炎症因子介导树突状细胞过度表达HVEM重建特异性自身免疫耐受
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摘要
本研究共分四个部分:第一部分构建了IL1/IL6重组体启动子调控荧光素酶表达的重组腺病毒载体和报告质粒,旨在通过一系列体内外实验检验IL1/IL6是否可诱导性表达外源基因。第二部分在前面已确定IL1/IL6启动子具有可调控活性的基础上,构建了该启动子调控HVEM表达的重组腺病毒载体,并将其转染小鼠骨髓来源的髓样树突状细胞(dendritic cell,DC),以检测DC经诱导表达HVEM后有何生理改变。结果证实HVEM修饰的DC可拮抗LPS诱导的DC成熟,下调相关细胞因子表达,抑制特异性T细胞的增殖反应。第三部分通过建立实验性自身免疫性心肌炎动物模型,确证HVEM修饰的DC能够在体内抑制自身反应性T细胞的活化、下调自身抗体的产生,减少致病性Th17亚群的生成,并较大程度地减轻心肌的自身免疫病损。第四部分在体内外已确定HVEM修饰的DC具有免疫保护作用的基础上,初步探讨其免疫耐受的机制,通过HVEM修饰的DC与小鼠淋巴结来源的CD4+ T细胞进行混合培养发现,HVEM修饰的DC能够延滞Treg的凋亡,并具有诱导产IL-10的Tr1生成的能力。这些结果表明,HVEM修饰的DC可能部分通过诱导调节性T细胞反应保护自身免疫损伤。
This study has four parts:In the first part we constructed the luciferase reporter plasmid and adenovirus containing IL1/IL6 hybrid promoter to evaluate its inducible expression characters in vitro and in vivo. In the second part, on the basis of confirmative conclusion of inducible ability of IL1/IL6 hybrid promoter, we constructed another adenovirus which the IL1/IL6 drives HVEM expression, and transferred it into murine myeloid DCs. The physiological properties of HVEM modified DCs were analyzed. We found HVEM modified DCs resisted to mature induced by LPS, and inhibited allogenic CD4+ T cell proliferation. It also decreased secretion of proinflammatory factors. In the third part we established an experimental autoimmune myocarditis model to investigate the role of HVEM modified DCs in prevention against autoimmune lesion. HVEM modified DCs ameliorated myocarditis, inhibited autoimmune reaction and production of autoantibodies. In addition, it altered the ratio of Th subsets that the ratio of Th1 increased while that of Th17 decreased. In the fourth part we found the HVEM modified DCs regulated Tr1 reaction and prolonged the survival of Treg, which suggested the protection mechanisms of HVEM modified DCs might partly depend on induction of regulatory T cells.
This study has four parts:In the first part we constructed the luciferase reporter plasmid and adenovirus containing IL1/IL6 hybrid promoter to evaluate its inducible expression characters in vitro and in vivo. In the second part, on the basis of confirmative conclusion of inducible ability of IL1/IL6 hybrid promoter, we constructed another adenovirus which the IL1/IL6 drives HVEM expression, and transferred it into murine myeloid DCs. The physiological properties of HVEM modified DCs were analyzed. We found HVEM modified DCs resisted to mature induced by LPS, and inhibited allogenic CD4+ T cell proliferation. It also decreased secretion of proinflammatory factors. In the third part we established an experimental autoimmune myocarditis model to investigate the role of HVEM modified DCs in prevention against autoimmune lesion. HVEM modified DCs ameliorated myocarditis, inhibited autoimmune reaction and production of autoantibodies. In addition, it altered the ratio of Th subsets that the ratio of Th1 increased while that of Th17 decreased. In the fourth part we found the HVEM modified DCs regulated Tr1 reaction and prolonged the survival of Treg, which suggested the protection mechanisms of HVEM modified DCs might partly depend on induction of regulatory T cells.
引文
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