Eisold Sven, Schmidt Jan, Ryschich Eduard, Gock Michael, Klar Ernst, von Knebel Doeberitz Magnus, Linnebacher Michael
Department of General Surgery, Thoracic and Vascular Surgery, University of Rostock, Rostock, Germany.
Pancreas. 2007 Jul;35(1):63-72. doi: 10.1097/mpa.0b013e31804b4941.
We analyzed the immunologic impact of adeno-associated virus type 2 (AAV-2), a small single-stranded parvovirus with tumorsuppressive properties, on DSL6A pancreatic carcinoma in syngeneic rats. Established tumors of animals treated with AAV-2 or mock infected were resected (Ro), and DSL6A cells were rechallenged on the different site. Eleven (92%) of 12 mock-infected animals but only 3 (25%) of 12 AAV-2-treated animals redeveloped tumors. Adeno-associated virus type 2 infection provoked systemic raises in monocytes and neutrophils numbers and in levels of the proinflammatory monocyte chemoattractant protein 1 and interleukin 10. Adeno-associated virus type 2-treated tumors were infiltrated with monocytes, macrophages, natural killer cells, CD4+ T cells, and especially CD8+ T cells. In cytotoxicity assays, AAV-2-infected DSL6A tumor cells were recognized by lymphocytes from AAV-2-treated animals and from controls. Yet, uninfected DSL6A cells were exclusively killed by lymphocytes from AAV-2-treated animals. Additionally, those lymphocytes displayed high natural killer cell activity but failed to attack unrelated tumor targets. Taken together, these results suggest that the antiviral response toward AAV-2 cross-activates the immune system toward simultaneously present tumor disease. This and the known potential to significantly reduce toxic side effects of chemotherapy make nonpathogenic viruses such as AAV-2 as "1-agent combination therapy" to an interesting treatment option of residual tumor disease.
我们分析了2型腺相关病毒（AAV-2），一种具有肿瘤抑制特性的小型单链细小病毒，对同基因大鼠DSL6A胰腺癌的免疫影响。切除用AAV-2处理或模拟感染的动物所形成的肿瘤（Ro），并在不同部位再次接种DSL6A细胞。12只模拟感染动物中有11只（92%）重新长出肿瘤，但12只接受AAV-2处理的动物中只有3只（25%）重新长出肿瘤。2型腺相关病毒感染导致单核细胞和中性粒细胞数量以及促炎单核细胞趋化蛋白1和白细胞介素10水平出现全身性升高。接受2型腺相关病毒处理的肿瘤中有单核细胞、巨噬细胞、自然杀伤细胞、CD4 + T细胞浸润，尤其是CD8 + T细胞。在细胞毒性试验中，感染AAV-2的DSL6A肿瘤细胞被来自接受AAV-2处理的动物和对照动物的淋巴细胞识别。然而，未感染的DSL6A细胞仅被来自接受AAV-2处理的动物的淋巴细胞杀死。此外，这些淋巴细胞表现出高自然杀伤细胞活性，但未能攻击无关的肿瘤靶标。综上所述，这些结果表明，针对AAV-2的抗病毒反应会交叉激活免疫系统以对抗同时存在的肿瘤疾病。鉴于此以及已知其具有显著降低化疗毒副作用的潜力，非致病性病毒如AAV-2作为“单药联合疗法”成为残留肿瘤疾病的一个有吸引力的治疗选择。
