Gene therapy with recombinant adenovirus vectors: Evaluation of the host immune response
Gene therapy with recombinant adenovirus vectors: Evaluation of the host immune response
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DOI：
10.1016/s0165-2478(97)00049-7
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发表时间：
1997-06-01
影响因子：
4.4
通讯作者：
Mehtali, M
中科院分区：
文献类型：
--
作者：
Christ, M;Lusky, M;Mehtali, M
E1、e3缺失、复制缺陷重组腺病毒因其在体内转移治疗基因的能力而被广泛研究。它们可以感染来自不同器官的多种分裂和静止细胞，并具有很大的包装能力。使用这些载体进行基因治疗的主要限制之一是转基因在体内的短暂表达和重新施用时转导效率差。尽管病毒El区缺失，但在体内低水平表达早期和晚期病毒基因。因此，病毒抗原加上转导细胞中来自转基因表达的抗原有助于细胞免疫反应，导致这些细胞的破坏。抗腺病毒抗体的产生、细胞免疫反应以及载体的早期非特异性清除构成了基因治疗成功的障碍。新的向量在E2a或E4区域有额外的缺失。对第二代载体进行体内评价。这些研究揭示了这些载体引发的免疫机制的复杂性以及这些评估中几个参数的重要性（即小鼠品系、转基因的性质、给药途径……）。为了抑制腺病毒中和抗体的产生，防止进一步给药载体，采取了免疫抑制策略。使用免疫抑制药物（环磷酰胺，FK506）或单克隆抗体阻断T细胞受体或共刺激途径的治疗方案允许延长转基因表达和/或再给药腺病毒载体。此外，转导效率可以通过短暂抑制非特异性免疫机制来提高，从而导致载体的早期清除。综上所述，这些策略可以通过降低宿主对腺病毒载体的免疫反应来进一步改善基因治疗方案。(C) 1997爱思唯尔科学有限公司
E1, E3-deleted, replication-deficient recombinant adenoviruses are widely studied as vectors for their capacity to transfer therapeutic genes in vivo. They can infect a wide variety of dividing and quiescent cells from different organs and possess a large packaging capacity. One of the major limitations in the use of these vectors for gene therapy is the transient expression of the transgene in vivo and the poor transduction efficiency when re-administered. Despite the deletion of the viral El region, low level of early and late viral genes are expressed in vivo. Thus, viral antigens plus those derived from transgene expression in transduced cells contribute to cellular immune responses leading to the destruction of these cells. Production of anti-adenovirus antibodies, the cellular immune response as well as the early non-specific clearance of the vectors, constitute barriers to successful gene therapy. New vectors have been derived with additional deletions in the E2a or the E4 regions. Such second generation vectors were evaluated in vivo. These studies have revealed the complexity of the immune mechanisms elicited by these vectors and the importance of several parameters in these evaluations (i.e. mouse strains, nature of the transgene, route of administration...). In order to inhibit the production of neutralizing antibodies to adenovirus that prevent from further readministration of the vectors, immunosuppressive strategies were undertaken. Treatment regimens with immunosuppressive drugs (cyclophosphamide, FK506) or with monoclonal antibodies that block either the T cell receptor or costimulation pathways allow prolonged transgene expression and/or readministration of adenoviral vectors. In addition, transduction efficiencies may be increased by transiently inhibiting non-specific immune mechanisms that lead to the dramatic early clearance of the vectors. Taken together, these strategies may improve further gene therapy protocols by decreasing the host immune response to adenoviral vectors. (C) 1997 Elsevier Science B.V.