【摘要】： 日本血吸蟲(chóng)病(schistosomiasis japonica)迄今仍然是我國(guó)主要公共衛(wèi)生問(wèn)題之一。依據(jù)疾病傳播的生態(tài)學(xué)原理確定的綜合防治措施雖然有效,但效果難以鞏固。鑒于疫苗在許多傳染病控制中無(wú)可比擬的作用,試圖發(fā)展血吸蟲(chóng)病疫苗是二十世紀(jì)六十年代以來(lái)世界各國(guó)有關(guān)科學(xué)家為之奮斗的目標(biāo)。但經(jīng)過(guò)長(zhǎng)期努力,迄今尚未能成功研制出有效的抗血吸蟲(chóng)感染的疫苗,其原因在于對(duì)血吸蟲(chóng)感染中存在的一些免疫現(xiàn)象及其分子機(jī)制的認(rèn)識(shí)還比較模糊,因而極大地限制了我們明確選擇日本血吸蟲(chóng)病疫苗發(fā)展。 輻照致弱尾蚴疫苗免疫可以誘導(dǎo)相對(duì)高水平的保護(hù)力。由于現(xiàn)實(shí)的條件和倫理的原因,不能以輻照致弱尾蚴直接免疫人。關(guān)于輻照尾蚴免疫誘導(dǎo)高保護(hù)力的機(jī)制,現(xiàn)有的主要觀點(diǎn)是:輻照誘導(dǎo)了尾蚴成分的改變并因此更加有效地誘導(dǎo)了免疫活化;另一種觀點(diǎn)認(rèn)為輻照致弱尾蚴不能發(fā)育為成蟲(chóng)產(chǎn)卵,從而避免了蟲(chóng)卵沉積和蟲(chóng)卵抗原釋放對(duì)宿主免疫應(yīng)答的下調(diào)和抑制作用,從而可以使機(jī)體內(nèi)存在的,已經(jīng)被輻照致弱尾蚴抗原(attenuated cercaria antigen, ACA)活化的免疫細(xì)胞,對(duì)再次接觸到的來(lái)自正常尾蚴的抗原發(fā)生有效的活化并發(fā)揮有效的攻擊和殺傷效應(yīng)。以往研究多以體內(nèi)實(shí)驗(yàn)對(duì)獲得性免疫應(yīng)答的免疫效應(yīng)進(jìn)行觀察和分析,或者對(duì)正常尾蚴抗原(normal cercaria antigen, NCA)與ACA組分進(jìn)行比較分析。這些研究結(jié)果為理解輻照致弱尾蚴誘導(dǎo)保護(hù)力的分子機(jī)制提供了諸多支持。 基于先天免疫在啟動(dòng)和調(diào)節(jié)免疫應(yīng)答中的重要作用,觀察和比較日本血吸蟲(chóng)NCA和/或ACA以及可溶性蟲(chóng)卵抗原(soluble egg antigen, SEA)對(duì)抗原遞呈細(xì)胞(antigen presenting cells, APCs)的作用也具有重要意義,可為解釋輻照致弱尾蚴誘導(dǎo)保護(hù)力的分子機(jī)制提供新的視角。一方面,APCs攝取病原體成分并降解為小分子抗原肽,通過(guò)主要組織相容性復(fù)合體Ⅱ類(lèi)分子(major histocompatibility complexⅡ, MHCⅡ)遞呈給T細(xì)胞受體(T cell receptor, TCR)識(shí)別;另一方面,APCs通過(guò)模式識(shí)別受體(pattern recognition receptors, PRRs)識(shí)別病原體相關(guān)的分子模式(pathogen-associated molecular pattern,.PAMP),啟動(dòng)信號(hào)轉(zhuǎn)導(dǎo)和基因表達(dá),分泌各種細(xì)胞因子對(duì)免疫應(yīng)答起重要的調(diào)節(jié)作用。本研究基于APCs在啟動(dòng)和調(diào)節(jié)免疫應(yīng)答中的關(guān)鍵作用,著眼于血吸蟲(chóng)抗原對(duì)MHCⅡ表達(dá)的調(diào)節(jié),著重觀察了血吸蟲(chóng)感染早期和晚期階段涉及的兩種重要抗原,即NCA、ACA和SEA對(duì)小鼠巨噬細(xì)胞模型細(xì)胞系RAW264.7的免疫調(diào)節(jié)。 本研究結(jié)果證實(shí),日本血吸蟲(chóng)SEA可以顯著抑制IFN-γ誘導(dǎo)的巨噬細(xì)胞MHCⅡ的表達(dá);IFN-γ可以促進(jìn)SEA誘導(dǎo)巨噬細(xì)胞分泌IL-10和IL-6;IL-10對(duì)介導(dǎo)SEA誘導(dǎo)的MHCⅡ下調(diào)起重要作用,SEA也通過(guò)誘導(dǎo)IL-6抑制MHCⅡ表達(dá);在IFN-γ存在條件下,SEA誘導(dǎo)巨噬細(xì)胞分泌TGF-β的過(guò)程受到抑制并且未顯示TGF-β對(duì)MHCⅡ的抑制作用; SEA通過(guò)TLR4識(shí)別下調(diào)巨噬細(xì)胞MHCⅡ表達(dá)。 本研究結(jié)果顯示,NCA與ACA不同地調(diào)節(jié)巨噬細(xì)胞MHCⅡ分子表達(dá),NCA可以顯著下調(diào)IFN-γ誘導(dǎo)巨噬細(xì)胞表達(dá)MHCⅡ,而ACA對(duì)IFN-γ誘導(dǎo)巨噬細(xì)胞表達(dá)MHCⅡ不具有明顯影響;NCA在IFN-γ存在條件下誘導(dǎo)巨噬細(xì)胞產(chǎn)生的IL-10、IL-6和PGE2均顯著高于ACA刺激組。這些結(jié)果提示正常尾蚴可能通過(guò)誘導(dǎo)APCs分泌抑制性因子下調(diào)MHCⅡ表達(dá)實(shí)現(xiàn)免疫逃避,而輻照則可能由于導(dǎo)致尾蚴成分變化而廢除或者抑制了其中抑制MHCⅡ表達(dá)的因素,從而有效地致敏和活化了T細(xì)胞。 總之,本研究從日本血吸蟲(chóng)尾蚴和蟲(chóng)卵抗原對(duì)MHCⅡ表達(dá)的調(diào)節(jié)的角度,為血吸蟲(chóng)感染后期免疫應(yīng)答的下調(diào)和抑制以及正常尾蚴感染與輻照尾蚴免疫誘導(dǎo)的免疫應(yīng)答活化和效應(yīng)的差異提供了合理的解釋,其中的相關(guān)分子機(jī)制值得進(jìn)一步探討。
[Abstract]:The schistosomiasis japonica is still one of the main public health problems in China. The comprehensive prevention and control measures based on the ecology principle of disease transmission are effective, but the effect is difficult to consolidate. In view of the unparalleled role of vaccines in many infectious diseases control, attempts to develop schistosomiasis vaccines have been the goal of the world's scientists in the 1960s. However, after long-term efforts, effective vaccines against schistosome infection have not been successfully developed so far, and the reason is that some immune phenomena and their molecular mechanisms exist in the infection of schistosome, Therefore, we have greatly restricted the development of schistosomiasis vaccine in Japan. Induction of relatively high levels of immune responses induced by radiation-induced weak immune vaccine Due to the actual conditions and the ethical reasons, it cannot be directly irradiated by irradiation. The main point of view is that irradiation induces a change in the cytoskeleton component and thus more effectively induces immune activation; another view is that radiation-induced weakness does not develop as The adult oviposition, so as to avoid the down regulation and the inhibition of the egg deposition and egg antigen release on the host immune response, so that the existing antibody which is present in the organism, which has been activated by the irradiated weak nuclear antigen (ACA), can be caused to exist in the organism. immune cells that effectively activate and play an effective attack on antigens from normal cells that are again in contact, The effects of anti-killing effect on immune response in vivo were observed and analyzed, or normal cercasia antigen (NCA) and ACA component were analyzed. The results of these studies provide the molecular mechanism for understanding the protective force induced by irradiation. Many support. Based on the important role of innate immunity in the initiation and regulation of immune response, the antigen presenting cells (APCs) of Schistosoma japonicum NCA and/ or ACA and soluble egg antigen (SEA) were observed and compared. It also plays an important role in explaining the distribution of protective force induced by irradiation induced by irradiation. Submechanism provides a new perspective. On the one hand, APCs ingest pathogen components and degrade to small molecular antigenic peptides, which are presented to T cell receptors (TCR) by major histocompatibility complex II molecules (MHC II). On the other hand, APCs are identified by pattern recognition receptors. receptors, prrs) identification of pathogen-related molecular patterns (pathogen-associated molecula r pattern,. PAMP), activate signal transduction and gene expression, secrete various cytokines to immunize This study is based on the key role of APCs in the initiation and regulation of immune responses, focusing on the regulation of the expression of MHC 鈪，

本文編號(hào)：2312606