IL-10阻断剂提高HPV治疗性疫苗抗肿瘤效果和机制研究

Infection with certain types of human papillomaviruses results in the development of cervical cancer. Therapeutic vaccines provide a novel and exciting way for the management of HPV infection related diseases and cervical cancer, and are currently under intensive investigation. We have previously found that CTL responses induced by HPV therapeutic vaccines could been suppressed by HPV specific CD4+ GITR+ IL-10 secreting cells, while temporary blocking IL-10 signaling in HPV antigen primed mice can improve the CTL response.In the current project, we wish to investigate whether peptide based vaccine immunization and IL-10 signaling blockade will inhibit tumour growth in a mouse tumour model and investigate the underlying mechanisms if the hypothesis is correct. We will investigate the risk of causing autoimmune disease by blocking IL10 at the time of immunization. Moreover, we will design and synthesis clinical usable bioactive peptides that are able to block IL-10 signaling in vivo and a nanomaterial Graphene Oxide will be used to absorb IL-10 inhibitor, in order reduce the possible side effects caused by IL-10 blockade. The project will lay the foundation of developing a new type of safe and highly effective HPV therapeutic vaccine with independent intellectual property rights, and will also provide a platform for developing therapeutic vaccines against other diseases.

宫颈癌的发生与人乳头瘤病毒（HPV）持续感染密切相关。HPV治疗性疫苗是宫颈癌免疫防治领域的热点方向，但疗效甚微且进展缓慢。优化、提高HPV治疗性疫苗疗效成为亟待解决的命题。我们前期研究发现，慢性HPV感染者体内抗原特异性CD4+GITR+IL10+细胞可抑制治疗性疫苗诱导的细胞毒性T细胞（CTL）反应，免疫时暂时阻断IL-10，可提高疫苗诱导CTL的能力。在此基础上，率先提出IL-10阻断剂提高治疗性疫苗疗效的新策略。本项目通过分子动力学模拟方法设计独特的IL-10受体结合抑制肽；采用纳米材料Graphene Oxide携带IL-10阻断剂，以免过度阻断IL-10可能产生不利因素；研究含IL-10阻断剂的HPV治疗性疫苗的抑瘤作用与机理；评估其引发自身免疫反应的风险。为研发具有我国自主知识产权的新型安全高效的疫苗佐剂和HPV治疗性疫苗奠定基础，并为其它疾病治疗性疫苗的研究提供模式和平台。

宫颈癌的发生与人乳头瘤病毒（HPV）持续感染密切相关。HPV 治疗性疫苗是宫颈癌免疫防治领域的热点方向，但疗效甚微且进展缓慢。优化、提高HPV 治疗性疫苗疗效.成为亟待解决的命题。我们前期研究发现，慢性HPV 感染者体内抗原特异性CD4+GITR+IL10+细胞可抑制治疗性疫苗诱导的细胞毒性T 细胞（CTL）反应，免疫时暂时阻断IL-10，可提高疫苗诱导CTL 的能力。在此基础上，率先提出IL-10 阻断剂提高治疗性疫苗疗效的新策略。本项目通过分子动力学模拟方法设计独特的IL-10 受体结合抑制肽；采用纳米材料Graphene Oxide 携带IL-10 阻断剂，以免过度阻断IL-10 可能产生不利因素；研究含IL-10 阻断剂的HPV 治疗性疫苗的抑瘤作用与机理；评估其引发自身免疫反应的风险。为研发具有我国自主知识产权的新型安全高效的疫苗佐剂和HPV 治疗性疫苗奠定基础，并为其它疾病治疗性疫苗的研究提供模式和平台。