基于具有免疫调节活性的防御肽的肿瘤疫苗新型佐剂设计及分子作用机制研究

Adjuvants are crucial in affecting the application of the vaccine. As traditional vaccine adjuvant discovery was always empirical, lacking of rational guidance and evalution system, the need for new design and evaluation system for novel adjuvant discovery, especially tumor vaccine, is urgent. It was found in our previous study that complexing immunomodulatory defense peptide with aluminum hydrogel/polysaccharides can enhance the immune responses and antitumor effects. At the same time, with computer-aided drug design, we designed and screened a series of peptides to get more immunomodulatory, less toxic defense peptide (DP), which could change the type of immune reponse and reduce the toxicity of aluminum hydrogel/CpG ODNs compound. And the Al/CpG/defense peptide adjuvant (ACD) showed more effective antitumor effects than Al/CpG adjuvant. We had built a design and screening evaluation system of adjuvant complex based on immunomodulatory defense peptide. The main research topic of our project is exploring the immunoenchancement effects and molecular mechanism of ACD, discussing its role in the process from antigen uptake to presentation, studying the immune adjuvant mediated relationship between innate immunity and adaptive immunity, clarifying the mechanism of ACD on immune system and providing a novel adjuvant with safety and efficiency to the antitumor vaccine study.

佐剂是影响疫苗成功的关键因素之一，但传统佐剂的研发缺乏理性的指导和方法验证系统，需要新的设计思路及技术体系开展新型佐剂，尤其是肿瘤疫苗。前期研究表明：复合具有免疫调节活性的防御肽到铝佐剂/多糖可以更有效地激活免疫，增强抗肿瘤效果；设计并筛选到免疫活性更好、毒性更小的防御肽，可改变铝佐剂/CpG的免疫类型、降低CpG的副作用，具有更好的抗肿瘤作用，搭建了基于防御肽的复合佐剂设计及筛选评价体系。本课题重点研究铝佐剂/CpG/防御肽(ACD)复合佐剂系统的免疫增强作用和免疫学分子机制，探讨该新型佐剂从抗原摄取到抗原加工递呈中的作用过程，探讨佐剂各组份结合模式识别受体后信号通路的crosstalk，探讨佐剂复合物介导的天然免疫和获得性免疫之间的关系，最终阐明ACD复合佐剂系统的作用机制。一方面建立的设计及评价系统将有助于新型佐剂的研发，另一方面为肿瘤疫苗研究提供一个可选择的安全、有效的新型佐剂。

佐剂是影响疫苗成功的关键因素之一，但传统佐剂的研发缺乏理性的指导和方法验证系统，需要新的设计思路及技术体系开展新型佐剂，尤其是肿瘤疫苗。前期研究建立基于具有免疫调节活性的防御肽的新型复合佐剂的设计、筛选的评价体系，开发的新型铝佐剂/CpG/防御肽(ACD)复合佐剂系统的有效性已获证实，该复合佐剂疫苗系统在多种肿瘤模型中均能有效地抑制肿瘤的生长。本课题重点对ACD复合佐剂系统的免疫增强作用和免疫学分子机制进行了研究，通过多种生物学方式初步证实最优化防御DP7在免疫细胞中的潜在作用靶点为GPR35，探讨了CpG/DP7复合佐剂对树突状细胞的抗原摄取和成熟的促进作用。基于铝佐剂、CpG、防御肽DP7各组分的分子作用靶点，探讨了ACD 复合佐剂在免疫细胞中信号通路的crosstalk，最终阐明了ACD复合佐剂系统的作用机制。该研究建立的设计及评价系统将有助于新型佐剂的研发，而且为肿瘤疫苗研究提供一个可选择的安全、有效的新型佐剂。