本文選題：佐劑 + 乙肝DNA疫苗　； 參考：《中國農(nóng)業(yè)大學(xué)》2014年博士論文

【摘要】：感染性疾病一直嚴重威脅著人類的健康和公共衛(wèi)生的安全,已知60%以上的感染性疾病都是由病毒感染所引起的,而我國是乙肝重災(zāi)區(qū),將近9.3%的人口是乙肝病毒攜帶者,每年有近20萬人死于HBV感染相關(guān)的疾病。2013年3月突如其來的H7N9禽流感病毒已造成超過419人感染,其中約127人死亡,嚴重威脅著人們的生命安全和社會的安定。但是目前我們對病毒感染性疾病的預(yù)防和治療尚缺乏有效的應(yīng)對辦法,因此研發(fā)安全有效的防治措施具有非常重要的意義。 由于DNA疫苗可以同時激活體液免疫和細胞免疫反應(yīng),因此被廣泛應(yīng)用于慢性乙肝等病毒感染性疾病的治療,但在臨床研究過程中發(fā)現(xiàn)DNA疫苗在大動物和人體內(nèi)引起的免疫反應(yīng)相對較弱。本實驗室之前的研究發(fā)現(xiàn)臨床上正在應(yīng)用的兩種小分子藥物：西咪替丁和吡喹酮可以通過不同的方式增強乙肝DNA疫苗的治療效果,本研究主要探討西咪替丁聯(lián)合吡喹酮是否可以產(chǎn)生協(xié)同效果進一步增強乙肝DNA疫苗的治療效果。結(jié)果顯示,西咪替丁聯(lián)合吡喹酮作為乙肝DNA疫苗的佐劑可以顯著降低體內(nèi)CD4+CD25+Foxp3+調(diào)節(jié)性T細胞的數(shù)量和功能,從而增強乙肝DNA疫苗所誘導(dǎo)的抗原特異性CD8+T細胞的殺傷功能,進一步研究發(fā)現(xiàn)CD8+T細胞主要通過分泌IFN-y和IL-17A來發(fā)揮其殺傷作用,在HBsAg轉(zhuǎn)基因小鼠模型中進一步證明了其治療效果。鑒于這兩種藥物的既往臨床安全性,有望作為乙肝DNA疫苗的候選佐劑。 IL-17是一種主要由Th17細胞分泌的新型細胞因子,被認為是連接固有免疫和適應(yīng)性免疫反應(yīng)的橋梁,而且在多種自主免疫性疾病(如銀屑病、炎癥性腸炎、多發(fā)性硬化癥和類風濕性關(guān)節(jié)炎等)的發(fā)病過程中起到非常重要的作用。之前研究發(fā)現(xiàn)如果體內(nèi)的IL-17A缺失后,小鼠對流感病毒的易感性明顯增強,伴隨著小鼠的體重和存活率下降,表明IL-17A在病毒感染過程中具有非常重要的作用。本研究通過檢測不同流感病毒感染后患者血清中各種細胞因子的變化水平,我們發(fā)現(xiàn)血清中IL-17A的濃度越高,流感患者的病情相對較輕,預(yù)示著IL-17A可能參與到流感病毒感染的過程中并起到保護性的效果。在小鼠H7N9流感病毒的攻毒模型基礎(chǔ)上,我們進一步證明IL-17A可以促進體內(nèi)細胞因子IFN-γ的表達,從而抑制流感病毒的復(fù)制,降低肺部的病毒載量,增強小鼠抵抗H7N9禽流感病毒感染的能力。而且IL-17A在體外同樣能夠促進人外周血中的CD8+T細胞分泌IFN-γ的能力。本研究結(jié)果為研發(fā)基于IL-17A的新型抗H7N9禽流感病毒感染策略提供了新思路。
[Abstract]:Infectious diseases have been a serious threat to human health and public health. More than 60% of the known infectious diseases are caused by viral infection. In China, hepatitis B is a major disaster area, and nearly 9.3% of the population is hepatitis B virus carriers. Nearly 200000 people die each year from diseases associated with HBV infection. In March 2013, the sudden H7N9 avian influenza virus has infected more than 419 people, of whom about 127 have died, threatening people's lives and social stability. However, the prevention and treatment of viral infectious diseases is still lack of effective response, so it is of great significance to develop safe and effective prevention and treatment measures. Because DNA vaccine can activate both humoral and cellular immune responses, it has been widely used in the treatment of chronic hepatitis B and other viral infectious diseases. However, the immune response caused by DNA vaccine in large animals and humans is relatively weak. Previous studies in our laboratory have found that cimetidine and praziquantel, two small molecular drugs in clinical use, can enhance the efficacy of hepatitis B DNA vaccines in different ways. The aim of this study was to investigate whether cimetidine combined with praziquantel could produce synergistic effect to further enhance the therapeutic effect of hepatitis B DNA vaccine. The results showed that cimetidine combined with praziquantel as adjuvant of hepatitis B DNA vaccine could significantly reduce the number and function of CD4 CD25 Foxp3 regulatory T cells in vivo and enhance the antigen-specific CD8 T cell killing function induced by hepatitis B DNA vaccine. It was further found that CD8 T cells secreted IFN-y and IL-17A to exert their killing effect, which further proved its therapeutic effect in HBsAg transgenic mice. In view of the clinical safety of these two drugs, they are expected to be used as adjuvants for hepatitis B DNA vaccine. IL-17 is a novel cytokine secreted mainly by Th17 cells, which is considered to be a bridge between innate and adaptive immune responses, and is found in many autoimmune diseases such as psoriasis, inflammatory enteritis. Multiple sclerosis and rheumatoid arthritis, etc.) play a very important role in the pathogenesis. Previous studies showed that the susceptibility of mice to influenza virus was significantly increased after the absence of IL-17A in vivo, and the weight and survival rate of mice decreased, indicating that IL-17A plays a very important role in the process of virus infection. In this study, we detected the levels of cytokines in the serum of patients infected with different influenza viruses. We found that the higher the concentration of IL-17A in serum, the lighter the condition of influenza patients. This indicates that IL-17A may be involved in the process of influenza virus infection and play a protective role. Based on the model of H7N9 influenza virus in mice, we further prove that IL-17A can promote the expression of cytokine IFN- 緯 in vivo, thus inhibit the replication of influenza virus and reduce the viral load in lung. Enhance the ability of mice to resist H7N9 avian influenza virus infection. Moreover, IL-17A can also promote the ability of CD8 T cells to secrete IFN- 緯 in human peripheral blood in vitro. The results of this study provide a new idea for the development of new anti-H7N9 avian influenza virus infection strategy based on IL-17A.
【學(xué)位授予單位】：中國農(nóng)業(yè)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R512.62;R511.7

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相關(guān)期刊論文 前2條

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