Wolkers Monika C, Toebes Mireille, Okabe Masaru, Haanen John B A G, Schumacher Ton N M
Department of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
J Immunol. 2002 May 15;168(10):4998-5004. doi: 10.4049/jimmunol.168.10.4998.
An increasing number of clinical trials has been initiated to test the potential of prophylactic or curative vaccination with tumor Ag-encoding DNA vaccines. However, in the past years it has become apparent that for many Ags and in particular for tumor Ags the intracellular processing and presentation are suboptimal. To improve epitope-directed DNA vaccines we have developed a murine model system in which epitope-specific, DNA vaccine-induced T cell immunity can be followed by MHC tetramer technology directly ex vivo. We have used this well-defined model to dissect the parameters that are crucial for the induction of strong cytotoxic T cell immunity using two independent model Ags. These experiments have led to a set of five guidelines for the design of epitope-directed DNA vaccines, indicating that carboxyl-terminal fusion of the epitope to a carrier protein of foreign origin is the most favorable strategy. DNA vaccines that are based on these guidelines induce high-magnitude CD8(+) T cell responses in >95% of vaccinated animals. Moreover, T cell immunity induced by this type of optimized DNA vaccine provides long-term protection against otherwise lethal tumor challenges.
越来越多的临床试验已启动，以测试编码肿瘤抗原的DNA疫苗进行预防性或治疗性接种的潜力。然而，在过去几年中已变得明显的是，对于许多抗原，特别是肿瘤抗原，其细胞内加工和呈递并不理想。为了改进表位导向的DNA疫苗，我们开发了一种小鼠模型系统，在该系统中，表位特异性的、DNA疫苗诱导的T细胞免疫可以通过MHC四聚体技术直接在体外进行跟踪。我们使用这个定义明确的模型，利用两种独立的模型抗原剖析了诱导强大细胞毒性T细胞免疫至关重要的参数。这些实验得出了一套表位导向DNA疫苗设计的五条指导原则，表明将表位羧基末端与外源载体蛋白融合是最有利的策略。基于这些指导原则的DNA疫苗在>95%的接种动物中诱导出高强度的CD8(+) T细胞反应。此外，这种优化的DNA疫苗诱导的T细胞免疫提供了针对否则会致命的肿瘤攻击的长期保护。
