Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells.
Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells.
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DOI：
10.1016/j.jaci.2019.08.029
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发表时间：
2020-02
期刊：
影响因子：
--
通讯作者：
Zimmermann VS
中科院分区：
文献类型：
--
作者：
Pouzolles M;Machado A;Guilbaud M;Irla M;Gailhac S;Barennes P;Cesana D;Calabria A;Benedicenti F;Sergé A;Raman I;Li QZ;Montini E;Klatzmann D;Adjali O;Taylor N;Zimmermann VS
T细胞免疫缺陷的患者通常通过异基因造血干细胞移植治疗，但对于没有匹配供体的患者需要替代方案。一种创新的胸腺内（IT）基因治疗方法，直接靶向胸腺，可能会改善结果。确定IT-腺相关病毒（AAV）血清型对ZAP-70缺陷小鼠模型中胸腺细胞亚群的有效性并纠正T细胞免疫缺陷。将AAV血清型胸腺内注射到WT小鼠中并监测基因转移效率。ZAP-70 −/−小鼠胸腺内注射携带ZAP-70基因的AAV8载体。评估了T细胞结构、免疫表型、TCR克隆型、T细胞功能、对转基因和自身抗体的免疫应答、载体拷贝数和整合。AAV 8、9和10血清型在原位基因转移后均转导胸腺细胞亚群，转导高达5%的细胞。将AAV8-ZAP-70载体IT注射到ZAP-70 −/−小鼠中导致快速胸腺细胞分化，与胸腺髓质的发育相关。引人注目的是，在基因转移的10天内检测到表达自身免疫调节因子AIRE的胸腺髓质上皮细胞，这与外周中具有不同TCR克隆型的功能性效应子和调节性T细胞亚群的存在相关。虽然胸腺细胞重建是短暂的，但携带约1个AAV基因组/细胞的基因校正的外周T细胞持续> 40周，并且检测到AAV载体整合。胸腺内AAV转导的祖细胞促进胸腺结构的快速恢复，具有产生长期外周T细胞功能的单波胸腺生成。胸腺内AAV介导的基因治疗为免疫缺陷患者提供了一种新的治疗选择，促进了胸腺环境的快速重建和随后的T细胞重建。
Patients with T cell immunodeficiencies are generally treated by allogeneic hematopoietic stem cell transplantation but alternatives are needed for patients without matched donors. An innovative intrathymic (IT) gene therapy approach, directly targeting the thymus, may improve outcome. To determine the efficacy of IT-adeno-associated virus (AAV) serotypes to transduce thymocyte subsets and correct the T cell immunodeficiency in a ZAP-70-deficient murine model. AAV serotypes were injected intrathymically into WT mice and gene transfer efficiency was monitored. ZAP-70−/− mice were intrathymically injected with an AAV8 vector harboring the ZAP-70 gene. Thymus structure, immunophenotyping, TCR clonotypes, T cell function, immune responses to transgenes and autoantibodies, vector copy number and integration were evaluated. AAV 8, 9 and 10 serotypes all transduced thymocyte subsets following in situ gene transfer, with transduction of up to 5% of cells. IT injection of an AAV8-ZAP-70 vector into ZAP-70−/− mice resulted in a rapid thymocyte differentiation, associated with the development of a thymic medulla. Strikingly, medullary thymic epithelial cells expressing the autoimmune regulator AIRE were detected within 10 days of gene transfer, correlating with the presence of functional effector and regulatory T cell subsets with diverse TCR clonotypes in the periphery. While thymocyte reconstitution was transient, gene-corrected peripheral T cells, harboring approximately 1 AAV genome/ cell, persisted for >40 weeks and AAV vector integration was detected. Intrathymic AAV-transduced progenitors promote a rapid restoration of the thymus architecture with a single wave of thymopoiesis generating long-term peripheral T cell function. Intrathymic AAV-mediated gene therapy presents a novel therapeutic option for immunodeficient patients, promoting a rapid reconstitution of the thymic environment and subsequent T cell reconstitution.
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影响因子：
7.3
作者：
Al-Herz W;Bousfiha A;Casanova JL;Chatila T;Conley ME;Cunningham-Rundles C;Etzioni A;Franco JL;Gaspar HB;Holland SM;Klein C;Nonoyama S;Ochs HD;Oksenhendler E;Picard C;Puck JM;Sullivan K;Tang ML
通讯作者：
Tang ML
胸腺和最近的胸腺移民在维持成年外周淋巴细胞库中的作用。
影响因子：
15.3
作者：
Berzins, S P;Boyd, R L;Miller, J F
通讯作者：
Miller, J F
影响因子：
15.9
作者：
Adjali, O;Marodon, G;Klatzmann, D
通讯作者：
Klatzmann, D
影响因子：
56.9
作者：
Anderson, MS;Venanzi, ES;Mathis, D
通讯作者：
Mathis, D
DOI：
10.1073/pnas.0504268102
发表时间：
2005-09-20
影响因子：
11.1
作者：
Adjali, O;Vicente, RR;Taylor, N
通讯作者：
Taylor, N