Zhang Xiaopeng, Yu Changming, Zhao Jian, Fu Ling, Yi Shaoqiong, Liu Shuling, Yu Ting, Chen Wei
State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 20 Dongdajie, Fengtai, Beijing 100071, China.
J Gene Med. 2007 Aug;9(8):715-26. doi: 10.1002/jgm.1067.
DNA vaccines have been shown to be an effective approach to induce antigen-specific cellular and humoral immunity. However, the lower immune intensity in clinical trials limits the application of DNA vaccine. Here we intend to develop a new DNA vaccine based on prostate stem-cell antigen (PSCA), which has been suggested as a potential target for prostate cancer therapy, and enhance the DNA vaccine potency with heat shock proteins (HSPs) as adjuvant.
A series of DNA plasmids encoding human PSCA, human HSP70 and their conjugates was constructed and injected into male mice intramuscularly (i.m.). To evaluate the immune responses and therapeutic efficacy of these plasmids, major histocompatibility complex (MHC)-restricted PSCA and HSP70-specific epitopes were predicted and a mouse model with a human PSCA-expressing tumor was constructed.
The result showed that mice vaccinated with PSCA-HSP plasmids generated the strongest PSCA-specific CD8+ T-cell immune response, but the CD4+ TH1 and TH2 cell immune responses were similar with those vaccinated with other HSP-adjuvant PSCA plasmids or only PSCA DNA. The immunity of HSP70 was also observed and the mice i.m. injected with PSCA+ HSP mixed plasmids generated the lowest anti-HSP antibodies. Furthermore, these vaccinations inhibited the growth of PSCA-expressing tumors and prolonged mouse survival.
These observations emphasize and extend the potential of the human HSP70 gene as adjuvant for DNA vaccines, and the vaccine based on PSCA and HSP70 is of potential value for treating prostate cancer.
DNA疫苗已被证明是诱导抗原特异性细胞免疫和体液免疫的有效方法。然而，临床试验中较低的免疫强度限制了DNA疫苗的应用。在此，我们打算开发一种基于前列腺干细胞抗原（PSCA）的新型DNA疫苗，PSCA已被认为是前列腺癌治疗的潜在靶点，并以热休克蛋白（HSPs）作为佐剂增强DNA疫苗的效力。
构建了一系列编码人PSCA、人HSP70及其缀合物的DNA质粒，并通过肌肉注射（i.m.）将其注入雄性小鼠体内。为了评估这些质粒的免疫反应和治疗效果，预测了主要组织相容性复合体（MHC）限制的PSCA和HSP70特异性表位，并构建了表达人PSCA的肿瘤小鼠模型。
结果显示，接种PSCA-HSP质粒的小鼠产生了最强的PSCA特异性CD8+T细胞免疫反应，但CD4+TH1和TH2细胞免疫反应与接种其他HSP佐剂PSCA质粒或仅接种PSCA DNA的小鼠相似。还观察到了HSP70的免疫性，肌肉注射PSCA+HSP混合质粒的小鼠产生的抗HSP抗体最低。此外，这些疫苗接种抑制了表达PSCA的肿瘤生长并延长了小鼠存活时间。
这些观察结果强调并扩展了人HSP70基因作为DNA疫苗佐剂的潜力，基于PSCA和HSP70的疫苗对治疗前列腺癌具有潜在价值。
