Transduction of dendritic cells by DNA viral vectors directs the immune response to transgene products in muscle fibers
Transduction of dendritic cells by DNA viral vectors directs the immune response to transgene products in muscle fibers
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DOI：
10.1128/jvi.72.5.4212-4223.1998
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发表时间：
1998-05-01
影响因子：
5.4
通讯作者：
Wilson, JM
中科院分区：
文献类型：
--
作者：
Jooss, K;Yang, YP;Wilson, JM
对载体校正细胞的免疫反应限制了基因疗法治疗慢性疾病（如遗传性缺陷状态）的应用。我们发现重组腺相关病毒（AAV）在体内有效地转导肌纤维，而不会激活细胞和体液对新抗原转基因产物（如β -半乳糖苷酶）的免疫，这与重组腺病毒的经验不同，重组腺病毒对转基因产物的活跃t细胞反应会破坏目标肌纤维。肌内注射表达lacZ的腺病毒（AdlacZ）后激活的T细胞可以破坏aavlacz转导的肌纤维，这表明在AAV基因治疗的背景下，免疫无反应性的先前状态。感染AdlacZ的树突状细胞过继转移导致免疫介导的aavlacz转导肌纤维的消除。在过继性转移实验中，aavlacz转导的抗原呈递细胞不能表现出β -半乳糖苷酶活性，也不能引发转基因免疫。这些研究表明，树突状细胞的载体介导转导对于肌肉基因治疗的细胞免疫反应是必要的，而AAV避免了这一步骤，为其在基因治疗中的应用提供了一个有用的生物生态位。
Immune responses to vector-corrected cells have limited the application of gene therapy for treatment of chronic disorders such as inherited deficiency states. We have found that recombinant adeno-associated virus (AAV) efficiently transduces muscle fibers in vivo without activation of cellular and humoral immunity to neoantigenic transgene products such as beta-galactosidase, which differs from the experience with recombinant adenovirus, where vibrant T-cell responses to the transgene product destroy the targeted muscle fibers. T cells activated following intramuscular administration of adenovirus expressing lacZ (AdlacZ) can destroy AAVlacZ-transduced muscle fibers, indicating a prior state of immunologic nonresponsiveness in the context of AAV gene therapy. Adoptive transfer of dendritic cells infected with AdlacZ leads to immune mediated elimination of AAVlacZ-transduced muscle fibers. AAVlacZ-transduced antigen-presenting cells fail to demonstrate beta-galactosidase activity and are unable to elicit transgene immunity in adoptive transfer experiments. These studies indicate that vector-mediated transduction of dendritic cells is necessary for cellular immune responses to muscle gene therapy, a step which AAV avoids, providing a useful biological niche for its use in gene therapy.