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

宫颈癌是由人乳头瘤病毒引起的证据令人信服。一旦病毒进入宫颈细胞，它就会产生一种名为E7的蛋白质，这种蛋白质的功能是使细胞癌变。宫颈癌是澳大利亚妇女死亡的第五大常见原因，也是全世界妇女的主要杀手。这种疾病在那些免疫系统受损的妇女中尤其严重，这表明癌细胞的免疫控制。目前的治疗方法，包括手术切除，往往是不够的，并没有有效的药物来对抗病毒。这些观察结果表明，疫苗是有必要的，E7蛋白可能是疫苗的理想靶点。宫颈肿瘤细胞被称为ctl的特殊免疫系统细胞杀死，ctl识别表面与自身mhc分子结合的外来抗原片段（E7）。我们的工作表明，多种抗原片段可以在基因疫苗中编码并拼接在一起，这将刺激ctl在许多“自我”分子情况下发挥作用。我们的实验室已经开发了几种人类宫颈癌小鼠模型，并且（与其他实验室一起）已经研究出E7蛋白的哪些部分在作为疫苗给予时对发展适当的免疫反应以控制肿瘤生长很重要。一种动物模型是由经过基因工程改造的老鼠组成的，这些老鼠可以产生几种类型的自我分子和E7。这些小鼠由于E7的表达而产生皮肤肿瘤。该系统提供了由E7表达引起的女性宫颈上皮肿瘤的模型。因此，我们可以提出这样的问题：我们能否引发在人类自身环境中起作用的CTL反应？这些CTL反应是否会阻止e7诱导的上皮肿瘤的生长？该项目的成果将是研制出一种预防宫颈癌的疫苗，这种疫苗可以直接在携带适当自我分子的妇女身上进行临床试验。

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.