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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Prevention of cytotoxic T lymphocyte responses to factor IX-expressing hepatocytes by gene transfer-induced regulatory T cells
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Prevention of cytotoxic T lymphocyte responses to factor IX-expressing hepatocytes by gene transfer-induced regulatory T cells

机译：通过基因转移诱导的调节性T细胞预防对表达IX因子的肝细胞的细胞毒性T淋巴细胞反应

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摘要

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 adenoassociated 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.
机译：通过基因替代疗法治疗遗传性疾病，例如出血性血友病B型血友病[凝血因子IX（F.IX）缺乏]，受到了对治疗性基因产物和基因转移载体的免疫应答风险的困扰。通过腺相关病毒载体介导的肝基因转移，将两种不同品系的免疫感受态小鼠耐受人F.IX。随后通过全身施用E1 / E3缺失的腺病毒载体对这些动物进行攻击，已知该载体可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淋巴细胞激活肝中F.IX和CD8〜+细胞浸润。而且，尽管体外T细胞对腺病毒抗原有反应，但从腺病毒载体获得的肝F.IX表达仍持续和大量增加。通过调节性CD4〜+ T细胞的活化可预防体内对治疗性和病毒性载体衍生抗原的细胞溶解反应，该介导的CD4 + T细胞介导的对肝脏炎症性淋巴细胞反应的抑制被抑制。该结果表明，调节性T细胞活化的增强应提供新的手段，以避免基因转移中的破坏性免疫反应。

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