

表型分析

T、B、NK 細胞 FACS 檢測

圖 1.M-NSG 小鼠脾臟中 T、B 和 NK 細胞缺失。取 BALB/c、NOD-scid 和 M-NSG 小鼠的脾臟細胞，通過 FACS 對其中 T、B 和 NK 細胞的組成進行分析 (A) 并進行統(tǒng)計對比 (B)。

圖 2.M-NSG 小鼠血液中 T、B 和 NK 細胞缺失。取 BALB/c、NOD-scid 和 M-NSG 小鼠的外周血，通過 FACS 對其中 T、B 和 NK 細胞的組成進行分析 (A) 并進行統(tǒng)計對比 (B)。

M、MΦ、DC 細胞 FACS 檢測

圖 3.M-NSG 小鼠脾臟中單核細胞、巨噬細胞和 DC 細胞比例。取 BALB/c、NOD-scid 和 M-NSG 小鼠的脾臟細胞，通過 FACS 對其中單核細胞、巨噬細胞和 DC 細胞的組成進行分析 (A) 并進行統(tǒng)計對比 (B)。

圖 4.M-NSG 小鼠外周血中單核細胞、巨噬細胞和 DC 細胞比例。取 BALB/c、NOD-scid 和 M-NSG 小鼠的外周血，通過 FACS 對其中單核細胞、巨噬細胞和 DC 細胞的組成進行分析 (A) 并進行統(tǒng)計對比 (B)。

圖5. M-NSG小鼠生長曲線（n=720）

圖6. M-NSG小鼠血清抗體亞類檢測（雄性，8周齡）。

圖7. M-NSG 各組織病理學(xué)檢測。A:除脾臟和胸腺外，其他組織未見明顯異常，包括：腦、視網(wǎng)膜、脊髓、心臟、肝、肺、腎、小腸、大腸、胃、唾液腺、胰腺、卵巢、子宮、睪丸、附睪、骨骼肌、皮膚和棕色脂肪（雌性，6周齡）；B,C: M-NSG小鼠的脾臟缺乏白髓，淋巴細胞減少（6周齡）。

表1. M-NSG小鼠血常規(guī)檢測

表2. M-NSG小鼠血生化檢測

CDX/PDX成瘤及藥效驗證

圖8.?A549 肺腫瘤細胞（A）或?Raji 淋巴瘤細胞（B）在 M-NSG 小鼠上的成瘤驗證。

基于 M-NSG 小鼠成功建立的 CDX 模型

圖9.利用淋巴癌（Raji）CDX模型進行抗人CD47抗體藥效驗證實驗。

圖10. 利用肺癌（A549）CDX模型進行CAR-T藥效驗證實驗。

圖11. 移植CAR-T的M-NSG小鼠體內(nèi)的GVHD研究。

圖12. 肝癌PDX在 M-NSG 小鼠上的成瘤驗證。

人源免疫系統(tǒng)重建模型?

利用重度免疫缺陷M-NSG小鼠可以通過移植人源外周血細胞、造血干細胞等，實現(xiàn)在小鼠體內(nèi)重塑人源免疫系統(tǒng)，為免疫學(xué)、腫瘤學(xué)及人類傳染疾病等研究提供有力工具。

PBMC人源化小鼠

Hu-PBMC模型，或者被稱為Hu-PBL（perihperal blood lymphocyte, PBL）模型，是一種構(gòu)建較為簡單和經(jīng)濟的免疫系統(tǒng)人源化小鼠模型。Hu-PBMC模型的移植方式主要有腹腔注射與尾靜脈注射，通常以4-6周齡的M-NSG小鼠作為移植受體，PBMC移植/接種量通常在5~10*10^6/小鼠。該模型常被用于研究人效應(yīng)T細胞的活化以及評估免疫抑制藥物。

Hu-PBMC模型的供體篩選

圖13.? M-NSG小鼠中進行Hu-PBMC重建的供體篩選。

圖14.流式分析Hu-PBMC模型外周血淋巴細胞亞群。將人PBMCs(5E6)靜脈注射M-NSG小鼠（雌性，6-8周齡，n=4）。植入human PBMCs后取不同時間點的小鼠血液進行流式細胞分析。

圖15. 利用骨髓瘤（H929）Hu-PBMC模型進行體內(nèi)藥效研究。

圖16. 利用乳腺癌（MDA-MB-231）Hu-PBMC模型進行體內(nèi)藥效研究。

HSC人源化小鼠

Hu-HSC模型，也叫hu-CD34+，或叫hu-SRC（scid-repopulatingcell），已經(jīng)被廣泛應(yīng)用于研究人類造血發(fā)育、細胞介導(dǎo)的免疫反應(yīng)以及HIV和EBV等病毒感染性疾病中。?其構(gòu)建方式是將來自人臍帶血、骨髓、G-CSF激活的外周血或胎肝的人CD34+ HSCs通過靜脈內(nèi)（i.v.）或股骨內(nèi)（i.f.）注射到成年免疫缺陷小鼠M-NSG中，得到的小鼠可以產(chǎn)生多種造血干細胞。

圖17. M-NSG小鼠中進行Hu-HSC重建的供體篩選。

圖18. 流式分析Hu-HSC模型外周血淋巴細胞亞群。

圖19. 利用乳腺癌（MDA-MB-231）Hu-HSC模型進行體內(nèi)藥效研究。

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