Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2Rγnull mice engrafted with mobilized human hemopoietic stem cells
Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2Rγnull mice engrafted with mobilized human hemopoietic stem cells
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DOI：
10.4049/jimmunol.174.10.6477
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发表时间：
2005-05-15
影响因子：
4.4
通讯作者：
Handgretinger, R
中科院分区：
文献类型：
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作者：
Shultz, LD;Lyons, BL;Handgretinger, R
伦理考量限制了对人类造血干细胞（HSC）的体内研究。为克服这一限制，已使用人类HSC移植的小动物模型。我们报道了一种白细胞介素 - 2受体共同γ链缺陷型NOD/LtSz - scid（NOD - scid IL2ry（null））小鼠的新遗传品系的开发和特性，并记录了它们支持人类动员的血液HSC移植和多谱系分化的能力。NOD - scid IL2Rγ（null）小鼠缺乏成熟淋巴细胞和自然杀伤细胞，能存活超过16个月，即使在亚致死剂量照射后也能抵抗淋巴瘤的发生。用人类HSC移植NOD - scid IL2Rγ（null）小鼠在宿主骨髓中产生的人类CD45（+）细胞百分比比用类似方法处理的NOD - scid小鼠高6倍。这些人类细胞包括B细胞、自然杀伤细胞、髓系细胞、浆细胞样树突状细胞和造血干细胞。移植后的NOD - scid IL2Rγ（null）小鼠的脾脏含有人类Ig（+）B细胞和较少数量的人类CD3（+）T细胞。同时给予人类Fc - IL7融合蛋白导致高百分比的人类CD4（+）CD8（+）胸腺细胞以及人类CD4（+）CD8（ - ）和CD4（ - ）CD8（+）外周血和脾脏T细胞。NOD - scid IL2Rγ（null）小鼠中从头开始的人类T细胞发育通过以下几点得到验证：1）高水平的T细胞受体切除环，2）复杂的T细胞受体β链库多样性，3）对植物血凝素和链球菌超抗原、链球菌致热外毒素的增殖反应。因此，移植了人类动员的血液干细胞的NOD - scid IL2Rγ（null）小鼠为强大的多谱系人类HSC移植提供了一种新的体内长期存活模型。
Ethical considerations constrain the in vivo study of human hemopoietic stem cells (HSC). To overcome this limitation, small animal models of human HSC engraftment have been used. We report the development and characterization of a new genetic stock of IL-2R common gamma-chain deficient NOD/LtSz-scid (NOD-scid IL2ry(null)) mice and document their ability to support human mobilized blood HSC engraftment and multilineage differentiation. NOD-scid IL2R gamma(null) mice are deficient in mature lymphocytes and NK cells, survive beyond 16 mo of age, and even after sublethal irradiation resist lymphoma development. Engraftment of NOD-scid IL2R gamma(null) mice with human HSC generate 6-fold higher percentages of human CD45(+) cells in host bone marrow than with similarly treated NOD-scid mice. These human cells include B cells, NK cells, myeloid cells, plasmacytoid dendritic cells, and HSC. Spleens from engrafted NOD-scid IL2R gamma(null) mice contain human Ig(+) B cells and lower numbers of human CD3(+) T cells. Coadministration of human Fc-IL7 fusion protein results in high percentages of human CD4(+)CD8(+) thymocytes as well human CD4(+)CD8(-) and CD4(-)CD8(+) peripheral blood and splenic T cells. De novo human T cell development in NOD-scid IL2R gamma(null) mice was validated by 1) high levels of TCR excision circles, 2) complex TCRP repertoire diversity, and 3) proliferative responses to PHA and streptococcal superantigen, streptococcal pyrogenic exotoxin. Thus, NOD-scid IL2R gamma(null) mice engrafted with human mobilized blood stem cells provide a new in vivo long-lived model of robust multilineage human HSC engraftment.