IL-10对口蹄疫病毒感染后免疫调控机理影响的研究
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摘要
口蹄疫的频繁爆发引起了世界各国的广泛关注,但由于口蹄疫病毒(Foot-and-mouth disease virus,FMDV)非常容易发生变异,导致新的变异株不断出现与更迭,使传统的疫苗防制措施不能有效地应对口蹄疫的爆发和流行。研究表明口蹄疫病毒感染引起机体分泌多种细胞因子,不同细胞因子通过调节免疫应答、影响病毒复制等机制在疾病的发生过程中具有重要作用。
树突状细胞(dendritic cell,DC)是目前所知的机体内功能最强的抗原递呈细胞(antigen presenting cells,APC),同时也是唯一能将抗原递呈给初始T细胞,并且能激发初次免疫应答的APC,因此其在免疫应答的诱导中具有独特的地位。而髓系树突状细胞主要分布于机体的表皮和上皮,是进行免疫应答的始动者,同时怀疑其可能是感染病毒后机体启动最初免疫应答的主要细胞,在病毒感染的过程中具有重要的调节作用,因此口蹄疫病毒作用于树突状细胞的过程对于机体的免疫状态具有重要的影响。
Th1/Th2应答优势的转变在FMDV致病机制中具有重要作用,FMDV的复制引起细胞表面标志的丢失,因此病毒可以逃避免疫监视系统的监控。在病毒感染过程中DC可能协助病毒传输或贮存,通过DC对于FMDV的递呈等功能的作用能够对机体的免疫调节过程产生一定的影响。另外,由于DC可通过调节Th1/Th2之间的平衡,调控机体免疫状态,从而促进抗病毒的免疫应答。而且IL-10可抑制DC成熟,经IL-10处理的DC刺激CD4~+T细胞应答的能力明显降低。许多调节DC分泌IL-10的因素都可能影响DC功能,甚至决定免疫反应的发展方向和结局,从而影响疾病的发生与发展。因此IL-10、抗IL-10抗体、IL-10分泌的调节因子可作为干预手段在以DC为靶细胞的人工免疫调控中发挥作用,达到预防并干扰疾病发生与发展的目的。本研究通过对FMDV感染DC后的抗原递呈以及IL-10调节免疫应答的作用进行了研究,并对IL-10 RNAi的抗口蹄疫病毒感染的免疫机制进行了探讨。
本研究以FMDV WFL株为研究对象,采用重组细胞因子GM-CSF及IL-4进行诱导的方法成功培养出DC,在FMDV WFL株感染DC后发现,FMDV WFL可以感染未成熟以及成熟的DC,但在光镜下未能观察到明显的细胞病变,通过间接免疫荧光试验可以观察到FMDV能成功感染未成熟DC及成熟的DC,荧光定量RT-PCR鉴定结果证实,未成熟DC吞噬病毒的能力较强,而成熟DC则抗原递呈能力较强,可以有效地促进小鼠脾淋巴细胞生长和增殖的能力。
通过调节培养环境中IL-10的浓度来研究FMDV感染DC后对于其分泌各种调节性细胞因子的影响发现,如果在培养液中加入了重组小鼠IL-10,感染FMDV的DCIL-12、IFN-γ在细胞转录水平下降较为明显,IL-4、IL-6、IL-10的转录水平升高。在加入IL-10抗体后,IL-1、IL-4、IL-6、IL-10的转录水平下降,而IFN-γ转录水平升高。由ELISA检测结果可知:在加入重组小鼠IL-10后,经FMDV感染后其DC所分泌的IL-1、IL-4、IL-6、IL-12、IFN-γ的量差异不显著。而在加入了IL-10抗体后,IL-12和IFN-γ的分泌量增加。同时可知:在使用了重组小鼠IL-10和IL-10抗体后进行FMDV的感染可知IL-10抗体可以促使淋巴细胞增殖指数升高。流式细胞仪检测后结果表明,在使用IL-10和IL-10抗体后,FMDV的感染后DC中MHCⅠ、MHCⅡ的表达量均有所降低,但是IL-10抗体可以抑制MHCⅠ表达量的降低,但使用IL-10后CD11c表达量降低,而使用IL-10抗体后,CD11c表达则升高。
随之,我们结合RNA二级结构预测分析,设计了针对小鼠IL-10的siRNA模板,同时设计了一个无关对照siRNA模板,分别克隆到siRNA表达载体上,并将干扰片段分别连接于hU6、mU6和h7SK启动子的下游,分别操纵shRNA转录结构单元,使之形成启动子—shRNA正义链—loop环—shRNA反义链—终止信号结构,并连接到RNAi载体中,通过酶切鉴定以及序列测定分析后可知成功构建了含有EGFP报告基因的小鼠IL-10RNAi表达质粒。细胞实验证明,所构建的RNAi载体能够通过相关转染试剂进入DC中,但对于DC这类原代培养细胞的转染效率不高。将所构建的质粒注射小鼠后进行FMDV WFL感染试验后证明,本实验构建的RNA干扰载体对于机体的免疫状态的调节具有影响,进行FMDV WFL感染小鼠后导致Th1类细胞因子IL-12升高和Th2类细胞因子IL-6的分泌量降低。经流式细胞仪测试后显示该质粒对FMDV WFL株感染小鼠后CD3+、CD4+T细胞均有上调作用。
通过本研究我们得出以下结论:通过抑制DC分泌IL-10的因素可以影响DC对于病毒感染后的免疫调节功能,从而影响FMDV感染机体后免疫调控作用的发生与发展。所以,在FMDV感染过程中抑制IL-10可以在一定程度上促进机体的免疫应答,通过本研究为探索IL-10对病毒感染机体后免疫应答的调控机制做一前期铺垫,也为进一步研制基于病毒感染后重要的细胞因子IL-10的调节制剂的研究做一探索。
Foot-and-mouth disease virus(FMDV) is a member of the family Picornaviridae. Many researchers have studied this disease,although the FMDV shows high genetic and antigenic variability,so that the traditionary vaccine can't control the epidemic and the explosion of FMD.The research presented that the bodies can secrete many cytokines when which affected by fmdvs,and the cytokines can regulate immune response of the bodies,so they played an important role in virus disease.For FMDV can cause the animals secreted many kinds of cytokines,and which have very important effects on immune state of animals.And Dendritic cells(DC) are the most potent antigen presenting cells(APC) of the immune system,the APCs could capable of stimulating resting T cells to generate an antigen specific primary immune response.So it has a special place in induce of immune response.We thought that the DC have the important affect through the process of viral infection.For that the bone marrow-derived dendritic cells were distributed in the epidermis,and we thought which was the major immunocyte for start the initial immune response,so they have the very important rules in control of the dieases.
Now we thought that the changes of Th1/Th2 were very important for the research of pathogenic mechanism for FMDVs.The cell-surface maker would be lossed because of the virus' replication,which would caused the virus refrain from the bodies' immunological surveillance.Otherwise,the DCs could promote the antiviral immunologic response through regulate the balance of Th1/Th2.In addition to its effects on suppressing inflammatory and Th1 responses and IL-10 strongly inhibits the maturation of DCs and the cellullar immunologic response.Certain populations of DCs appear to produce IL-10,which may promote the generation of regulatory CD4~+ T cell populations.So,many factors which could regulated the secrete of IL-10 could affect the function of DCs and influence the development of disease.Therefore,we though that the regulatory factor which can affect the IL-10 would be a very important means to deal with the FMDV.For this reason,in the research,we used the IL-10 and IL-10 neutralizing antibody to regulate the immune state of bodies when they were infected by FMDVs.
At frist,we used to generate dendritic cells(DCs) by culturing them in recombinant granulocyte macrophage-colony stimulating factor(GM-CSF) and recombinant interleukin-4(IL-4).We found that the fmdvs can infect the imDCs and mDCs.But we can't saw the cytopathic effects when used the light microscope:but we could saw from the indirect immunofluorescence microscope that the fmdvs could infect the imDCs and mDCs.And that the imDC have the powerful abilities to intake the virus,in the other hand,the mDC could stimulated the body to present the antigenes.
If we added the recombination mouse IL-10 to the DCs which was infected by fmdvs,that the expressed of IL-12 and IFN-γwere decreased in transcriptional level,but the IL-4,IL-6,IL-10 were increased,if we added the IL-10 neutralizing antibody in the culture hole,the IL-I,IL-4,IL-6 and IL-10 became decreased,but the expression of IFN-γbecame higher.So we thought that IL-10 could affected the immunological response of the immune system when the immunological cell was infected by fmdvs.
When we detected the cytokine of the supernatant of DCs by ELISA,that the secretory volume of IL-1,IL-4,IL-6,IL-12 and IFN-γhad no significant difference.But if we used the IL-10 neutralizing antibody to the DCs,we can seen that the secretory volume of IL-12 and IFN-γwere increased.The others had no significant difference.So we thought these were because of many factors which deal with the cells.The capabilities of antigen presentation were all have affected if we used the IL-10 or the IL-10 neutralizing antibody in the holes which were infected by fmdvs, and the proliferation index(SI) of lymphocyte which the IL-10 neutralizing antibody we used were higher than that used of IL-10.
When detected the surface marker of MHCⅠ,MHCⅡand the CD11c of the DCs which were infected by fmdvs by flow cytometry,that the MHCⅠand MHCⅡwere all decreased when we used the IL-10 and the IL-10 neutralizing antibody,but if we used the IL-10 the CD11c could decreased,In contrast,the IL-10 neutralizing antibody caused the produced of the expression of CD11c became increased a little.
So we designed the target of the IL-10 combined with the secondary structure prediction of mRNA.And cloned them into the expression vector behind of the promoter U6,mU6 and h7SK.Whereafter the DNA sequencing of the plasmids were detected by restriction enzyme digestion and sequence determination,which verified that we make successful construction of siRNA vectors which include of the gene of EGFP And the structure of which was Promotor,positive-sense strand of shRNA, loop,antisense strand of shRNA,terminate signal.
The products can be transfected into the DCs by the transfection anget of FuGENE HD from Roch,but transfection efficiency was very low.After we injected the plasmids to the mices,then the virus were infected to the mice through belly cavity,that the plasmids could affect the immune states of the mice.And the secretory volume of IL-12 and IL-6 have somewhat changed after FMDV WFL was infected. Through the detection of the splenic lymphocyte by flow cytometry,we can known that the plasmid can affect the expressed of the CD3~+、CD4~+、CD8~+ of the mice which was infeted by fmdvs.So we thought that these researches can be revealed the immunological response and the mechanism of the viral infection.
树突状细胞(dendritic cell,DC)是目前所知的机体内功能最强的抗原递呈细胞(antigen presenting cells,APC),同时也是唯一能将抗原递呈给初始T细胞,并且能激发初次免疫应答的APC,因此其在免疫应答的诱导中具有独特的地位。而髓系树突状细胞主要分布于机体的表皮和上皮,是进行免疫应答的始动者,同时怀疑其可能是感染病毒后机体启动最初免疫应答的主要细胞,在病毒感染的过程中具有重要的调节作用,因此口蹄疫病毒作用于树突状细胞的过程对于机体的免疫状态具有重要的影响。
Th1/Th2应答优势的转变在FMDV致病机制中具有重要作用,FMDV的复制引起细胞表面标志的丢失,因此病毒可以逃避免疫监视系统的监控。在病毒感染过程中DC可能协助病毒传输或贮存,通过DC对于FMDV的递呈等功能的作用能够对机体的免疫调节过程产生一定的影响。另外,由于DC可通过调节Th1/Th2之间的平衡,调控机体免疫状态,从而促进抗病毒的免疫应答。而且IL-10可抑制DC成熟,经IL-10处理的DC刺激CD4~+T细胞应答的能力明显降低。许多调节DC分泌IL-10的因素都可能影响DC功能,甚至决定免疫反应的发展方向和结局,从而影响疾病的发生与发展。因此IL-10、抗IL-10抗体、IL-10分泌的调节因子可作为干预手段在以DC为靶细胞的人工免疫调控中发挥作用,达到预防并干扰疾病发生与发展的目的。本研究通过对FMDV感染DC后的抗原递呈以及IL-10调节免疫应答的作用进行了研究,并对IL-10 RNAi的抗口蹄疫病毒感染的免疫机制进行了探讨。
本研究以FMDV WFL株为研究对象,采用重组细胞因子GM-CSF及IL-4进行诱导的方法成功培养出DC,在FMDV WFL株感染DC后发现,FMDV WFL可以感染未成熟以及成熟的DC,但在光镜下未能观察到明显的细胞病变,通过间接免疫荧光试验可以观察到FMDV能成功感染未成熟DC及成熟的DC,荧光定量RT-PCR鉴定结果证实,未成熟DC吞噬病毒的能力较强,而成熟DC则抗原递呈能力较强,可以有效地促进小鼠脾淋巴细胞生长和增殖的能力。
通过调节培养环境中IL-10的浓度来研究FMDV感染DC后对于其分泌各种调节性细胞因子的影响发现,如果在培养液中加入了重组小鼠IL-10,感染FMDV的DCIL-12、IFN-γ在细胞转录水平下降较为明显,IL-4、IL-6、IL-10的转录水平升高。在加入IL-10抗体后,IL-1、IL-4、IL-6、IL-10的转录水平下降,而IFN-γ转录水平升高。由ELISA检测结果可知:在加入重组小鼠IL-10后,经FMDV感染后其DC所分泌的IL-1、IL-4、IL-6、IL-12、IFN-γ的量差异不显著。而在加入了IL-10抗体后,IL-12和IFN-γ的分泌量增加。同时可知:在使用了重组小鼠IL-10和IL-10抗体后进行FMDV的感染可知IL-10抗体可以促使淋巴细胞增殖指数升高。流式细胞仪检测后结果表明,在使用IL-10和IL-10抗体后,FMDV的感染后DC中MHCⅠ、MHCⅡ的表达量均有所降低,但是IL-10抗体可以抑制MHCⅠ表达量的降低,但使用IL-10后CD11c表达量降低,而使用IL-10抗体后,CD11c表达则升高。
随之,我们结合RNA二级结构预测分析,设计了针对小鼠IL-10的siRNA模板,同时设计了一个无关对照siRNA模板,分别克隆到siRNA表达载体上,并将干扰片段分别连接于hU6、mU6和h7SK启动子的下游,分别操纵shRNA转录结构单元,使之形成启动子—shRNA正义链—loop环—shRNA反义链—终止信号结构,并连接到RNAi载体中,通过酶切鉴定以及序列测定分析后可知成功构建了含有EGFP报告基因的小鼠IL-10RNAi表达质粒。细胞实验证明,所构建的RNAi载体能够通过相关转染试剂进入DC中,但对于DC这类原代培养细胞的转染效率不高。将所构建的质粒注射小鼠后进行FMDV WFL感染试验后证明,本实验构建的RNA干扰载体对于机体的免疫状态的调节具有影响,进行FMDV WFL感染小鼠后导致Th1类细胞因子IL-12升高和Th2类细胞因子IL-6的分泌量降低。经流式细胞仪测试后显示该质粒对FMDV WFL株感染小鼠后CD3+、CD4+T细胞均有上调作用。
通过本研究我们得出以下结论:通过抑制DC分泌IL-10的因素可以影响DC对于病毒感染后的免疫调节功能,从而影响FMDV感染机体后免疫调控作用的发生与发展。所以,在FMDV感染过程中抑制IL-10可以在一定程度上促进机体的免疫应答,通过本研究为探索IL-10对病毒感染机体后免疫应答的调控机制做一前期铺垫,也为进一步研制基于病毒感染后重要的细胞因子IL-10的调节制剂的研究做一探索。
Foot-and-mouth disease virus(FMDV) is a member of the family Picornaviridae. Many researchers have studied this disease,although the FMDV shows high genetic and antigenic variability,so that the traditionary vaccine can't control the epidemic and the explosion of FMD.The research presented that the bodies can secrete many cytokines when which affected by fmdvs,and the cytokines can regulate immune response of the bodies,so they played an important role in virus disease.For FMDV can cause the animals secreted many kinds of cytokines,and which have very important effects on immune state of animals.And Dendritic cells(DC) are the most potent antigen presenting cells(APC) of the immune system,the APCs could capable of stimulating resting T cells to generate an antigen specific primary immune response.So it has a special place in induce of immune response.We thought that the DC have the important affect through the process of viral infection.For that the bone marrow-derived dendritic cells were distributed in the epidermis,and we thought which was the major immunocyte for start the initial immune response,so they have the very important rules in control of the dieases.
Now we thought that the changes of Th1/Th2 were very important for the research of pathogenic mechanism for FMDVs.The cell-surface maker would be lossed because of the virus' replication,which would caused the virus refrain from the bodies' immunological surveillance.Otherwise,the DCs could promote the antiviral immunologic response through regulate the balance of Th1/Th2.In addition to its effects on suppressing inflammatory and Th1 responses and IL-10 strongly inhibits the maturation of DCs and the cellullar immunologic response.Certain populations of DCs appear to produce IL-10,which may promote the generation of regulatory CD4~+ T cell populations.So,many factors which could regulated the secrete of IL-10 could affect the function of DCs and influence the development of disease.Therefore,we though that the regulatory factor which can affect the IL-10 would be a very important means to deal with the FMDV.For this reason,in the research,we used the IL-10 and IL-10 neutralizing antibody to regulate the immune state of bodies when they were infected by FMDVs.
At frist,we used to generate dendritic cells(DCs) by culturing them in recombinant granulocyte macrophage-colony stimulating factor(GM-CSF) and recombinant interleukin-4(IL-4).We found that the fmdvs can infect the imDCs and mDCs.But we can't saw the cytopathic effects when used the light microscope:but we could saw from the indirect immunofluorescence microscope that the fmdvs could infect the imDCs and mDCs.And that the imDC have the powerful abilities to intake the virus,in the other hand,the mDC could stimulated the body to present the antigenes.
If we added the recombination mouse IL-10 to the DCs which was infected by fmdvs,that the expressed of IL-12 and IFN-γwere decreased in transcriptional level,but the IL-4,IL-6,IL-10 were increased,if we added the IL-10 neutralizing antibody in the culture hole,the IL-I,IL-4,IL-6 and IL-10 became decreased,but the expression of IFN-γbecame higher.So we thought that IL-10 could affected the immunological response of the immune system when the immunological cell was infected by fmdvs.
When we detected the cytokine of the supernatant of DCs by ELISA,that the secretory volume of IL-1,IL-4,IL-6,IL-12 and IFN-γhad no significant difference.But if we used the IL-10 neutralizing antibody to the DCs,we can seen that the secretory volume of IL-12 and IFN-γwere increased.The others had no significant difference.So we thought these were because of many factors which deal with the cells.The capabilities of antigen presentation were all have affected if we used the IL-10 or the IL-10 neutralizing antibody in the holes which were infected by fmdvs, and the proliferation index(SI) of lymphocyte which the IL-10 neutralizing antibody we used were higher than that used of IL-10.
When detected the surface marker of MHCⅠ,MHCⅡand the CD11c of the DCs which were infected by fmdvs by flow cytometry,that the MHCⅠand MHCⅡwere all decreased when we used the IL-10 and the IL-10 neutralizing antibody,but if we used the IL-10 the CD11c could decreased,In contrast,the IL-10 neutralizing antibody caused the produced of the expression of CD11c became increased a little.
So we designed the target of the IL-10 combined with the secondary structure prediction of mRNA.And cloned them into the expression vector behind of the promoter U6,mU6 and h7SK.Whereafter the DNA sequencing of the plasmids were detected by restriction enzyme digestion and sequence determination,which verified that we make successful construction of siRNA vectors which include of the gene of EGFP And the structure of which was Promotor,positive-sense strand of shRNA, loop,antisense strand of shRNA,terminate signal.
The products can be transfected into the DCs by the transfection anget of FuGENE HD from Roch,but transfection efficiency was very low.After we injected the plasmids to the mices,then the virus were infected to the mice through belly cavity,that the plasmids could affect the immune states of the mice.And the secretory volume of IL-12 and IL-6 have somewhat changed after FMDV WFL was infected. Through the detection of the splenic lymphocyte by flow cytometry,we can known that the plasmid can affect the expressed of the CD3~+、CD4~+、CD8~+ of the mice which was infeted by fmdvs.So we thought that these researches can be revealed the immunological response and the mechanism of the viral infection.
引文
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