A novel immunodeficient mouse model -: RAG2 x common cytokine receptor γ chain double mutants -: Requiring exogenous cytokine administration for human hematopoietic stem cell engraftment
A novel immunodeficient mouse model -: RAG2 x common cytokine receptor γ chain double mutants -: Requiring exogenous cytokine administration for human hematopoietic stem cell engraftment
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DOI：
10.1089/107999099313983
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发表时间：
1999-05-01
影响因子：
2.3
通讯作者：
de Verneuil, H
中科院分区：
文献类型：
--
作者：
Mazurier, F;Fontanellas, A;de Verneuil, H
将基因导入从脐带血、骨髓或动员的外周血细胞中采集的未成熟的人造血细胞，可用于治疗遗传性和获得性造血系统疾病。免疫缺陷小鼠模型已被频繁用于检测人造血干/祖细胞的生长和分化。事实上，在NOD/SCID小鼠的人/鼠嵌合体中首次报道了高水平的人类细胞植入，这现在被认为是这类实验的标准。然而，NOD/SCID小鼠有一些明显的缺点(包括自发形成肿瘤)，限制了它们的普遍使用。我们将重组酶激活基因-2(RAG2)和常见的细胞因子受体伽马链(Gamma-c)突变结合起来，建立了一种新的免疫缺陷小鼠模型。RAG2(-/-)/Gamma c(-)双突变小鼠完全类淋巴样(T-、B-、NK-)，无自发肿瘤形成，造血参数正常。有趣的是，与NOD/SCID模型相比，外源性人细胞因子IL-3粒细胞-巨噬细胞集落刺激因子(GM-CSF)和促红细胞生成素显著促进了人脐血细胞在RAG2(-/-)/Gamma c(-)小鼠体内的植入。RAG2(-/-)/Gamma c(-)小鼠模型的这一独特功能特别适合于评估不同细胞因子在体内人类淋巴细胞生成和干细胞/祖细胞功能中的作用。
Gene transduction into immature human hematopoietic cells collected from umbilical cord blood, bone marrow, or mobilized peripheral blood cells could be useful for the treatment of genetic and acquired disorders of the hematopoietic system, Immunodeficient mouse models have been used frequently as recipients to assay the growth and differentiation of human hematopoietic stem/progenitor cells. Indeed, high levels of human cell engraftment were first reported in human/murine chimeras using NOD/SCID mice, which now are considered as the standard for these types of experiments. However, NOD/SCID mice have some clear disadvantages (including spontaneous tumor formation) that limit their general use. We have developed a new immunodeficient mouse model by combining recombinase activating gene-2 (RAG2) and common cytokine receptor gamma chain (gamma c) mutations. The RAG2(-/-)/gamma c(-) double mutant mice are completely alymphoid (T-, B-, NK-), show no spontaneous tumor formation, and exhibit normal hematopoietic parameters. Interestingly, human cord blood cell engraftment in RAG2(-/-)/gamma c(-) mice was greatly enhanced by the exogenous administration of human cytokines interleukin-(IL-3) granulocyte-macrophage colony-stimulating factor, (GM-CSF), and erythropoietin in contrast to the NOD/SCID model. This unique feature of the RAG2(-/-)/gamma c(-) mouse model should be particularly well suited for assessing the role of different cytokines in human lymphopoiesis and stem/progenitor cell function in vivo.