Gene therapy for Wiskott-Aldrich syndrome: rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice
Gene therapy for Wiskott-Aldrich syndrome: rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice
复制标题
DOI：
10.1182/blood-2002-05-1423
复制
发表时间：
2003-03-15
期刊：
影响因子：
20.3
通讯作者：
Snapper, SB
中科院分区：
文献类型：
--
作者：
Klein, C;Nguyen, D;Snapper, SB
Wiskott-Aldrich 综合征 (WAS) 是一种 X 连锁原发性免疫缺陷病，由最近发现的 WASP 基因突变引起。 WASP 在 T 细胞受体介导的肌动蛋白细胞骨架信号传导中发挥重要作用。在这些研究中，我们评估了使用逆转录病毒基因转移到 WASP 缺陷的造血干细胞 (HSC) 中来挽救 WAS 特有的 T 细胞信号传导缺陷的可行性。移植已用表达 WASP 的逆转录病毒转导的 WASP 缺陷 (WKO) HSC 后，成熟的 B 和 T 细胞以正常数量发育。最重要的是，T细胞中抗原受体诱导的增殖缺陷得到了显着改善。此外，在受体骨髓嵌合体中，通过逆转录病毒介导的WASP表达，可以预防或改善WKO HSC对结肠炎的易感性。在移植表达 WASP 同源蛋白 N-WASP 的 WASP 缺陷型 HSC 后，也可以部分逆转 T 细胞信号传导缺陷。此外，我们使用竞争性再增殖实验和 Southern blot 分析记录了淋巴组织中 WT 相对于 WKO 细胞的选择性优势。我们的结果提供了原理证明，即通过逆转录病毒转导的 HSC 移植可以改善 WAS 相关的 T 细胞信号传导缺陷，而不会产生明显的毒性，并且可能会鼓励临床基因治疗试验。
The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency that is caused by mutations in the recently identified WASP gene. WASP plays an important role in T-cell receptor-mediated signaling to the actin cytoskeleton. In these studies we assessed the feasibility of using retroviral gene transfer into WASP-deficient hematopoietic stem cells (HSCs) to rescue the T-cell signaling defect that is characteristic of WAS. Upon transplantation of WASP-deficient (WKO) HSCs that have been transduced with WASP-expressing retroviruses, mature B and T cells developed in normal numbers. Most importantly, the defect in antigen receptor-induced proliferation was significantly improved in T cells. Moreover, the susceptibility of colitis by WKO HSCs was prevented or ameliorated in recipient bone marrow chimeras by retrovirus-mediated expression of WASP. A partial reversal of the T-cell signaling defect could also be achieved following transplantation of WASP-deficient HSCs expressing the WASP-homologous protein N-WASP. Furthermore, we have documented, a selective advantage of WT over WKO cells in lymphoid tissue using competitive repopulation experiments and Southern blot analysis. Our results provide proof of principle that the WAS-associated T-cell signaling defects can be improved upon transplantation of retrovirally transduced HSCs without overt toxicity and may encourage clinical gene therapy trials.