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使用FK506免疫抑制来控制第一代腺病毒介导的基因转移引发的免疫反应。

FK506 immunosuppression to control the immune reactions triggered by first-generation adenovirus-mediated gene transfer.

作者信息

Vilquin J T, Guérette B, Kinoshita I, Roy B, Goulet M, Gravel C, Roy R, Tremblay J P

机构信息

Centre de Recherche en Neurobiologie, Université Laval, Hôpital de l'Enfant-Jésus, Québec, Canada.

出版信息

Hum Gene Ther. 1995 Nov;6(11):1391-401. doi: 10.1089/hum.1995.6.11-1391.

Abstract

Despite good initial success in vivo, gene transfer using first-generation replication-defective adenovirus has been reported to lead to transient reporter gene expression and to trigger inflammatory reactions in various organs and animal models. To gain more knowledge on this phenomenon, immune reactions were investigated following in vivo transfection of adult immunocompetent mouse muscle using a delta E1/E3a adenoviral vector encoding a beta-galactosidase (beta-Gal) expression cassette. Cellular and humoral immune reactions, and rejection of beta-Gal-positive muscle fibers, occurred within 3 weeks. The muscles showed massive infiltration by macrophages, natural killer cells, and CD8+ leukocytes. The mRNA levels of granzyme B and interferon-gamma were increased 6 days after vector injection, indicating that the infiltrating lymphocytes were activated. Antibodies were formed against the adenovirus group antigen and the beta-Gal gene product 2 weeks after construct injection. The immunosuppressant FK506, however, blocked the cellular infiltration and the humoral response and allowed strong, stable transgene expression over 1 month. These data emphasize the immune problems related to the use of delta E1/E3a adenoviruses as vectors for gene therapy, and they underline the potential of FK506 as an immunosuppressant adjunct treatment for adenovirus-mediated gene transfer.

摘要

尽管第一代复制缺陷型腺病毒在体内最初取得了良好的成功,但据报道,使用其进行基因转移会导致报告基因短暂表达,并在各种器官和动物模型中引发炎症反应。为了更多地了解这一现象,我们使用编码β-半乳糖苷酶(β-Gal)表达盒的δE1/E3a腺病毒载体,对成年具有免疫活性的小鼠肌肉进行体内转染后,研究了免疫反应。细胞免疫和体液免疫反应以及对β-Gal阳性肌纤维的排斥反应在3周内发生。肌肉出现巨噬细胞、自然杀伤细胞和CD8+白细胞的大量浸润。载体注射6天后,颗粒酶B和干扰素-γ的mRNA水平升高,表明浸润的淋巴细胞被激活。构建体注射2周后,针对腺病毒群抗原和β-Gal基因产物形成了抗体。然而,免疫抑制剂FK506可阻断细胞浸润和体液反应,并使转基因在1个月以上保持强烈、稳定的表达。这些数据强调了与使用δE1/E3a腺病毒作为基因治疗载体相关的免疫问题,并突出了FK506作为腺病毒介导的基因转移免疫抑制辅助治疗的潜力。

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