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Suppression of adenoviral-induced host immuneresponse by TGF?1 expression

机译：TGF？1表达抑制腺病毒诱导的宿主免疫反应

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Adenoviral vector (Ad) is the most commonly used viral vector in gene therapy because of its high transduction efficiency. However, Ad has its limitation due to its transient gene expression and reduced efficacy of repeated vector administration, thanks to host cellular and humoral immune responses. Although it is well known that Ad causes immune response to secondary Ad administration and thus hampers the repeated Ad-mediated gene transfer, the systemic comparison between different viral delivery routes and the optimal elapsed time between repetitive viral deliveries has yet to be extensively studied. In this study, in order to determine (i) to what extent the host immune system attenuates the function of the secondary-administrated Ad; and (ii) whether transforming growth factor-! 1 (TGF?1), an immune suppressor, would reduce this immune response, immune-competent C57BL/6 mice carrying subcutaneous prostate tumors were administrated by either intratumoral (i.t.) or intravenous (i.v.) injection of primary Ad (namely, the 1st viral administration: with either Ad expressing tumor suppressor gene p16, AdRSVp16, or Ad expressing reporter gene ?-galactosidase, AdRSVlacZ), then followed by i.t. injection of secondary Ad (AdRSVlacZ) in the presence or absence of co-delivery of Ad expressing TGF?1 (AdRSVTGF?1). Sera were purified from blood samples collected at various time points. Anti-adenoviral (anti-Ad) antibody in serum and its neutralizing ability to secondary Ad infection were evaluated. No immune response was observed in mice within 3 days after fisrt viral injection regardless of i.t. or i.v. injection. After 7 days, mice by i.v. viral injection developed a strong immune response and this immune potency was increased over the time up to 8 weeks. In contrast, mice by i.t. viral injection had only a minor immune response at day 7, and this response waned in 14 days after viral injection. The immune response was mainly caused by native Ad proteins rather than by transgenes. Moreover, expression of TGF?1 by co-delivery of AdRSVTGF?1 with secondary AdRSVlacZ reduced anti-Ad antibody in sera and prolonged transgene lacZ expression. These results suggest that repeated administration of therapeutic Ad for solid-tumor (such as gene therapy for prostate cancer) by directly i.t. injection with reasonable intervals may provide a rational approach in a clinical setting. The addition of immune suppressor like TGF?1 may be useful to minimize the immune response to the secondary Ad challenge. These results suggest that with reasonable and justified intervals between repeated viral administration, plus the aid of immune response suppressor, local delivery of Ad vector for solid tumor gene therapy should be efficacious with no or minimalimmune response.
机译：腺病毒载体（Ad）由于其高转导效率，是基因治疗中最常用的病毒载体。然而，由于宿主细胞和体液免疫应答，Ad由于其瞬时基因表达和重复施用载体的功效降低而受到其限制。尽管众所周知，Ad引起对二次Ad给药的免疫反应，因此阻碍了重复的Ad介导的基因转移，但是尚未广泛研究不同病毒递送途径之间的系统比较以及重复病毒递送之间的最佳经过时间。在这项研究中，为了确定（i）宿主免疫系统在多大程度上减弱了二次给药Ad的功能; （ii）是否改变了增长因子！ 1（TGFβ1）是一种免疫抑制剂，会降低这种免疫反应，因此，通过瘤内（it）或静脉内（iv）注射原发性Ad（即第1次病毒给药：使用表达Ad的抑癌基因p16，AdRSVp16或表达Ad的报告基因β-半乳糖苷酶（AdRSVlacZ），然后进行在存在或不存在共同递送表达TGF？1的Ad（AdRSVTGF？1）的情况下，注入次要Ad（AdRSVlacZ）。从在不同时间点收集的血液样品中纯化血清。评估血清中的抗腺病毒（anti-Ad）抗体及其对继发性Ad感染的中和能力。首次注射病毒后3天内，在小鼠中未观察到免疫反应，而与i.t.无关。或i.v.注射。 7天后，通过i.v.病毒注射产生了强烈的免疫反应，并且这种免疫力在长达8周的时间内都得到了提高。相比之下，i.t。的老鼠病毒注射在第7天只有轻微的免疫反应，这种反应在病毒注射后的14天内减弱。免疫反应主要是由天然Ad蛋白引起的，而不是由转基因引起的。而且，通过AdRSVTGFβ1与第二AdRSVlacZ的共同递送的TGFβ1的表达降低了血清中的抗Ad抗体，并延长了转基因lacZ的表达。这些结果表明直接通过腹膜内注射重复施用用于实体瘤的治疗性Ad（例如用于前列腺癌的基因治疗）。以合理的间隔注射可能会为临床提供合理的方法。加入诸如TGFβ1之类的免疫抑制剂可能有助于使对次级Ad激发的免疫反应最小化。这些结果表明，在重复施用病毒之间有合理和合理的间隔，再加上免疫应答抑制剂的帮助，用于实体瘤基因治疗的Ad载体的局部递送应是有效的，无或仅有最小的免疫应答。

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