川牛膝多糖对小鼠免疫反应的影响及机理研究
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摘要
传染病特别是病毒性传染病,在全世界范围内对畜牧业造成严重损失,接种疫苗是目前控制传染病最有效的手段。然而,养殖场虽然按免疫程序进行了严格的疫苗接种,但在很多情况下动物仍然难以产生有效的免疫应答,至使很多传染病不能完全被控制。如注射疫苗的同时,配合应用适当的免疫增强剂可以辅助疫苗产生较好的免疫应答,提高其免疫效力,从而提高疫苗免疫的效果。应用免疫增强剂成为目前提高疫苗免疫效果的重要手段之一。现有的研究表明,中药及其有效成分能够显著提高疫苗的免疫效果,很多中药及其主要成分作为疫苗的免疫增强剂已开始在动物及人的临床上使用。四川省是我国最大的中药产区,四川道地药材一向以其品质优而著称。本论文在现有文献的基础上选取10种具有免疫调节作用的四川产道地药材,包括川牛膝,川杜仲,川明参,川麦冬,川续断,川丹参,川泽泻,川芎,川白芷,川佛手；从中筛选出具有免疫增强作用的药材,并进一步研究其水提物的主要成分对疫苗免疫反应的影响及分子机理,为进一步从川产道地药材中开发免疫增强剂提供科学依据。本文具体开展的研究和取得的结果如下：
1.十种川产道地药材水提物对小鼠注射卵清白蛋白(OVA)免疫反应的影响
目的从10种川产道地药材中筛选出能够增强OVA受免小鼠免疫反应的中药。方法选取4-6周龄ICR小鼠为试验动物。将每种药材水提物设置高、中、低三个剂量组,每组5只,水提物灌胃0.25mL/只,1次/d,连续灌胃4d后,注射OVA进行首次免疫,两周后二次免疫,二免后14d进行眼眶采血,检测OVA特异性IgG水平。对IgG水平较高的几种中药进一步测定其特异性抗体亚类的水平。结果与对照组相比,川牛膝能显著提高OVA受免小鼠血清中特异性IgG、IgG1、IgG2a和IgG2b水平(P<0.05)。川明参、川杜仲可以显著提高受免小鼠血清中OVA特异性IgG水平(P<0.05)。
2.口服川牛膝水提物对小鼠注射卵清白蛋白(OVA)后免疫反应的影响。
目的观察不同剂量川牛膝水提物(RC)对小鼠注射卵清蛋白(OVA)后免疫反应的影响。方法试验选取4-6周龄ICR小鼠42只,随机分为6组,每组7只。各试验组小鼠分别灌服RC(0、0.05、0.1、0.2、0.4和0.8g),连续给药4d后,注射OVA进行首次免疫,间隔14d后二次免疫。二免后2周采集血清测定OVA特异性IgG和IgG亚类水平,同时无菌取脾,测定淋巴细胞增殖能力,淋巴细胞分泌细胞因子的水平。结果结果显示,与对照组相比在二免后14d,RC(0.2、0.4和0.8g)诱导产生了较高水平的OVA特异性IgG和抗体亚类IgG1, IgG2a, IgG2b; RC促进了淋巴细胞,增值反应,同时能够显著增加淋巴细胞分泌IL-4、IFN-γ的水平,另外,RC对实验鼠的体重无任何影响。结论川牛膝水提物能显著促进OVA受免小鼠体液免疫反应,细胞免疫反应和细胞因子的分泌。
3.川牛膝多糖(RCPS)在体外对淋巴细胞免疫活性的影响
目的探讨川牛膝多糖在体外对淋巴细胞免疫活性的影响。方法本试验提取了川牛膝多糖(RCPS),检测RCPS对小鼠脾淋巴细胞的最大无毒浓度,在无毒浓度范围内,将RCPS与脾淋巴细胞共同培养,观察RCPS对淋巴细胞增殖(?)淋巴细胞分泌细胞因子IL-4、IFN-γ和"NK细胞的杀伤活性的影响。结果结果表明,RCPS在淋巴细胞上的最大无毒浓度为500μg/mL。浓度为31.25、125和500μg/mL的川牛膝多糖能够显著促进T、B淋巴细胞的增殖,显著促进淋巴细胞分泌细胞因子IL-4、IFN-γ,显著促进NK细胞的杀伤活性。结论川牛膝多糖在体外能促进T、B淋巴细胞增殖,促进淋巴细胞分泌细胞因子,促进NK细胞的杀伤活性。
4.川牛膝多糖(RCPS)对小鼠注射卵清蛋白(OVA)后免疫反应的影响
目的探讨口服RCPS对小鼠注射卵清蛋白(OVA)后体液免疫和细胞免疫反应的影响,进而探讨了其增强免疫反应的机制。方法试验选取4-6周龄ICR小鼠42只,随机分为6组,每组7只。试验组小鼠免疫前分别灌服不同剂量RCPS(0,25,50,100mg/kg体重),连续给药4d后,注射OVA进行首次免疫,间隔14d后二次免疫。二免后2周采集血清测定抗体和抗体亚类水平,同时无菌取脾,测定淋巴细胞增殖能力,胞内细胞因子的表达水平,腹腔巨噬细胞吞噬活性、NK细胞和CTL细胞杀伤能力,共刺激信号分子(CD40、CD80和CD86)和CD4+CD25+Foxp3+Treg细胞的表达水平。结果结果显示,与对照组相比在二免后14d, RCPS促进了淋巴细胞增值反应,诱导产生了较高水平的OVA特异性IgG和IgG亚类IgG1, IgG2a, IgG2b,同时能够上调CD4+T细胞IL-2、IL-4、IFN-γ和CD8+T栅IFN-γ的表达,并增强了腹腔巨噬细胞的吞噬活性,NK细胞和CTL细胞杀伤能力：RCPS显著上调了树突细胞(DCs)表面分子CD40、CD80和CD86的表达水平,显著下调了Treg细胞的表达水平。结论综上所述,免疫前口服RCPS可提高OVA受免小鼠Th1、Th2型免疫反应,从而增强了小鼠的细胞和体液免疫反应,其免疫增强作用的机制可能是通过促进树突细胞成熟和下调Treg细胞的表达来激活T细胞引发免疫反应。
5.川牛膝多糖(RCPS)对小鼠注射口蹄疫疫苗后免疫反应的影响
目的探讨口服RCPS对小鼠注射O型口蹄疫疫苗后体液免疫和细胞免疫反应的影响,进而探讨了其增强免疫反应的分子机制。方法试验选取4-6周龄ICR小鼠60只,随机分为6组,每组10只。试验组小鼠免疫前分别灌服不同剂量RCPS (0,25,50,100mg/kg体重),连续给药4d后,注射口蹄疫疫苗进行首次免疫,间隔14d后二次免疫。二免后2周采集血清检测特异性IgG和IgG亚类的水平。同时无菌采集脾脏,制备脾细胞悬液,测定淋巴细胞增殖指数,胞内细胞因子(CD4+T细胞IL-2、IL-4、IFN-γ和CD8+T细胞IFN-γ)的表达水平,腹腔巨噬细胞吞噬活性,NK、CTL细胞的杀伤活性,共刺激分子(CD40, CD80, CD86)的表达水平,CD4+CD25+Foxp3+调节性T细胞的表达率。同时应用实时定量PCR检测了细胞因子(IL-2、IL-4.IL-10、 IFN-γ),内源性抗原肽(MHCⅠ)、外源性抗原肽(MHCⅡ)、CXC趋化因子受体4(CXCR4)、CC趋化因子受体7(CCR7)、TOLL样受体2(TLR-2)、TOLL样受体4(TLR-4)、转录因子T-bet、GATA-3、转化生长因子p(TGF-β)等分子mRNA表达水平。结果结果显示,与对照组相比在二免后14d, RCPS诱导产生了较高水平的IgG和IgG亚类(IgG1, IgG2a, IgG2b),促进了淋巴细胞增值反应和腹腔巨噬细胞的吞噬能力,并增强了NK细胞和CTL细胞杀伤活性,同时能够上调了CD4+T细胞IL-2、IL-4、IFN-y和CD8+T细胞IFN-γ的表达。明显增强了共刺激信号分子(CD40,CD80, CD86)的表达水平,明显下调了调节性T细胞CD4+CD25+Foxp3+的表达百分比。上调了细胞因子(IL-2、IL-4、IL-10、IFN-y), MHC Ⅰ, MHC Ⅱ, CXCR4, CCR7, TLR-2, TLR-4等信号通路分子的mRNA表达水平,下调了TGF-β mRNA表达水平。结论RCPS配合FMD疫苗免疫小鼠,显著增强了小鼠体液免疫和细胞免疫水平,其机制可能是通过激活TLR-2, TLR-4信号通路促进树突细胞的成熟和迁移和通过下调TGF-p和CD4+CD25+Foxp3+的表达途径增强了小鼠对FMD疫苗的免疫反应。
6.本研究的结论
综上所述,口服川牛膝多糖能增强模式抗原OVA和口蹄疫疫苗受免小鼠体液免疫、细胞免疫反应和Th1、Th2型细胞因子的产生。初步阐明其机制可能是通过激活TLR-2, TLR-4信号通路,促进树突细胞的成熟,和下调TGF-β和Treg细胞的表达,引发机体免疫反应,提高疫苗的免疫效果。另外,川牛膝多糖配合疫苗能诱导产生平衡的Th1、Th2型免疫反应,其分子机制是通过上调T-bet和GATA3的基因表达调控初始T同时向Th1/Th2型细胞发育。
Infectious diseases, especially virus diseases, are worldwide concern as they usually cause great loss in domestic animal and poultry industry. Vaccination remains the most effective biomedical approach for the control of infectious diseases. Although the strict immune program had been taken in the farms, some infectious diseases are still hard to be controlled due to the lack of effective immune responses to vaccination. The majority of vaccines require association with adjuvants capable of increasing the potency or stimulating the appropriate immune response. The application of adjuvant, one of the methods to improve the efficacy of vaccine, has been considered as an important strategy. There are many growing evidences that medicinal herbs and the ingredients enhance the immune response to vaccines direct against infectious agents. Several herbal extracts as adjuvant of vaccines has been use in the human and animal clinical trials."Sichuan herbs" are well known because the medicinal quality of the herbals Produced in Si Chuan Province believed to be better than in other Province of China. We choose ten well known herbs include Cyathula officinalis Kuan, Eucommia ulmoides Oliv, Chuanminshen violaceum, Ophiopogon japonicus,Alisma orientalis,Salvia miltiorrhiza, Dipsacaceae, Rhizoma Ligustici Chuanxiong, Radix Angelicae Dahuricae, bergamol. screening the immunoenhancement herbs from those ten "Sichuan herbs"and following to study the Effects of oral administration of herbals extract on immuno response to the vaccination in mice. The relating studies carried out and results obtained are as follows:
1. Effects of ten Sichuan herbals Extract on the Immune Responses to Ovalbumin in Mice
Objective This study was investigated the effects of oral administration the water extract from the ten Sichuan herbs on the immune responses in mice immunized with ovalbumin (OVA). Method One hundred fifty five Institute of Cancer Research (ICR) mice were randomly divided into Thirty one groups with five animals in each group, and daily orally administered daily for4days with a high, medium or low dose of herbal exract respectively. After that, the animals were subcutaneously immunized twice with OVA (10μg) at2-week intervals. Blood samples were collected on day14after,boosting for, measurement of OVA-specific IgG titers and the IgG subclasses. Results Our data indicated that the OVA-specific IgG titers and the level of IgG subclass was significantly enhanced in mice orally administered exact of Radix Cyathulae officinalis Kuan (RC) when compared to the control group (P<0.05). OVA-specific IgG titers were significantly improved in mice orally administered the exact from Eucommia ulmoides Oliv and the Chuanminshen violaceum when compared to the control group (P<0-05).
2. Effects of the Extract from Radix Cyathulae (RC) on the Immune Responses to Ovalbumin in Mice
Objective This study was designed to evaluate the effects of oral administration of the water extract from the Radix Cyathula (RC) on the immune responses in mice immunized with ovalbumin (OVA). Method Forty two Institute of Cancer Research (ICR) mice were randomly divided into six groups with seven animals in each group, and orally administered daily for4days at a dose equivalent to0,0.05,0.1,0.2,0.4or0.8g of the RC exract, respectively. After that, the animals were subcutaneously immunized twice with OVA at2-week intervals. Blood samples and spleen were collected on day14after boosting for measurement of OVA-specific IgG titers and the IgG subclasses, lymphocyte proliferation as well as the production of IL-4and IFN-y. Results Our data indicated that the OVA-specific IgG titers and the level of IgG subclass was significantly enhanced in mice orally administered RC at the dose of0.2,0.4or0.8g when compared to the control group (P<0.05). The splenocyte proliferation response and the production of IL-4and IFN-y were also significantly improved (P<0.05). Besides, the body weight of the mice administered with the RC extract (0,0.1,0.2,0.4or0.8g) was no significant difference compared to the mice administered saline.Considering the immunomodulatory effect and safety of RC presented in this study, it deserves further investigation to evaluate the potential improvement of vaccination in other animals such as pigs, goats and cattle. Conclution Our data show that RC significantly enhanced OVA-specific IgG and IgG subclasses titers, lymphocyte proliferation, the production of IL-4and IFN-y.
3. Effects of Polysaccharide from the Radix Cyathulae officinalis Kuan (RCPS) on the Immune Activity of Lymphocyte in vitro
Objective This study was to extract Polysaccharide from the Radix Cyathulae officinalis Kuan (RCPS) and to explore the effects on the immune activity in vitro. Method firstly, the highest non-toxic concentrations of RCPS on splenocytes were measurement. Effect of RCPS on lymphocyte proliferation, the production of IL-4and IFN-y from lymphocyte, NK cell Killing activity were investigated. Results The results showed that the highest non-toxic concentrations of RCPS at500μg/mL, The splenocyte proliferation response and the production of IL-4and IFN-γ were also significantly improved (P<0.05) after the splenocytes were stimulated by RCPS. Besides, RCPS promoted the NK cell activity. Conclution Our findings show that RCPS significantly enhanced lymphocyte proliferation, the production of IL-4and IFN-y and NK activity in vitro.
4. Effects of the Polysaccharide from the Radix Cyathulae officinalis Kuan (RCPS) on the Immune Response to Ovalbumin in Mice
Objective This study was designed to investigate the effects of oral administration of the polysaccharide from the Radix Cyathulae officinalis Kuan (RCPS) on the specific cellular and humoral immune responses in mice. Methods Forty two ICR mice were randomly divided into six groups (n=7), and orally administered at a dose equivalent to0,25mg,50mg,100mg of the RCPS for continuous4days respectively. After that, the animal were subcutaneously immunized twice with OVA at2weeks intervals. Blood samples and spleen collected on day14after boosting for measurement including serum OVA-specific antibody level, lymphocyte proliferation, expression of surface and intracellular molecules, phagocytic capacity of peritoneal macrophage, NK (Nature killer) and CTL (cytotoxic lymphocyte) Killing activity, The frequency of costimulatory molecule (CD40, CD80, CD86) and CD4+CD25+Foxp3+Treg cells. Results In this study, our findings demonstrated that oral administration of RCPS significantly enhanced OVA-specific IgG, IgG1, IgG2a, and IgG2b antibody titers, splenocyte proliferation, the phagocytic capacity of peritoneal macrophage, and the activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL). Furthermore, RCPS promoted the level of interleukin-2(IL-2), IFN-γ and IL-4in CD4+T cells and level of IFN-y in CD8+T cells. In addition, RCPS enhanced the expression of CD40, CD80and CD86on the dendritic cells (DCs). Importantly, RCPS down-regulated the frequency of CD4+CD25+Foxp3+Treg cells. C Taken together, these results suggested that RCPS could increase both cellular and humoral immune responses via up-regulating-DCs maturation, and suppressing Treg frequency.
5. Effects of the Polysaccharide from the Radix Cyathulae officinalis Kuan (RC)on the immune Response to Foot-and-Mouth Disease Vaccine in Mice
Objective This study was designed to investigate the effects of oral administration of the polysaccharide from the Radix Cyathulae officinalis Kuan (RCPS) on the specific cellular and humoral immune responses in mice to explore its mechanisms. Methods Sixty ICR mice were randomly divided into six groups (n=10), and orally administered at a dose equivalent to0,25,50,100mg of the RCPS for continuous4days respectively. After that, the animal were subcutaneously immunized twice with FMDV vaccine at2weeks intervals. Blood samples and spleen collected on day14after boosting for measurement of were determined, including serum antibody level, lymphocyte proliferation, the phagocytic capacity of peritoneal macrophage, Natural killer cell (NK) and cytotoxic T lymphocyte(CTL) activity, expression of surface and intracellular molecules, the frequency of CD4+CD25+Foxp3+regulatory T cells (Treg cells), the mRNA level of interleukin-2(IL-2), interleukin-4(IL-4), interleukin-10(IL-10), interferon-y (IFN-y), major histocompatibility complex Ⅰ (MHC Ⅰ), major histocompatibility complex Ⅱ (MHCⅡ), CXC chemokine receptor4(CXCR4), CC chemokine receptor7(CCR7), Toll like receptor2(TLR-2), Toll like receptor4(TLR-4), transcription factor T-bet, GATA-3,transforming growth factor-β (TGF-β) were detected by Real-Time PCR. Results In this study, our findings show that addition of the RCPS increased FMDV-specific antibody production, lymphocyte proliferation, phagocytic capacity of peritoneal macrophage, NK and CTL activity. Production of IL-2, IFN-y and IL-4in CD4+T cells and IFN-y in CD8+T cells were dramatically:increased. Expression-of CD40,CD80, CD80,CD86were was significantly increased. In addition, the frequency of CD4+CD25+Foxp3+regulatory T cells were down-regulated. The mRNA expression of the MHC I, MHC II, CXCR4, TLR-2TLR-4, T-bet, GATA-3, IL-2, IL-4, IL-10, IFN-y were up-regulated. The mRNA level of TGF-β were down-regulated. Conclution Taken together, these results demonstrate that RCPS can enhance both cellular and humoral immune responses via up-regulating DCs maturation through TLR2, TLR4signaling pathway, and inhibit the expression of TGF-β and frequency of Treg cells.
6. Conclution of this study
Taken together, these results demonstrate that RCPS can enhance both cellular and humoral immune responses in mice immunized with FMD vaccine via up-regulating DCs maturation through TLR2, TLR4signaling pathway, and inhibit the expression of TGF-β and frequency of Treg cells. RCPS promoted a balanced Thl/Th2immune response via the develop of ThO cells to Thl/Th2cells through up-regulated T-bet, GATA-3mRNA level.
1.十种川产道地药材水提物对小鼠注射卵清白蛋白(OVA)免疫反应的影响
目的从10种川产道地药材中筛选出能够增强OVA受免小鼠免疫反应的中药。方法选取4-6周龄ICR小鼠为试验动物。将每种药材水提物设置高、中、低三个剂量组,每组5只,水提物灌胃0.25mL/只,1次/d,连续灌胃4d后,注射OVA进行首次免疫,两周后二次免疫,二免后14d进行眼眶采血,检测OVA特异性IgG水平。对IgG水平较高的几种中药进一步测定其特异性抗体亚类的水平。结果与对照组相比,川牛膝能显著提高OVA受免小鼠血清中特异性IgG、IgG1、IgG2a和IgG2b水平(P<0.05)。川明参、川杜仲可以显著提高受免小鼠血清中OVA特异性IgG水平(P<0.05)。
2.口服川牛膝水提物对小鼠注射卵清白蛋白(OVA)后免疫反应的影响。
目的观察不同剂量川牛膝水提物(RC)对小鼠注射卵清蛋白(OVA)后免疫反应的影响。方法试验选取4-6周龄ICR小鼠42只,随机分为6组,每组7只。各试验组小鼠分别灌服RC(0、0.05、0.1、0.2、0.4和0.8g),连续给药4d后,注射OVA进行首次免疫,间隔14d后二次免疫。二免后2周采集血清测定OVA特异性IgG和IgG亚类水平,同时无菌取脾,测定淋巴细胞增殖能力,淋巴细胞分泌细胞因子的水平。结果结果显示,与对照组相比在二免后14d,RC(0.2、0.4和0.8g)诱导产生了较高水平的OVA特异性IgG和抗体亚类IgG1, IgG2a, IgG2b; RC促进了淋巴细胞,增值反应,同时能够显著增加淋巴细胞分泌IL-4、IFN-γ的水平,另外,RC对实验鼠的体重无任何影响。结论川牛膝水提物能显著促进OVA受免小鼠体液免疫反应,细胞免疫反应和细胞因子的分泌。
3.川牛膝多糖(RCPS)在体外对淋巴细胞免疫活性的影响
目的探讨川牛膝多糖在体外对淋巴细胞免疫活性的影响。方法本试验提取了川牛膝多糖(RCPS),检测RCPS对小鼠脾淋巴细胞的最大无毒浓度,在无毒浓度范围内,将RCPS与脾淋巴细胞共同培养,观察RCPS对淋巴细胞增殖(?)淋巴细胞分泌细胞因子IL-4、IFN-γ和"NK细胞的杀伤活性的影响。结果结果表明,RCPS在淋巴细胞上的最大无毒浓度为500μg/mL。浓度为31.25、125和500μg/mL的川牛膝多糖能够显著促进T、B淋巴细胞的增殖,显著促进淋巴细胞分泌细胞因子IL-4、IFN-γ,显著促进NK细胞的杀伤活性。结论川牛膝多糖在体外能促进T、B淋巴细胞增殖,促进淋巴细胞分泌细胞因子,促进NK细胞的杀伤活性。
4.川牛膝多糖(RCPS)对小鼠注射卵清蛋白(OVA)后免疫反应的影响
目的探讨口服RCPS对小鼠注射卵清蛋白(OVA)后体液免疫和细胞免疫反应的影响,进而探讨了其增强免疫反应的机制。方法试验选取4-6周龄ICR小鼠42只,随机分为6组,每组7只。试验组小鼠免疫前分别灌服不同剂量RCPS(0,25,50,100mg/kg体重),连续给药4d后,注射OVA进行首次免疫,间隔14d后二次免疫。二免后2周采集血清测定抗体和抗体亚类水平,同时无菌取脾,测定淋巴细胞增殖能力,胞内细胞因子的表达水平,腹腔巨噬细胞吞噬活性、NK细胞和CTL细胞杀伤能力,共刺激信号分子(CD40、CD80和CD86)和CD4+CD25+Foxp3+Treg细胞的表达水平。结果结果显示,与对照组相比在二免后14d, RCPS促进了淋巴细胞增值反应,诱导产生了较高水平的OVA特异性IgG和IgG亚类IgG1, IgG2a, IgG2b,同时能够上调CD4+T细胞IL-2、IL-4、IFN-γ和CD8+T栅IFN-γ的表达,并增强了腹腔巨噬细胞的吞噬活性,NK细胞和CTL细胞杀伤能力：RCPS显著上调了树突细胞(DCs)表面分子CD40、CD80和CD86的表达水平,显著下调了Treg细胞的表达水平。结论综上所述,免疫前口服RCPS可提高OVA受免小鼠Th1、Th2型免疫反应,从而增强了小鼠的细胞和体液免疫反应,其免疫增强作用的机制可能是通过促进树突细胞成熟和下调Treg细胞的表达来激活T细胞引发免疫反应。
5.川牛膝多糖(RCPS)对小鼠注射口蹄疫疫苗后免疫反应的影响
目的探讨口服RCPS对小鼠注射O型口蹄疫疫苗后体液免疫和细胞免疫反应的影响,进而探讨了其增强免疫反应的分子机制。方法试验选取4-6周龄ICR小鼠60只,随机分为6组,每组10只。试验组小鼠免疫前分别灌服不同剂量RCPS (0,25,50,100mg/kg体重),连续给药4d后,注射口蹄疫疫苗进行首次免疫,间隔14d后二次免疫。二免后2周采集血清检测特异性IgG和IgG亚类的水平。同时无菌采集脾脏,制备脾细胞悬液,测定淋巴细胞增殖指数,胞内细胞因子(CD4+T细胞IL-2、IL-4、IFN-γ和CD8+T细胞IFN-γ)的表达水平,腹腔巨噬细胞吞噬活性,NK、CTL细胞的杀伤活性,共刺激分子(CD40, CD80, CD86)的表达水平,CD4+CD25+Foxp3+调节性T细胞的表达率。同时应用实时定量PCR检测了细胞因子(IL-2、IL-4.IL-10、 IFN-γ),内源性抗原肽(MHCⅠ)、外源性抗原肽(MHCⅡ)、CXC趋化因子受体4(CXCR4)、CC趋化因子受体7(CCR7)、TOLL样受体2(TLR-2)、TOLL样受体4(TLR-4)、转录因子T-bet、GATA-3、转化生长因子p(TGF-β)等分子mRNA表达水平。结果结果显示,与对照组相比在二免后14d, RCPS诱导产生了较高水平的IgG和IgG亚类(IgG1, IgG2a, IgG2b),促进了淋巴细胞增值反应和腹腔巨噬细胞的吞噬能力,并增强了NK细胞和CTL细胞杀伤活性,同时能够上调了CD4+T细胞IL-2、IL-4、IFN-y和CD8+T细胞IFN-γ的表达。明显增强了共刺激信号分子(CD40,CD80, CD86)的表达水平,明显下调了调节性T细胞CD4+CD25+Foxp3+的表达百分比。上调了细胞因子(IL-2、IL-4、IL-10、IFN-y), MHC Ⅰ, MHC Ⅱ, CXCR4, CCR7, TLR-2, TLR-4等信号通路分子的mRNA表达水平,下调了TGF-β mRNA表达水平。结论RCPS配合FMD疫苗免疫小鼠,显著增强了小鼠体液免疫和细胞免疫水平,其机制可能是通过激活TLR-2, TLR-4信号通路促进树突细胞的成熟和迁移和通过下调TGF-p和CD4+CD25+Foxp3+的表达途径增强了小鼠对FMD疫苗的免疫反应。
6.本研究的结论
综上所述,口服川牛膝多糖能增强模式抗原OVA和口蹄疫疫苗受免小鼠体液免疫、细胞免疫反应和Th1、Th2型细胞因子的产生。初步阐明其机制可能是通过激活TLR-2, TLR-4信号通路,促进树突细胞的成熟,和下调TGF-β和Treg细胞的表达,引发机体免疫反应,提高疫苗的免疫效果。另外,川牛膝多糖配合疫苗能诱导产生平衡的Th1、Th2型免疫反应,其分子机制是通过上调T-bet和GATA3的基因表达调控初始T同时向Th1/Th2型细胞发育。
Infectious diseases, especially virus diseases, are worldwide concern as they usually cause great loss in domestic animal and poultry industry. Vaccination remains the most effective biomedical approach for the control of infectious diseases. Although the strict immune program had been taken in the farms, some infectious diseases are still hard to be controlled due to the lack of effective immune responses to vaccination. The majority of vaccines require association with adjuvants capable of increasing the potency or stimulating the appropriate immune response. The application of adjuvant, one of the methods to improve the efficacy of vaccine, has been considered as an important strategy. There are many growing evidences that medicinal herbs and the ingredients enhance the immune response to vaccines direct against infectious agents. Several herbal extracts as adjuvant of vaccines has been use in the human and animal clinical trials."Sichuan herbs" are well known because the medicinal quality of the herbals Produced in Si Chuan Province believed to be better than in other Province of China. We choose ten well known herbs include Cyathula officinalis Kuan, Eucommia ulmoides Oliv, Chuanminshen violaceum, Ophiopogon japonicus,Alisma orientalis,Salvia miltiorrhiza, Dipsacaceae, Rhizoma Ligustici Chuanxiong, Radix Angelicae Dahuricae, bergamol. screening the immunoenhancement herbs from those ten "Sichuan herbs"and following to study the Effects of oral administration of herbals extract on immuno response to the vaccination in mice. The relating studies carried out and results obtained are as follows:
1. Effects of ten Sichuan herbals Extract on the Immune Responses to Ovalbumin in Mice
Objective This study was investigated the effects of oral administration the water extract from the ten Sichuan herbs on the immune responses in mice immunized with ovalbumin (OVA). Method One hundred fifty five Institute of Cancer Research (ICR) mice were randomly divided into Thirty one groups with five animals in each group, and daily orally administered daily for4days with a high, medium or low dose of herbal exract respectively. After that, the animals were subcutaneously immunized twice with OVA (10μg) at2-week intervals. Blood samples were collected on day14after,boosting for, measurement of OVA-specific IgG titers and the IgG subclasses. Results Our data indicated that the OVA-specific IgG titers and the level of IgG subclass was significantly enhanced in mice orally administered exact of Radix Cyathulae officinalis Kuan (RC) when compared to the control group (P<0.05). OVA-specific IgG titers were significantly improved in mice orally administered the exact from Eucommia ulmoides Oliv and the Chuanminshen violaceum when compared to the control group (P<0-05).
2. Effects of the Extract from Radix Cyathulae (RC) on the Immune Responses to Ovalbumin in Mice
Objective This study was designed to evaluate the effects of oral administration of the water extract from the Radix Cyathula (RC) on the immune responses in mice immunized with ovalbumin (OVA). Method Forty two Institute of Cancer Research (ICR) mice were randomly divided into six groups with seven animals in each group, and orally administered daily for4days at a dose equivalent to0,0.05,0.1,0.2,0.4or0.8g of the RC exract, respectively. After that, the animals were subcutaneously immunized twice with OVA at2-week intervals. Blood samples and spleen were collected on day14after boosting for measurement of OVA-specific IgG titers and the IgG subclasses, lymphocyte proliferation as well as the production of IL-4and IFN-y. Results Our data indicated that the OVA-specific IgG titers and the level of IgG subclass was significantly enhanced in mice orally administered RC at the dose of0.2,0.4or0.8g when compared to the control group (P<0.05). The splenocyte proliferation response and the production of IL-4and IFN-y were also significantly improved (P<0.05). Besides, the body weight of the mice administered with the RC extract (0,0.1,0.2,0.4or0.8g) was no significant difference compared to the mice administered saline.Considering the immunomodulatory effect and safety of RC presented in this study, it deserves further investigation to evaluate the potential improvement of vaccination in other animals such as pigs, goats and cattle. Conclution Our data show that RC significantly enhanced OVA-specific IgG and IgG subclasses titers, lymphocyte proliferation, the production of IL-4and IFN-y.
3. Effects of Polysaccharide from the Radix Cyathulae officinalis Kuan (RCPS) on the Immune Activity of Lymphocyte in vitro
Objective This study was to extract Polysaccharide from the Radix Cyathulae officinalis Kuan (RCPS) and to explore the effects on the immune activity in vitro. Method firstly, the highest non-toxic concentrations of RCPS on splenocytes were measurement. Effect of RCPS on lymphocyte proliferation, the production of IL-4and IFN-y from lymphocyte, NK cell Killing activity were investigated. Results The results showed that the highest non-toxic concentrations of RCPS at500μg/mL, The splenocyte proliferation response and the production of IL-4and IFN-γ were also significantly improved (P<0.05) after the splenocytes were stimulated by RCPS. Besides, RCPS promoted the NK cell activity. Conclution Our findings show that RCPS significantly enhanced lymphocyte proliferation, the production of IL-4and IFN-y and NK activity in vitro.
4. Effects of the Polysaccharide from the Radix Cyathulae officinalis Kuan (RCPS) on the Immune Response to Ovalbumin in Mice
Objective This study was designed to investigate the effects of oral administration of the polysaccharide from the Radix Cyathulae officinalis Kuan (RCPS) on the specific cellular and humoral immune responses in mice. Methods Forty two ICR mice were randomly divided into six groups (n=7), and orally administered at a dose equivalent to0,25mg,50mg,100mg of the RCPS for continuous4days respectively. After that, the animal were subcutaneously immunized twice with OVA at2weeks intervals. Blood samples and spleen collected on day14after boosting for measurement including serum OVA-specific antibody level, lymphocyte proliferation, expression of surface and intracellular molecules, phagocytic capacity of peritoneal macrophage, NK (Nature killer) and CTL (cytotoxic lymphocyte) Killing activity, The frequency of costimulatory molecule (CD40, CD80, CD86) and CD4+CD25+Foxp3+Treg cells. Results In this study, our findings demonstrated that oral administration of RCPS significantly enhanced OVA-specific IgG, IgG1, IgG2a, and IgG2b antibody titers, splenocyte proliferation, the phagocytic capacity of peritoneal macrophage, and the activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL). Furthermore, RCPS promoted the level of interleukin-2(IL-2), IFN-γ and IL-4in CD4+T cells and level of IFN-y in CD8+T cells. In addition, RCPS enhanced the expression of CD40, CD80and CD86on the dendritic cells (DCs). Importantly, RCPS down-regulated the frequency of CD4+CD25+Foxp3+Treg cells. C Taken together, these results suggested that RCPS could increase both cellular and humoral immune responses via up-regulating-DCs maturation, and suppressing Treg frequency.
5. Effects of the Polysaccharide from the Radix Cyathulae officinalis Kuan (RC)on the immune Response to Foot-and-Mouth Disease Vaccine in Mice
Objective This study was designed to investigate the effects of oral administration of the polysaccharide from the Radix Cyathulae officinalis Kuan (RCPS) on the specific cellular and humoral immune responses in mice to explore its mechanisms. Methods Sixty ICR mice were randomly divided into six groups (n=10), and orally administered at a dose equivalent to0,25,50,100mg of the RCPS for continuous4days respectively. After that, the animal were subcutaneously immunized twice with FMDV vaccine at2weeks intervals. Blood samples and spleen collected on day14after boosting for measurement of were determined, including serum antibody level, lymphocyte proliferation, the phagocytic capacity of peritoneal macrophage, Natural killer cell (NK) and cytotoxic T lymphocyte(CTL) activity, expression of surface and intracellular molecules, the frequency of CD4+CD25+Foxp3+regulatory T cells (Treg cells), the mRNA level of interleukin-2(IL-2), interleukin-4(IL-4), interleukin-10(IL-10), interferon-y (IFN-y), major histocompatibility complex Ⅰ (MHC Ⅰ), major histocompatibility complex Ⅱ (MHCⅡ), CXC chemokine receptor4(CXCR4), CC chemokine receptor7(CCR7), Toll like receptor2(TLR-2), Toll like receptor4(TLR-4), transcription factor T-bet, GATA-3,transforming growth factor-β (TGF-β) were detected by Real-Time PCR. Results In this study, our findings show that addition of the RCPS increased FMDV-specific antibody production, lymphocyte proliferation, phagocytic capacity of peritoneal macrophage, NK and CTL activity. Production of IL-2, IFN-y and IL-4in CD4+T cells and IFN-y in CD8+T cells were dramatically:increased. Expression-of CD40,CD80, CD80,CD86were was significantly increased. In addition, the frequency of CD4+CD25+Foxp3+regulatory T cells were down-regulated. The mRNA expression of the MHC I, MHC II, CXCR4, TLR-2TLR-4, T-bet, GATA-3, IL-2, IL-4, IL-10, IFN-y were up-regulated. The mRNA level of TGF-β were down-regulated. Conclution Taken together, these results demonstrate that RCPS can enhance both cellular and humoral immune responses via up-regulating DCs maturation through TLR2, TLR4signaling pathway, and inhibit the expression of TGF-β and frequency of Treg cells.
6. Conclution of this study
Taken together, these results demonstrate that RCPS can enhance both cellular and humoral immune responses in mice immunized with FMD vaccine via up-regulating DCs maturation through TLR2, TLR4signaling pathway, and inhibit the expression of TGF-β and frequency of Treg cells. RCPS promoted a balanced Thl/Th2immune response via the develop of ThO cells to Thl/Th2cells through up-regulated T-bet, GATA-3mRNA level.
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