The studies on the practical application of NOD-sc/d, yc null mice allowing an efficient transplantation of human cells, to human disease models

NOD-sc/d、yc 缺失小鼠的实际应用研究，可将人类细胞有效移植到人类疾病模型中

• 批准号: 13558100
• 负责人: ITO Mamoru
• 金额: $ 7.42万
• 依托单位: Central Institute for Experimental Animals
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13558100/
• 关键词: experimental animals; NOD-scid. γc null mice; Immunodeficiency; Xenotransplantation; CD34+ stem cells; HIV-1; HTLV-1; NOD-scid,γKOマウス

1. We have eliminated C57BL/6 genes which originated frolL-2Rγ KO mice and still remained in NOG mice, by further backcross mating to NOD/Shi- scid mice. The reproduction efficacy of NOG mice was almost same to that of NOD/Shi- scid mice. The reproduction efficacy of NOG mice was almost same to that of NOD/Shi- scid mice.2. After intravenous inoculation of human cord blood CD34^+ cells, the NOG mice allowed the extremely higher growth rate of human cells when compared with NOD/Shi-scid mice. In addition, human CD4^+ T and CD8^+ T cells could differentiate in these mice. Human B cells also generated and reproduced human immunoglobulins in NOG mice.3. When HIV-1 was inoculated to PBL-NOG-hu mice, which were inoculated with human PBMC, the significantly high level of HIV-1 p24 gag as well as HIV-1 RNA in plasma and cell-associated HIV-1 DNA were detected, respectively. Simultaneously, the remarkable level of human CD4+ cell depletion was observed.4. In HTLV-1 infection NOG model, two to 3 … More weeks after subcutaneous inoculation of HTLV-1 infected cell lines in the post-auricular region of NOG mice, a visible tumor developed in the site. Almost all cell lines formed a progressively growing large tumor mass with leukemic infiltration of cells in various organs.5. Seven weeks after intravenous inoculation of U266 cells, which were IL-6 dependent human myeloma cell line, to NOG mice, U226 cells massively infiltrated in bone marrow of NOG mice and also invaded into the spiral cord plexus, and finally caused hind leg paralysis, weight loss and distress as observed in human patients.6. NOG mice showed high growth rate of primary human tumor transplantation. When human pancreas tumor cells, i.e. Capan-1 and PANC-1, were inoculated into the mouse spleen, the high metastasis rates in liver were observed in NOG mice but not NOD/Shi- scid mice. These results indicated that NOG mice were extremely useful tools for human disease model.These results indicated that NOG mice were extremely useful tools for human disease model. Less

1.通过与NOD/Shi-scid小鼠的回交，我们消除了源自1 L-2 R γ KO小鼠而仍保留在NOG小鼠中的C57 BL/6基因。NOG小鼠的生殖效能与NOD/Shi-scid小鼠基本相同。NOG小鼠的生殖效能与NOD/Shi-scid小鼠基本相同.静脉注射人脐带血CD 34 ^+细胞后，NOG小鼠的人细胞生长速度比NOD/Shi-scid小鼠高得多。此外，人CD 4 ^+ T细胞和CD 8 ^+ T细胞在这些小鼠中可以分化。人B细胞也能在NOG小鼠中产生和复制人免疫球蛋白。将HIV-1接种于PBL-NOG-hu小鼠，并将其与人PBMC一起接种，在血浆和细胞相关的HIV-1 DNA中分别检测到HIV-1 p24 gag和HIV-1 RNA的显著高水平。与此同时，人CD 4+细胞的耗竭水平显著降低.在HTLV-1感染NOG模型中，2至3 ...更多信息 在NOG小鼠的耳后区域皮下接种HTLV-1感染的细胞系5周后，在该部位产生可见的肿瘤。几乎所有的细胞系都形成了一个进行性生长的大肿瘤块，白血病细胞浸润到各个器官。将IL-6依赖性人骨髓瘤细胞系U266细胞静脉接种至NOG小鼠7周后，U226细胞大量浸润NOG小鼠的骨髓，并侵入螺旋索丛，最终导致人类患者观察到的后肢麻痹、体重减轻和痛苦. NOG小鼠显示出高的原发性人肿瘤移植生长率。将人胰腺癌细胞（Capan-1和PANC-1）接种于小鼠脾脏后，NOG小鼠的肝转移率较高，而NOD/Shi-scid小鼠的肝转移率较低。这些结果表明，NOG小鼠是非常有用的人类疾病模型的工具。少

项目成果

Kosugi H, Ito M, Yamamoto Y, Towatari M, Ueda R, Saito H, Naoe T.: "In vivo Effects of a Histone Deacetylase Inhibitor, FK228, on Human Acute Promyelocytic Leukemia in NOD / Shi-scid / scid Mice."Jpn J Cancer Res.. 92. 529-536 (2001)

Kosugi H、Ito M、Yamamoto Y、Towatari M、Ueda R、Saito H、Naoe T.：“组蛋白脱乙酰酶抑制剂 FK228 对 NOD / Shi-scid / scid 小鼠中人类急性早幼粒细胞白血病的体内作用。”

Saito, Y.: "The in vivo development of human T cells from CD34(+) cells in the murine thymic environment"Int Immunol.. 14. 1113-1124 (2002)

Saito, Y.：“在小鼠胸腺环境中从 CD34(+) 细胞体内开发人 T 细胞”Int Nutrition.. 14. 1113-1124 (2002)

Ma, F.: "Growth of human T cell acute lymphoblastic leukemia lymphoblasts in NOD/SCID mouse fetal thymus organ culture"Leukemia. 16. 1541-1548 (2002)

Ma, F.：“人 T 细胞急性淋巴细胞白血病淋巴母细胞在 NOD/SCID 小鼠胎儿胸腺器官培养物中的生长”白血病。

Miura, Y: "Tumor necrosis factor-related apoptosis-inducing ligand induces neuronal death in a murine model of HIV central nervous system infection"Proc.Natl.Acad.Sci. USA.. 100. 2777-22782 (2003)

Miura，Y：“肿瘤坏死因子相关的凋亡诱导配体在 HIV 中枢神经系统感染的小鼠模型中诱导神经元死亡”Proc.Natl.Acad.Sci。

Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K, UeyamaY, Koyanagi Y, Sugamura K, Tsuji K, Heike T, Nakahata T.: "NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells."Blood. 100. 3175-3182 (2002)

Ito M、Hiramatsu H、Kobayashi K、Suzue K、Kawahata M、Hioki K、UeyamaY、Koyanagi Y、Sugamura K、Tsuji K、Heike T、Nakahata T.：“NOD/SCID/gamma(c)(null) 小鼠：