【摘要】 对多株肿瘤细胞的研究表明胃泌素释放肽(GRP)可作为生长因子刺激多种肿瘤的生长,并提示GRP可作为肿瘤免疫治疗的靶点。该研究构建了一系列抗GRP的核酸疫苗以激活针对GRP特异性的体液免疫应答,达到阻断GRP的目的。为打破机体已建立的GRP免疫耐受,将6个串联重复的B细胞表位GRP18~27作为抗原插入到真核表达质粒载体pCR3.1中,并辅之以多种免疫分子佐剂以达到增强核酸疫苗免疫原性的目的。构建的抗GRP核酸疫苗免疫小鼠后,pCR3.1-VS-HSP65-TP-GRP6-M2免疫组诱导出的特异性针对GRP的抗体滴度显著高于其它疫苗免疫组,并在随后的体内抗肿瘤实验中显著的抑制了GRP依赖性的RM-1移植瘤的生长。构建的这种高免疫源性和高效抑制肿瘤生长的抗GRP核酸疫苗为针对GRP依赖性的肿瘤及其并发症的免疫疗法提够了一种新的策略。更多还原

【Abstract】 Over the last two decades,several lines of experimental evidence have demonstrated that the gastrin-releasing peptide(GRP) may act as a growth factor in many types of cancer,suggesting that GRP might be a putative target for immunotherapy in neoplastic diseases.In this investigation,anti-GRP DNA vaccines have been designed to induce specific deprivation of GRP by strong humoral immune response.To break the already established tolerance of this self-peptide in vivo,6 copies of the B cell epitope GRP18~27 in linear alignment(GRP6) have been inserted in a eukaryotical expression vector(pCR3.1) as immunogen.Furthermore,tandem repeated GRP18~27 was fused to different immunoadjuvants to optimize its immunogenicity.Immunization of mice with pCR3.1-VS-HSP65-TP-GRP6-M2 elicited much higher levels of specific anti-GRP antibodies and effectively inhibited the growth of a GRP-dependent tumor RM-1 in vivo.The highly immunogenic and potent anti-tumorigenic activities of the anti-GRP DNA vaccine offered a novel immunotherapeutic approach in the treatment of the GRP-dependent tumor and its complications.更多还原