Castiglione Filippo, Toschi Federico, Bernaschi Massimo, Succi Sauro, Benedetti Roberta, Falini Brunangelo, Liso Arcangelo
Istituto Applicazioni del Calcolo (IAC) M. Picone, Consiglio Nazionale delle Ricerche (CNR), Viale del Policlinico, 137-00161 Rome, Italy.
J Theor Biol. 2005 Dec 21;237(4):390-400. doi: 10.1016/j.jtbi.2005.04.024. Epub 2005 Jul 22.
Vaccination protocols designed to elicit anti-cancer immune responses have, many times, failed in producing tumor eradication and in prolonging patient survival. Usually in cancer vaccination, epitopes from one organism are included in the genome or linked with some protein of another in the hope that the immunogenic properties of the latter will boost an immune response to the former. However, recent results have demonstrated that injections of two different vectors encoding the same recombinant antigen generate high levels of specific immunity. Systematic comparison of the efficacy of different vaccination protocols has been hampered by technical limitations, and clear evidence that the use of multiple vectors has advantages over single carrier injections is lacking. We used a computational model to investigate the dynamics of the immune response to different anti-cancer vaccines based on randomly generated antigen/carrier compounds. The computer model was adapted for simulations to this new area in immunology research and carefully validated to the purpose. As a matter of fact, it reproduces a relevant number of experimental observations. The model shows that when priming and boosting with the same construct, competition rather than cooperation develops amongst T cell clones of different specificities. Moreover, from the simulations, it appears that the sequential use of multiple carriers may generate more robust anti-tumor immune responses and may lead to effective tumor eradication in a higher percentage of cases. Our results provide a rational background for the design of novel strategies for the achievement of immune control of cancer.
旨在引发抗癌免疫反应的疫苗接种方案多次未能实现肿瘤根除和延长患者生存期。通常在癌症疫苗接种中，来自一种生物体的表位被纳入基因组或与另一种生物体的某种蛋白质相连，希望后者的免疫原性特性能够增强对前者的免疫反应。然而，最近的结果表明，注射两种编码相同重组抗原的不同载体可产生高水平的特异性免疫。不同疫苗接种方案疗效的系统比较受到技术限制的阻碍，并且缺乏明确证据表明使用多种载体比单次载体注射具有优势。我们使用计算模型来研究基于随机生成的抗原/载体化合物的不同抗癌疫苗的免疫反应动态。该计算机模型经过调整以适应免疫研究这一新领域的模拟，并针对该目的进行了仔细验证。事实上，它再现了大量实验观察结果。该模型表明，当用相同构建体进行初次免疫和加强免疫时，不同特异性的T细胞克隆之间会产生竞争而非合作。此外，从模拟结果来看，顺序使用多种载体可能会产生更强有力的抗肿瘤免疫反应，并可能在更高比例的病例中实现有效的肿瘤根除。我们的结果为设计实现癌症免疫控制的新策略提供了合理依据。
