Immunology of gene therapy with adenoviral vectors in mouse skeletal muscle.
Immunology of gene therapy with adenoviral vectors in mouse skeletal muscle.
复制标题
小鼠骨骼肌中腺病毒载体基因治疗的免疫学。
DOI：
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复制
发表时间：
1996
影响因子：
3.5
通讯作者：
James M. W ilson
中科院分区：
文献类型：
--
作者：
Yiping Yang;S. E. Haecker;Qin Su;James M. W ilson
骨骼肌是获得性和遗传性疾病的体细胞基因转移的有吸引力的靶点。在骨骼肌中直接注射腺病毒载体导致重组基因在大量肌纤维中表达。转基因表达在大多数器官中是短暂的，并且当在成年免疫活性小鼠中进行实验时与大量炎症相关。在这份报告中，我们利用各种体内和体外模型的T和B细胞功能的特点的免疫反应的性质，腺病毒载体注射到小鼠骨骼肌。依赖于CD 4+和CD 8 + T细胞的细胞免疫有助于重组基因表达的丧失和局部炎症的发展。T细胞的抗原特异性活化发生在病毒蛋白和报告基因β-半乳糖苷酶两者上。还产生了针对载体衣壳蛋白的全身水平的中和抗体。导致转基因表达丧失的破坏性免疫应答主要针对β-半乳糖苷酶，因为当β-半乳糖苷酶作为lacZ转基因小鼠中的新抗原被消除时，转基因表达是稳定的。基于在载体递送时瞬时消融CD 4 + T细胞活化，开发了防止对该疗法的细胞和体液免疫的策略。当载体与包括环磷酰胺、抗CD 4+细胞的mAb和抗CD 40配体的mAb在内的几种免疫调节剂之一一起施用时，获得了令人鼓舞的结果。这些研究表明，细胞和体液免疫反应引起的背景下，基因治疗针对骨骼肌腺病毒载体。CD 4 + T细胞活化的瞬时消融防止了CD 8 + T和B细胞的效应应答。
Skeletal muscle is an attractive target for somatic gene transfer of both acquired and inherited disorders. Direct injection of adenoviral vectors in the skeletal muscle leads to recombinant gene expression in a large number of muscle fibers. Transgene expression has been transient in most organs and associated with substantial inflammation when experiments are performed in adult immune competent mice. In this report, we utilize a variety of in vivo and in vitro models of T and B cell function to characterize the nature of the immune response to adenoviral vectors injected into murine skeletal muscle. Cellular immunity dependent on CD4+ and CD8+ T cells contributes to the loss of recombinant gene expression and the development of localized inflammation. Antigen specific activation of T cells occurs to both viral proteins and the reporter gene beta-galactosidase. Systemic levels of neutralizing antibody to the capsid proteins of the vector are also generated. Destructive immune responses responsible for loss of transgene expression are largely directed against beta-galactosidase in that transgene expression was stable when beta-galactosidase was eliminated as a neoantigen in mice transgenic for lacZ. A strategy to prevent the cellular and humoral immunity to this therapy was developed based on transiently ablating CD4+ T cell activation at the time of vector delivery. Encouraging results were obtained when vector was administered with one of several immune modulating agents including cyclophosphamide, mAb to CD4+ cells, and mAb to CD40 ligand. These studies indicate that cellular and humoral immune responses are elicited in the context of gene therapy directed to skeletal muscle with adenoviral vectors. Transient ablation of CD4+ T cell activation prevents the effects responses of the CD8+ T and B cells.
影响因子：
56.9
作者：
BARR, E;LEIDEN, JM
通讯作者：
LEIDEN, JM
影响因子：
56.9
作者：
DHAWAN, J;PAN, LC;BLAU, HM
通讯作者：
BLAU, HM
通过 T 淋巴细胞亚群耗竭延长小鼠肝脏中腺病毒转基因表达。
DOI：
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发表时间：
1996
期刊：
Gene therapy.
影响因子：
--
作者：
DeMatteo,RP;Markmann,JF;Kozarsky,KF;Barker,CF;Raper,SE
通讯作者：
Raper,SE