Long-Term Persistence of a Polyclonal T Cell Repertoire After Gene Therapy for X-Linked Severe Combined Immunodeficiency
Long-Term Persistence of a Polyclonal T Cell Repertoire After Gene Therapy for X-Linked Severe Combined Immunodeficiency
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DOI：
10.1126/scitranslmed.3002715
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发表时间：
2011-08-24
影响因子：
17.1
通讯作者：
Thrasher, Adrian J.
中科院分区：
文献类型：
--
作者：
Gaspar, H. Bobby;Cooray, Samantha;Thrasher, Adrian J.
X连锁严重联合免疫缺陷(SCID-X1)是由常见的细胞因子受体伽马链突变引起的。这些突变典型地导致功能T细胞和自然杀伤细胞谱系的完全缺失，以及本质上的B细胞功能受损。虽然人类白细胞抗原(HLA)相合的造血干细胞移植(HSCT)在SCID-X1患者中非常成功，但不相合的程序可能会导致长期的免疫缺陷、移植物抗宿主病和总死亡率的增加。在这里，10名儿童接受了用常规伽玛逆转录病毒载体转导的自体CD34(+)造血干/祖细胞治疗。这些患者没有接受骨髓抑制调节，并在细胞输注后接受了免疫恢复监测。所有患者均存活，中位随访时间为80个月(54至107个月)，所有患者均恢复了功能性多克隆T细胞谱系。体液免疫仅部分恢复，但在一些患者中足以停止免疫球蛋白替代；然而，3名患者在停止抗生素预防和/或免疫球蛋白替代后出现抗生素反应性急性肺部感染。1例因插入突变后原癌基因LMO-2表达上调而发展为急性T细胞急性淋巴细胞性白血病，但在化疗过程中维持多克隆T细胞库，进入缓解状态。因此，没有骨髓抑制条件的SCID-X1基因治疗有效地恢复了T细胞免疫，并与长达9年的高存活率有关。有必要使用旨在限制突变的载体和加强B细胞重组的策略进行进一步的研究，以确定这种治疗方式和传统的SCID-X1造血干细胞移植的作用。
X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the common cytokine receptor gamma chain. These mutations classically lead to complete absence of functional T and natural killer cell lineages as well as to intrinsically compromised B cell function. Although human leukocyte antigen (HLA)-matched hematopoietic stem cell transplantation (HSCT) is highly successful in SCID-X1 patients, HLA-mismatched procedures can be associated with prolonged immunodeficiency, graft-versus-host disease, and increased overall mortality. Here, 10 children were treated with autologous CD34(+) hematopoietic stem and progenitor cells transduced with a conventional gammaretroviral vector. The patients did not receive myelosuppressive conditioning and were monitored for immunological recovery after cell infusion. All patients were alive after a median follow-up of 80 months (range, 54 to 107 months), and a functional polyclonal T cell repertoire was restored in all patients. Humoral immunity only partially recovered but was sufficient in some patients to allow for withdrawal of immunoglobulin replacement; however, three patients developed antibiotic-responsive acute pulmonary infection after discontinuation of antibiotic prophylaxis and/or immunoglobulin replacement. One patient developed acute T cell acute lymphoblastic leukemia because of up-regulated expression of the proto-oncogene LMO-2 from insertional mutagenesis, but maintained a polyclonal T cell repertoire through chemotherapy and entered remission. Therefore, gene therapy for SCID-X1 without myelosuppressive conditioning effectively restored T cell immunity and was associated with high survival rates for up to 9 years. Further studies using vectors designed to limit mutagenesis and strategies to enhance B cell reconstitution are warranted to define the role of this treatmentmodality alongside conventional HSCT for SCID-X1.