雙功能HPV治療性融合蛋白疫苗的抗癌作用實驗研究
發(fā)布時間：2019-05-30 05:46
【摘要】： 人乳頭瘤病毒(human papillomaviruse,HPV),特別是高危型HPV16,的持續(xù)感染與宮頸癌等多種腫瘤的發(fā)生與演進(jìn)密切相關(guān)。由于預(yù)防性疫苗對已感染者無效,所以研制高效、安全的治療性疫苗,對于HPV相關(guān)腫瘤的治療將具有十分重要的意義。HPV治療性蛋白疫苗由于具有安全、可重復(fù)用藥和制備較簡單等諸多優(yōu)點(diǎn),已經(jīng)成為十分吸引人的策略。目前如何進(jìn)一步提高疫苗的療效仍是各國學(xué)者關(guān)注的熱點(diǎn)。熱休克蛋白(Heat shock proteins,HSP)家族,包括鈣網(wǎng)蛋白(calreticulin,CRT)和HSP70,已被證明是一類強(qiáng)有力的免疫佐劑,它能夠有效的增強(qiáng)抗原特異性的抗腫瘤免疫。以往的研究表明,鈣網(wǎng)蛋白的N端(NCRT)或HSP70的C端的功能片段(hsp)與HPV16 E7聯(lián)接后能誘導(dǎo)小鼠產(chǎn)生抗原特異性的CTL活性。 為此,本研究構(gòu)建了NCRT/E7/hsp重組融合蛋白疫苗,利用NCRT抗腫瘤血管生成和抗原遞呈作用聯(lián)合hsp較強(qiáng)的佐劑功能協(xié)同增強(qiáng)HPV16 E7治療性疫苗的效果。并評價此疫苗誘導(dǎo)的免疫反應(yīng)和抗腫瘤血管生成作用。我們的研究結(jié)果表明,NCRT與hsp不僅能協(xié)同增強(qiáng)E7特異性的CD8~+T細(xì)胞免疫反應(yīng),還能產(chǎn)生更強(qiáng)的抗腫瘤效應(yīng)。此外,NCRT/E7/hsp融合蛋白具有較強(qiáng)的抗血管生成作用,并能由此增強(qiáng)其抗腫瘤效應(yīng)。到目前為此,尚未見到類似的報道。因此,NCRT/ET/hsp能通過抗原特異性的抗腫瘤免疫和抗腫瘤血管生成兩方面功能更有效抑制HPV相關(guān)腫瘤,可能具有良好的應(yīng)用前景。
[Abstract]:The persistent infection of human papillomavirus (human papillomaviruse,HPV), especially high-risk HPV16, is closely related to the occurrence and evolution of cervical cancer and other tumors. Because preventive vaccines are not effective for infected people, the development of efficient and safe therapeutic vaccines will be of great significance for the treatment of HPV-related tumors. HPV therapeutic protein vaccines are safe. Many advantages, such as reusable drug use and simple preparation, have become a very attractive strategy. At present, how to further improve the efficacy of vaccines is still the focus of attention of scholars all over the world. Heat shock protein (Heat shock proteins,HSP family, including calmodulin (calreticulin,CRT) and HSP70, has been proved to be a class of powerful immune adjuvants, which can effectively enhance antigen-specific antitumor immunity. Previous studies have shown that the N-terminal (NCRT) of calmodulin or the C-terminal functional fragment (hsp) of HSP70 can induce antigen-specific CTL activity in mice after ligating with HPV16 E7. In this study, NCRT/E7/hsp recombinant fusion protein vaccine was constructed, and the therapeutic effect of HPV16 E7 vaccine was enhanced by the combination of NCRT anti-tumor angiogenesis and antigen presentation combined with hsp adjuvant function. The immune response and anti-tumor angiogenesis induced by the vaccine were evaluated. Our results show that NCRT and hsp can not only enhance the specific CD8~ T cell immune response of E7, but also produce stronger antitumor effect. In addition, NCRT/E7/hsp fusion protein has strong anti-angiogenic effect and can enhance its anti-tumor effect. So far, no similar reports have been seen. Therefore, NCRT/ET/hsp can inhibit HPV-related tumors more effectively through antigen-specific anti-tumor immunity and anti-tumor angiogenesis, and may have a good application prospect.
【學(xué)位授予單位】：中國協(xié)和醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2008
【分類號】：R392;R730.5
[Abstract]:The persistent infection of human papillomavirus (human papillomaviruse,HPV), especially high-risk HPV16, is closely related to the occurrence and evolution of cervical cancer and other tumors. Because preventive vaccines are not effective for infected people, the development of efficient and safe therapeutic vaccines will be of great significance for the treatment of HPV-related tumors. HPV therapeutic protein vaccines are safe. Many advantages, such as reusable drug use and simple preparation, have become a very attractive strategy. At present, how to further improve the efficacy of vaccines is still the focus of attention of scholars all over the world. Heat shock protein (Heat shock proteins,HSP family, including calmodulin (calreticulin,CRT) and HSP70, has been proved to be a class of powerful immune adjuvants, which can effectively enhance antigen-specific antitumor immunity. Previous studies have shown that the N-terminal (NCRT) of calmodulin or the C-terminal functional fragment (hsp) of HSP70 can induce antigen-specific CTL activity in mice after ligating with HPV16 E7. In this study, NCRT/E7/hsp recombinant fusion protein vaccine was constructed, and the therapeutic effect of HPV16 E7 vaccine was enhanced by the combination of NCRT anti-tumor angiogenesis and antigen presentation combined with hsp adjuvant function. The immune response and anti-tumor angiogenesis induced by the vaccine were evaluated. Our results show that NCRT and hsp can not only enhance the specific CD8~ T cell immune response of E7, but also produce stronger antitumor effect. In addition, NCRT/E7/hsp fusion protein has strong anti-angiogenic effect and can enhance its anti-tumor effect. So far, no similar reports have been seen. Therefore, NCRT/ET/hsp can inhibit HPV-related tumors more effectively through antigen-specific anti-tumor immunity and anti-tumor angiogenesis, and may have a good application prospect.
【學(xué)位授予單位】：中國協(xié)和醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2008
【分類號】：R392;R730.5
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