本文選題：日本血吸蟲 + 免疫調(diào)節(jié)　； 參考：《安徽醫(yī)科大學(xué)》2011年博士論文

【摘要】：目的 機(jī)體接觸包括蠕蟲在內(nèi)的病源微生物機(jī)會減少,尤其在幼年時(shí)期免疫系統(tǒng)失去病源微生物的塑造和協(xié)調(diào),是導(dǎo)致西方發(fā)達(dá)國家自身免疫性疾病和過敏性疾病發(fā)病率迅速增高的主要原因之一。蠕蟲感染能激發(fā)強(qiáng)烈的Th2免疫應(yīng)答,可以改善Th1介導(dǎo)的自身免疫性疾病的臨床癥狀和病理過程。日益增多的流行病學(xué)及實(shí)驗(yàn)研究證實(shí)了蠕蟲對自身免疫性疾病及過敏性疾病的保護(hù)作用,顯示了優(yōu)異的臨床應(yīng)用價(jià)值。目前利用豬鞭蟲卵治療炎癥性腸病(inflammatory bowel disease,IBD)患者已取得良好的臨床效果。 類風(fēng)濕性關(guān)節(jié)炎(rheumatoid arthritis,RA)是一種嚴(yán)重危害人類健康的慢性自身免疫性疾病,該病發(fā)病率和致殘率高,目前仍無有效的治療方法。研究表明,CD4+效應(yīng)T細(xì)胞和調(diào)節(jié)性T細(xì)胞免疫失衡參與RA發(fā)病的各個(gè)環(huán)節(jié),RA的致病與Th1/Th17密切相關(guān)。日本血吸蟲感染可誘導(dǎo)強(qiáng)烈的Th2優(yōu)勢應(yīng)答。本研究試圖利用血吸蟲感染和血吸蟲抗原誘導(dǎo)的Th2免疫偏移來恢復(fù)RA失衡的Th免疫應(yīng)答。用CIA鼠構(gòu)建血吸蟲感染的RA模型,觀察CD4+T細(xì)胞亞群的網(wǎng)絡(luò)調(diào)節(jié),探討RA的發(fā)病、轉(zhuǎn)歸及免疫抑制性的治療作用。為篩選特異性抑制RA過度的Th1/Th17免疫應(yīng)答的新型免疫調(diào)節(jié)劑奠定基礎(chǔ)。 方法: 建立雄性DBA/1小鼠膠原性關(guān)節(jié)炎(Collagen Induced-arthritis,CIA)模型,分別用單、雙性日本血吸蟲尾蚴(25±2條)于造模前2W、造模后4W(關(guān)節(jié)炎模型建立后)經(jīng)腹部皮膚感染小鼠,SPF級環(huán)境飼養(yǎng),關(guān)節(jié)炎指數(shù)評價(jià)多發(fā)性關(guān)節(jié)炎病變的發(fā)生及嚴(yán)重程度。12W后處死動物, ELISA (enzyme linked immunosorbent assay,ELISA)檢測血清膠原特異IgG、IgG1、IgG2a水平,比較血吸蟲干預(yù)對CIA鼠自身抗體形成的影響;流式細(xì)胞術(shù)(flow cytometry,FCM)檢測脾淋巴細(xì)胞CD4+T細(xì)胞亞群,分析血吸蟲感染對T細(xì)胞免疫應(yīng)答的作用;Real time PCR檢測炎癥關(guān)節(jié)內(nèi)部細(xì)胞因子mRNA表達(dá)水平;取足爪組織觀察血吸蟲感染對小鼠關(guān)節(jié)炎組織病理學(xué)的影響;評價(jià)血吸蟲活蟲感染對自身免疫性關(guān)節(jié)炎小鼠的免疫調(diào)節(jié)作用。 結(jié)果: 與對照組相比,預(yù)先感染日本血吸蟲尾蚴顯著減輕小鼠關(guān)節(jié)炎的病情,降低關(guān)節(jié)炎的發(fā)病率,改善病理損害;血清中膠原特異性IgG、IgG2a顯著降低,IgG1水平升高;脾淋巴細(xì)胞應(yīng)對多克隆及抗原特異性刺激誘發(fā)的增殖反應(yīng)明顯降低;日本血吸蟲感染顯著抑制CIA小鼠IFN-γ+CD4+ T細(xì)胞比例,提高IL-4+CD4+ T細(xì)胞百分比。僅在雙性感染的CIA鼠發(fā)現(xiàn)CD25highCD4+ Treg(regulatory T cells,Treg)的增殖及IL-17+CD4+ T細(xì)胞的抑制。血吸蟲感染顯著降低了脾細(xì)胞培養(yǎng)上清中INF-γ、TNF-α、IL-1β和IL-6的表達(dá)水平,提高IL-10表達(dá)。此外,血吸蟲感染顯著上調(diào)炎癥關(guān)節(jié)內(nèi)部炎癥因子及NF-κB配體-受體活化因子(receptor activator of NF-κB ligand, RANKL)的表達(dá)。對于已經(jīng)建立的感染模型并出現(xiàn)明顯臨床癥狀的CIA小鼠,感染血吸蟲尾蚴不僅不能改善病情,反而加重病情。 結(jié)論: 日本血吸蟲預(yù)先感染誘導(dǎo)的Th2優(yōu)勢應(yīng)答可顯著抑制CIA異常的Th1應(yīng)答,減少炎癥介質(zhì)的釋放,減輕病情,改善病理損害;雙性感染還可上調(diào)Treg,抑制CIA小鼠過度的Th17應(yīng)答。血吸蟲感染對CIA的保護(hù)作用依賴于Th2優(yōu)勢應(yīng)答的預(yù)先建立,使異種Ⅱ型膠原不能有效啟動致病性的Th1免疫應(yīng)答。血吸蟲成蟲抗原亦能有效激發(fā)抗炎性的Th2優(yōu)勢應(yīng)答。
[Abstract]:objective
One of the main reasons for the rapid increase in the incidence of autoimmune and allergic diseases in western developed countries is one of the main reasons for the decrease of organisms' exposure to pathogenic microorganisms, including worms, especially in the early years of the immune system, which leads to the rapid increase in the incidence of autoimmune diseases and allergic diseases in western developed countries. The clinical symptoms and pathological processes of autoimmune diseases mediated by good Th1. An increasing number of epidemiological and experimental studies have confirmed the protective effects of worms on autoimmune diseases and allergic diseases, showing excellent clinical value. Currently, the use of porcine flagellate eggs for the treatment of inflammatory bowel disease (inflammatory bowel disease, IBD) A good clinical effect has been achieved.
Rheumatoid arthritis (RA) is a chronic autoimmune disease which seriously endangers human health. The incidence and disability rate of this disease are high, and there is still no effective treatment. The study shows that the CD4+ effect T cell and the regulatory T cell immune imbalance are involved in every link of the pathogenesis of RA, and the pathogenesis of RA is closely related to Th1/Th17. Schistosoma japonicum infection can induce strong Th2 dominance response. This study attempts to restore the Th immune response to RA imbalance by using the Th2 immunization induced by Schistosoma infection and Schistosoma antigen. The RA model of Schistosoma infection was constructed with CIA mice, the network regulation of CD4+T cell subsets was observed, and the pathogenesis, prognosis and immunosuppression of RA were discussed. To lay the foundation for screening new immunomodulators that specifically inhibit RA over Th1/Th17 immune response.
Method:
The model of Collagen Induced-arthritis (CIA) in male DBA/1 mice was established, and the single and double sex Schistosoma japonicum cercariae (25 + 2) were used before the model of 2W. After modeling, 4W (after the establishment of arthritis model), the mice were infected with the abdominal skin, the SPF level environment was raised, and the arthritis index was used to evaluate the occurrence and severity of multiple arthritis. After 12W, the animals were killed, and ELISA (enzyme linked immunosorbent assay, ELISA) was used to detect the serum collagen specific IgG, IgG1 and IgG2a levels. The effects of schistosomiasis intervention on the formation of autoantibodies in CIA rats were compared, and the flow cytometry (flow) was used to detect the subsets of spleen lymphocyte subsets and the effect of schistosomiasis infection on the immune response of the cells. Al time PCR was used to detect the expression level of cytokine mRNA in the inflammatory joints, and the effect of schistosomiasis infection on the histopathology of arthritis in mice was observed and the immunoregulation effect of schistosomiasis on autoimmune arthritis mice was evaluated.
Result:
Compared with the control group, the pre infection of Schistosoma japonicum cercariae significantly alleviated the condition of arthritis in mice, reduced the incidence of arthritis and improved the pathological damage. The serum collagen specific IgG, IgG2a decreased significantly, and the level of IgG1 increased, and the proliferation response induced by polyclonal and antigen specific stimulation in spleen lymphocytes was significantly reduced; Japanese blood sucking. The proportion of IFN- gamma +CD4+ T cells in CIA mice was significantly inhibited and the percentage of IL-4+CD4+ T cells was increased. The proliferation of CD25highCD4+ Treg (regulatory T cells) and inhibition of IL-4+CD4+ cells were found only in the CIA mice infected with bisexual infection. In addition, IL-10 increased the expression of inflammatory factors in the inflammatory joints and the expression of NF- kappa B ligand receptor activator (receptor activator of NF- kappa B ligand, RANKL). The infection of the cercariae of the infected schistosoma cercariae was not only unable to improve the condition of the infected mice. Aggravate the condition.
Conclusion:
The preinfection induced Th2 response of Schistosoma japonicum can significantly inhibit the Th1 response of the abnormal CIA, reduce the release of the inflammatory mediators, reduce the condition and improve the pathological damage. The double sex infection can also increase the Treg and inhibit the excessive Th17 response of the CIA mice. The protection of the schistosomiasis infection to CIA depends on the pre establishment of the Th2 dominance response. Type II collagen can not effectively activate pathogenic Th1 immune response. Schistosoma japonicum adult antigen can also effectively stimulate the Th2 dominant response of anti-inflammatory.

【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2011
【分類號】：R392

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