HMGB1对HPV16型重组腺病毒载体疫苗免疫效果的影响及机制研究

Effect and Mechanism of HMGB1 on Immune Efficacy of Recombinant Adenovirus Vector-based Human Papillomavirus-16 Vaccine

目的探讨高迁移率族蛋白B1(HMGB1)分子与人乳头瘤病毒(HPV)16型E6E7重组腺病毒载体疫苗免疫效果的关系及机制。方法通过TC-1细胞移植诱导建立小鼠肿瘤模型,在接种HPV重组腺病毒载体疫苗的同时,给予注射HMGB1特异性拮抗剂HMGB1 A box,开展肿瘤抑制试验、小鼠免疫状态观察、肿瘤相关信号检测等研究。结果 A box蛋白与疫苗联用,可显著降低模型小鼠HMGB1血清水平,抑制肿瘤组织中NF-?B的m RNA高表达,提高疫苗的抗肿瘤活性。同时,它还可减少IL-4、促进IFN-?产生,使体内免疫平衡由Th2向Th1偏移。和肿瘤模型对照组相比,在接种疫苗并注射A box蛋白后,由肿瘤引起的NF-?B、Bcl-2、c-IAP2、VEGF、MMP-9的表达提高、Bax表达降低均得到显著扭转。结论 HMGB1分子可以削弱HPV重组腺病毒载体疫苗的免疫效果,其机制可能是HMGB1在调节免疫平衡状态及控制肿瘤细胞的凋亡、浸润、转移等多层面均能参与并发挥重要作用。

OBJECTIVE To study the influence of HMGB1 on the effect of recombinant adenovirus vector-based human papillomavirus-16 vaccine in mice model and explore the potential mechanism. METHODS HMGB1 antagonist, HMGB1 A box protein was injected into the model mice resulting from TC-1 cell transplantation. Anti-tumor test, immunological influence observation and tumor associated signaling molecules test were carried out with ecombinant adenovirus vector-based human papillomavirus-16 vaccination. RESULTS A box and vaccine combinating injection could decrease the serum HMGB1 level and inhibit NF-？B m RNA expression in model mice, accompanied with a lower tumor occurrence. It also regulated Th1/Th2 type cytokines balance by inducing IFN-？ and decreasing IL-4. And compared with model control group, HMGB1 inhibiting made the vaccine played a better performance in reducing NF-？B, Bcl-2, c-IAP2, VEGF, MMP-9 expression and increasing Bax expression in tumor model mice. CONCLUSION HMGB1 can block the immune response and anti-tumor effect of recombinant adenovirus vector-based human papillomavirus-16 vaccine in mouse model, and it probably resulted from HMGB1 playing an important role in cell apoptosis, tumor invasion and metastasis and immune balance regulation.