Prevention of cytotoxic T lymphocyte responses to factor IX-expressing hepatocytes by gene transfer-induced regulatory T cells
Prevention of cytotoxic T lymphocyte responses to factor IX-expressing hepatocytes by gene transfer-induced regulatory T cells
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DOI：
10.1073/pnas.0508685103
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发表时间：
2006-03-21
影响因子：
11.1
通讯作者：
Herzog, RW
中科院分区：
文献类型：
--
作者：
Dobrzynski, E;Fitzgerald, JC;Herzog, RW
通过基因替代疗法治疗遗传性疾病如出血性疾病血友病B [凝血因子IX（F.IX）缺乏]受到对治疗性基因产物和基因转移载体的免疫应答的风险的阻碍。用腺相关病毒载体介导的肝基因转移技术，对两个不同品系的免疫活性小鼠进行了人F.IX的免疫耐受。随后通过全身给予E1/E3缺失的腺病毒载体对这些动物进行攻击，已知该载体诱导对转基因产物的细胞毒性T淋巴细胞应答。免疫耐受阻止了细胞毒性T淋巴细胞对F.IX的活化和肝脏中的CD 8（+）细胞浸润。此外，尽管体外T细胞对腺病毒抗原有应答，但仍实现了来自腺病毒载体的肝F.IX表达的持续和实质性增加。在体内，通过激活调节性CD 4（+）T细胞（介导对肝脏炎性淋巴细胞反应的抑制），可以防止对治疗性抗原和病毒载体衍生抗原的细胞溶解反应。这一结果表明，调节性T细胞活化的增强应该提供新的手段，以避免在基因转移中的破坏性免疫反应。
Treatment of genetic disease such as the bleeding disorder hemophilia B [deficiency in blood coagulation factor IX (F.IX)] by gene replacement therapy is hampered by the risk of immune responses to the therapeutic gene product and to the gene transfer vector. Immune competent mice of two different strains were tolerized to human F.IX by hepatic gene transfer mediated by adenciassociated viral vector. These animals were subsequently challenged by systemic administration of an E1/E3-deleted adenoviral vector, which is known to induce a cytotoxic T lymphocyte response to the transgene product. Immune tolerance prevented cytotoxic T lymphocyte activation to F.IX and CD8(+) cellular infiltrates in the liver. Moreover, a sustained and substantial increase in hepatic F.IX expression from the adenoviral vector was achieved despite in vitro T cell responses to adenoviral antigens. Cytolytic responses to therapeutic and to viral vector-derived antigens had been prevented in vivo by activation of regulatory CD4(+) T cells, which mediated suppression of inflammatory lymphocyte responses to the liver. This result suggests that augmentation of regulatory T cell activation should provide new means to avoid destructive immune responses in gene transfer.