Bone Marrow Mesenchymal Stem Cells Loaded With an Oncolytic Adenovirus Suppress the Anti-adenoviral Immune Response in the Cotton Rat Model
Bone Marrow Mesenchymal Stem Cells Loaded With an Oncolytic Adenovirus Suppress the Anti-adenoviral Immune Response in the Cotton Rat Model
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DOI：
10.1038/mt.2010.131
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发表时间：
2010-10-01
影响因子：
12.4
通讯作者：
Lesniak, Maciej S.
中科院分区：
文献类型：
--
作者：
Ahmed, Atique U.;Rolle, Cleo E.;Lesniak, Maciej S.
溶瘤腺病毒治疗是一种有吸引力的癌症治疗方式。然而，在瘤内注射后，溶瘤病毒不能有效地从注射部位迁移，并被免疫系统快速清除。我们以前已经证明了增强的病毒输送和复制持久性在体内使用人骨髓来源的间充质干细胞（MSC）作为运载工具。在这项研究中，我们评估了免疫应答腺病毒（Ad）加载骨髓间充质干细胞使用半许可的棉鼠（CR）模型。首先，我们从CR骨髓抽吸物中分离MSC。实时荧光定量PCR分析显示CR MSCs支持体外Ads的复制。此外，我们观察到类似水平的抑制T细胞增殖的有丝分裂刺激，由单独的MSC和病毒加载的MSC。此外，我们发现MSC抑制了激活的T细胞产生干扰素-γ（IFN-γ）。在我们的体内模型中，与单独注射病毒相比，CR MSC增强了Ad的传播和持久性。总的来说，我们的数据表明，使用MSC作为溶瘤Ad的递送策略可能提供无数的益处，包括通过抑制抗病毒免疫应答改善递送、增强传播和增加病毒的持久性。
Oncolytic adenoviral virotherapy is an attractive treatment modality for cancer. However, following intratumoral injections, oncolytic viruses fail to efficiently migrate away from the injection site and are rapidly cleared by the immune system. We have previously demonstrated enhanced viral delivery and replicative persistence in vivo using human bone marrow-derived mesenchymal stem cells (MSCs) as delivery vehicles. In this study, we evaluated the immune response to adenovirus (Ad)-loaded MSCs using the semipermissive cotton rat (CR) model. First, we isolated MSCs from CR bone marrow aspirates. Real-time quantitative PCR analysis revealed that CR MSCs supported the replication of Ads in vitro. Moreover, we observed similar levels of suppression of T-cell proliferation in response to mitogenic stimulation, by MSCs alone and virus-loaded MSCs. Additionally, we found that MSCs suppressed the production of interferon-gamma (IFN-gamma) by activated T cells. In our in vivo model, CR MSCs enhanced the dissemination and persistence of Ad, compared to virus injection alone. Collectively, our data suggest that the use of MSCs as a delivery strategy for oncolytic Ad potentially offers a myriad of benefits, including improved delivery, enhanced dissemination, and increased persistence of viruses via suppression of the antiviral immune response.