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首页> 外文期刊>Vaccine >Comparative analysis of immunization schedules using a novel adenovirus-based immunotherapeutic targeting hepatitis B in naive and tolerant mouse models
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Comparative analysis of immunization schedules using a novel adenovirus-based immunotherapeutic targeting hepatitis B in naive and tolerant mouse models

机译：在幼稚和耐受小鼠模型中使用针对乙型肝炎的新型基于腺病毒的免疫治疗方案的比较分析

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Development of active targeted immunotherapeutics is a rapid developing field in the arena of chronic infectious diseases. The question of repeated, closely spaced administration of immunotherapeutics to achieve a rapid impact on the replicating agent is an important one. We analyzed here, using a prototype adenovirus-based immunotherapeutic encoding Core and Polymerase from the hepatitis B virus (Ad-HBV), the influence of closely spaced repeated immunizations on the level and quality of induced HBV-specific and vector-specific immune responses in various mouse models. Ad-HBV, whether injected once or multiple times, was able to induce HBV- and adeno-specific T cells both in HBV-free mice and in a HBV tolerant mouse model. Adenovirus-specific T cell responses and titers of neutralizing anti-Ad5 antibodies increased from time of the 3rd injection. Interestingly, single or multiple Ad-HBV injections resulted in detection of Polymerase-specific functional T cells in HBV tolerant mice. Overall no modulation of the levels of HBV-specific cytokine-producing (IFN gamma/TNF alpha) and cytolytic T cells was observed following repeated administrations (3 or 6 weekly injections) when compared with levels detected after a single injection with the exception of two markers: I. the proportion of HBV-specific IFN gamma-producing cells bearing the CD27+/CD43+ phenotype appeared to be sustained in C57BL/6J mice following 6 weekly injections; 2. the percentage of IFN gamma/TNF alpha Core-specific producing cells observed in spleens of HLA-A2 mice as well as of that specific of Polymerase observed in livers of HBV tolerant mice was maintained. In addition, percentage of HBV-specific T cells expressing PD-1 was not increased by multiple injections. Overall these data show that, under experimental conditions used, rapid, closely spaced administrations of an adenovirus-based HBV immunotherapeutics does not inhibit induced T-cell responses including in a HBV-tolerant environment
机译：活性靶向免疫疗法的开发是慢性传染病领域中一个快速发展的领域。重复、紧密间隔地施用免疫治疗药物以对复制剂产生快速影响是一个重要的问题。我们在这里使用基于腺病毒的原型免疫治疗编码来自乙型肝炎病毒（Ad-HBV）的核心和聚合酶，分析了紧密间隔的重复免疫对各种小鼠模型中诱导的HBV特异性和载体特异性免疫反应的水平和质量的影响。Ad-HBV，无论是注射一次还是多次，都能够在无HBV小鼠和HBV耐受小鼠模型中诱导HBV和腺特异性T细胞。腺病毒特异性 T 细胞反应和中和抗 Ad5 抗体的滴度从第 3 次注射时开始增加。有趣的是，单次或多次Ad-HBV注射导致在HBV耐受小鼠中检测到聚合酶特异性功能T细胞。总体而言，与单次注射后检测到的水平相比，重复给药（3 或 6 周注射）后未观察到 HBV 特异性细胞因子产生 （IFN γ/TNF α） 和细胞溶解 T 细胞水平的调节，但两个标志物除外：I. 携带 CD27+/CD43+ 表型的 HBV 特异性 IFN γ 产生细胞的比例似乎在 C57BL/6J 小鼠中持续 6 周注射;2.维持在HLA-A2小鼠脾脏中观察到的IFN γ / TNF α Core特异性产生细胞的百分比以及在HBV耐受小鼠肝脏中观察到的聚合酶特异性细胞的百分比。此外，表达PD-1的HBV特异性T细胞的百分比不会因多次注射而增加。总体而言，这些数据表明，在所使用的实验条件下，基于腺病毒的HBV免疫疗法的快速，紧密间隔的给药不会抑制诱导的T细胞反应，包括在HBV耐受环境中

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