VLP颗粒抗原降压疫苗免疫应答机制的研究

Hypertension is one of the most common diseases with serious hazard to human health. we successfully invented the ATRQ beta 001 antihypertensive Vaccine. However, prophase work focused on the vaccine preparation technology. In this project we will explore: ATRQ beta 001 vaccine increases the secretion of appropriate cytokines via initiating DCs and activating type 2 ERK-c-fos immune response pathway, to induce CD4 + T cell differentiate into Th2-like Tfh cells and IL-21 producing Tfh cells. Simultaneously, after formation of immune complexes with nonspeci?c Abs, the vaccine can be deposited on FDCs and assists B cell memory formation and subtype transformation under the help of Tfh cells and FDC, in order to produce sufficiently strong and persistent humoral immune response. So, our study inquiries the Immunology theory of ATRQ beta 001 therapeutic antihypertensive Vaccine on three levels: antigen presenting started by DCs, the aid of Th cell and B cell proliferation and differentiation, thereby clarifying the mechanism of the immune response of the vaccine. Finally that provides the immunology theoretical basis of therapeutic antihypertensive vaccine.

高血压是危害人类健康的重大疾病，我们发明了ATRQβ-001降压疫苗，前期工作侧重于该疫苗制备技术的攻关。本研究将探索：ATRQβ-001疫苗通过对DCs的启动并主要激活ERK-c-fos 2型免疫应答通路，产生易于诱导CD4+T细胞向Th2-like Tfh 及IL-21 producing Tfh细胞方向分化的细胞因子环境，强效启动Tfh细胞，同时与先天非特异性抗体系统形成ICs滞留于FDC上，借助Tfh细胞和FDC 联合辅助B细胞记忆形成及亚型转换，以产生足够强而持久的体液免疫应答。本研究将从DCs抗原提呈、Th细胞辅助及B细胞增殖分化等三个层面对其免疫学理论进行研究，阐明ATRQβ-001治疗性降压疫苗的免疫应答机制，提供治疗性降压疫苗的免疫学理论基础。

我们发明了以AP205 病毒样颗粒（AP205 VLP）为载体的治疗性降压疫苗ATR-AP205-001，可显著降低高血压模型动物的血压水平并保护靶器官。本研究我们主要关注降压疫苗的免疫效应及免疫安全性。与解聚化的二聚体疫苗ATR-Dimer-001相比，ATR-AP205-001早期快速进入引流淋巴结被膜下窦区域，随后被B细胞定向转移并持续呈递于滤泡树突状细胞（FDC）表面，而ATR-Dimer-001以扩散形式散在分布于淋巴结内，其抗原提呈效率明显不足。ATR-AP205-001疫苗同时有效活化树突状细胞，促进具有高效B细胞辅助作用的滤泡辅助性T细胞（Tfh）增殖。FDC持续抗原提呈作用联合Tfh强效辅助作用，共同诱导高效生发中心形成及随后的特异性抗体产生和持久免疫记忆，从而发挥高血压治疗作用。此外，与ATR-Dimer-001一样，ATR-AP205-001不引起CD8+T细胞及Th1/2/17细胞的增殖，多次免疫也不会引起Treg活化。我们的研究揭示了以VLP为载体的ATR-AP205-001疫苗高效免疫应答的过程及机制，验证了疫苗免疫的安全性，为以VLP为载体的治疗性疫苗的后期研究与应用提供免疫学理论基础。