Jensen E R, Selvakumar R, Shen H, Ahmed R, Wettstein F O, Miller J F
Department of Microbiology and Immunology, University of California, Los Angeles 90095-1747, USA.
J Virol. 1997 Nov;71(11):8467-74. doi: 10.1128/JVI.71.11.8467-8474.1997.
Listeria monocytogenes is a gram-positive, facultative intracellular bacterium that enters the cytoplasm of infected cells and spreads directly into neighboring cells without encountering the extracellular environment. Cytoplasmic L. monocytogenes efficiently presents secreted proteins to the major histocompatibility complex class I pathway which can stimulate protective T-cell-mediated immune responses. We have used a cottontail rabbit papillomavirus (CRPV) rabbit model to test the ability of recombinant L. monocytogenes strains secreting the viral E1 protein (E1-rLm) to protect outbred rabbits against CRPV- and CRPV DNA-induced tumors. CRPV infection of outbred rabbits serves as a model for oncogenic papillomaviruses since CRPV-induced papillomas progress with high frequency to malignant carcinoma. Rabbits were vaccinated with wild-type L. monocytogenes or E1-rLm and then challenged with CRPV or viral DNA. In contrast to 0% papilloma regression in control animals, 77% of E1-rLm-vaccinated rabbits generated protective immunity that controlled and induced complete regression of tumors induced by CRPV. Latent viral DNA was not detected at 71% of the papilloma regression sites examined 4.5 months postregression. E1-rLm responder rabbits were completely resistant to papilloma formation from viral DNA. In contrast to controls, peripheral blood mononuclear cells from E1-rLm responder rabbits were able to proliferate in response to in vitro E1 stimulation. These results indicate that E1-rLm immunization generated a systemic anti-CRPV E1 cell-mediated immune response which protected outbred rabbits from tumors induced by CRPV or CRPV DNA challenge.
单核细胞增生李斯特菌是一种革兰氏阳性兼性胞内细菌，它进入受感染细胞的细胞质，并直接扩散到邻近细胞，而不接触细胞外环境。细胞质中的单核细胞增生李斯特菌能有效地将分泌蛋白呈递给主要组织相容性复合体I类途径，从而刺激保护性T细胞介导的免疫反应。我们使用了棉尾兔乳头瘤病毒（CRPV）兔模型来测试分泌病毒E1蛋白的重组单核细胞增生李斯特菌菌株（E1-rLm）保护远交系兔免受CRPV和CRPV DNA诱导肿瘤的能力。远交系兔感染CRPV可作为致癌乳头瘤病毒的模型，因为CRPV诱导的乳头瘤经常进展为恶性癌。给兔子接种野生型单核细胞增生李斯特菌或E1-rLm，然后用CRPV或病毒DNA进行攻击。与对照动物中0%的乳头瘤消退率相比，77%接种E1-rLm的兔子产生了保护性免疫，可控制并诱导由CRPV诱导的肿瘤完全消退。在消退后4.5个月检查的71%的乳头瘤消退部位未检测到潜伏病毒DNA。E1-rLm反应兔对病毒DNA诱导的乳头瘤形成完全有抵抗力。与对照组相比，E1-rLm反应兔的外周血单核细胞能够在体外受到E1刺激时增殖。这些结果表明，E1-rLm免疫产生了全身性抗CRPV E1细胞介导的免疫反应，保护远交系兔免受CRPV或CRPV DNA攻击诱导的肿瘤。
