A polyepitope HPV16 E7 DNA vaccine restricted through multiple class 1 haplotypes protects against E7-expressing tumour

子宫颈癌是由人类乳头瘤病毒引起的证据是令人信服的。一旦病毒进入子宫颈细胞，它会产生一种名为E7的蛋白质，其功能是使细胞癌变。子宫颈癌是澳大利亚女性第五大常见死因，也是全球女性的主要杀手。这种疾病在免疫系统受损的女性中尤为严重，这表明癌细胞的免疫控制。目前的治疗方法包括手术切除通常是不够的，r是没有有效的药物来对抗病毒。这些观察表明，疫苗是必要的，E7蛋白可能是疫苗的理想靶点。宫颈肿瘤细胞被称为CTL的专门免疫系统细胞杀死，CTL识别其表面上与自身MHC分子结合的外来抗原（E7）片段。我们的工作已经表明，多个抗原片段可以编码和缝合在一起的基因疫苗，这将刺激CTL在一些“自我”分子的情况下发挥作用。我们的实验室已经开发了几个人类宫颈癌的小鼠模型，并（沿着其他）已经制定了E7蛋白的哪些部分是importatnt在发展适当的免疫反应，以控制肿瘤生长时，作为疫苗。一种动物模型由基因工程改造产生几种类型的自我分子和E7的小鼠组成。这些小鼠由于E7表达而发展皮肤肿瘤。该系统提供了E7表达引起的女性宫颈上皮肿瘤模型，从而我们可以提出这样的问题：我们能否诱导出在人类自身环境中发挥作用的CTL应答？这些CTL反应是否会阻止E7诱导的上皮肿瘤的生长？该项目的成果将是一种预防宫颈癌的疫苗，这种疫苗可以直接在携带适当自身分子的妇女中进行临床试验。

Evidence that cervical cancer is caused by Human Papillomavirus is compelling. Once the virus enters the cells of the cervix, it produces a protein named E7 which functions to make the cells cancerous. Cervical cancer is the 5th commonest cause of death in women in Australia, and the major killer of women world-wide.The disease is particularly severe in those women whose immune systems are impaired, indicating immunological control of the cancerous cells . Current therapies including surgical removal are frequently inadequate, and the r is no effective drug to combat the virus.These observations indicate that a vaccine is warranted, and that the E7 protein may be an ideal target for the vaccine. Cervical tumour cells are killed by specialised immune system cells named CTLs which recognise fragments of foreign antigen(E7) on their surface bound to selfMHC molecules. Our work has shown that multiple antigen fragments can be encoded and stitched together in a genetic vaccine which will stimulate CTLs to function in a number of 'self'molecule situations Our laboratory has developed several mouse models of human cervical cancer , and (along with others) has worked out which parts of the E7 protein are importatnt in developing an appropriate immune response to control tumour growth when given as a vaccine. One animal model consists of mice which are genetically engineered to produce several types of selfmolecules and also E7. Thes mice develop skin tumours as result of E7 expression. This system provides model of cervical epithelial tumours caused by E7 expression in women.Thus we can ask the questions o can we elicit CTL responses which function in the context of humanself ? o Will these CTL responses prevent the growth of E7-induced epithelial tumours? The OUTCOME of the project will be a vaccine which will prevent the establishment of cervical cancer which can progress directly into clinical trials in women bearing appropriate selfmolecules.