Restoration of human B-cell differentiation into NOD-SCID mice engrafted with gene-corrected CD34+cells isolated from artemis or RAG1-deficient patients
Restoration of human B-cell differentiation into NOD-SCID mice engrafted with gene-corrected CD34+cells isolated from artemis or RAG1-deficient patients
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DOI：
10.1038/sj.mt.6300353
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发表时间：
2008-02-01
影响因子：
12.4
通讯作者：
Cavazzana-Calvo, Marina
中科院分区：
文献类型：
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作者：
Lagresle-Peyrou, Chantal;Benjelloun, Fatine;Cavazzana-Calvo, Marina
由重组激活基因1（RAG 1）或Artemis基因突变引起的严重联合免疫缺陷（SCID）导致B细胞和T细胞分化的缺乏。唯一的治愈性治疗是异基因骨髓（BM）移植，当HLA相容的供体可用时，其显示高存活率，但当供体部分相容时，其具有较差的预后。因此，基因治疗可能是这些疾病的一个有前途的替代策略。在这里，我们报告说，慢病毒基因校正的BM CD 34+细胞（从Artemis或RAG 1缺陷患者分离）维持人类B细胞分化后，注射到非肥胖糖尿病/SCID（NOD-SCID）小鼠先前注入抗白细胞介素-2受体β链单克隆抗体。在大多数移植了Artemis转导细胞的小鼠BM中，人B细胞分化发生直到成熟阶段。当血清中存在人免疫球蛋白M（IgM）时，B细胞具有功能。在注射RAG 1转导的细胞后，体内发生人移植，但B细胞分化直到成熟阶段的频率较低。然而，当它发生时，它总是与人IgM的产生有关。这种整体方法代表了一种有用的工具，用于评估影响B细胞发育（如Artemis缺陷）的人SCID形式中的基因转移效率，并用于测试用于改善体内RAG 1互补的新载体。
Severe combined immunodeficiency ( SCID) caused by mutation of the recombination-activating gene 1 (RAG1) or Artemis gene lead to the absence of B- and T-cell differentiation. The only curative treatment is allogeneic bone marrow (BM) transplantation, which displays a high survival rate when an HLA compatible donor is available but has a poorer prognosis when the donor is partially compatible. Consequently, gene therapy may be a promising alternative strategy for these diseases. Here, we report that lentiviral gene-corrected BM CD34+ cells (isolated from Artemis- or RAG1-deficient patients) sustain human B-cell differentiation following injection into non-obese diabetic/SCID (NOD-SCID) mice previously infused with anti-interleukin-2 receptor beta chain monoclonal antibody. In most of the mice BM, engrafted with Artemis- transduced cells, human B- cell differentiation occurred until the mature stage. The B cells were functional as human immunoglobulin M (IgM) was present in the serum. Following injection with RAG1-transduced cells, human engraftment occurred in vivo but B-cell differentiation until the mature stage was less frequent. However, when it occurred, it was always associated with human IgM production. This overall approach represents a useful tool for evaluating gene transfer efficiency in human SCID forms affecting B-cell development (such as Artemis deficiency) and for testing new vectors for improving in vivo RAG1 complementation.