两种营养因素影响肠粘膜免疫和免疫系统发育的实验研究
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摘要
适宜的营养水平是儿童免疫系统发挥正常生理功能并不断向前发育成熟的重要保证。现实中对儿童的营养性干预主要见于两个方面：纠正营养失衡所造成的免疫功能受损及发育受阻,恢复正常状态下机体对疾病的防御能力；通过营造一个良好的营养环境,促进儿童时期免疫系统的生长发育,提高儿童时期的免疫能力,进而发挥疾病预防和促进远期健康的作用。本研究就维生素A调节肠粘膜免疫功能的作用途径与机制、双歧杆菌对局部和全身免疫系统发育的影响分别进行了探讨,以期在上述两个方面丰富儿童营养与免疫关系的认识。
目的通过研究维生素A在体内的活性代谢产物—视黄酸(retinoic acid, RA)对肠粘膜树突状细胞(dedritic cell, DC)的数量、成熟分化和细胞因子产生的影响,及其作用的途径,从免疫应答的初始环节探讨维生素A调节肠粘膜免疫的作用及其机制,为临床正确应用维生素A营养防治疾病提供理论和实验依据。
方法大鼠肠粘膜的集合淋巴结(Peyer's patches, PP结)体外培养,分为：对照组；RA组,加入全反式视黄酸(at-RA); RA+RO组,同时加入RA和视黄酸受体RARα特异性拮抗剂(Ro 41-5253)。于培养24h、48h收获组织块后,1、采用流式细胞仪检测大鼠DC表面分化标志,观察RA对PP结DC数目(OX62阳性细胞百分比)和成熟分化(OX6、CD86荧光强度)的影响；2、采用荧光定量PCR的方法,观察RA对PP结细胞因子基因转录水平的影响,以及RARαmRNA表达水平的相应变化。
结果1、培养24h和48h,三组PP结DC数目均无显著差异,但RA处理后DC的成熟度明显升高,该作用于培养24h显著；2、RA处理使得PP结细胞因子IL-12(主要由DC分泌)和IFN-γ(Thl细胞因子)的mRNA水平下调,调节性细胞因子IL-10的mRNA表达升高,而Th2细胞因子IL-4的产生无明显变化。此外,加入RA后可使RARα在PP结的基因表达上调；3、当Ro同时加入时,则可逆转RA的上述作用。
结论1、视黄酸可促进体外培养的PP结中DC的成熟,并使后续的免疫应答反应向调节性T细胞的方向偏倚,有利于粘膜免疫稳态的维持,防止局部过度炎症反应的发生；2、RARα参与了视黄酸对肠粘膜免疫的调节作用。
目的通过建立生后早期肠道双歧杆菌减灭或额外定植的动物模型,研究在免疫发育过程中,双歧杆菌对DC数量、成熟分化和功能的作用,以及对T细胞应答类型的调节、对抗体生成的影响,从抗原提呈、细胞免疫和体液免疫三方面,探讨双歧杆菌促进免疫系统发育的作用途径与机制,为在儿童中科学合理应用益生菌提供理论和实验依据。
方法饲养在严格屏障环境的新生大鼠从出生起每天给予大剂量抗生素肠道灭菌(低菌组)或口服接种长双歧杆菌(增菌组),分别于生后1W、3W和6W观察以下免疫发育指标：1、应用流式细胞术,了解双歧杆菌对PP结、脾脏和外周血中DC数目(OX62阳性细胞百分比)和成熟度(CD86荧光强度)、T细胞亚群分布,以及胸腺中T细胞发育成熟的影响；2、采用荧光定量PCR和ELISA的方法,了解双歧杆菌对肠粘膜和血浆细胞因子表达水平,以及体外培养的外周血单个核细胞(peripheral blood mononuclear cells, PBMCs)细胞因子基因转录水平的影响；3、应用ELISA的方法,了解双歧杆菌对PBMCs生成抗体(IgG和IgM)能力的影响。
结果1、低菌组PP结中DC的成熟度降低,增菌组则增高；低菌组胸腺中未成熟的CD4+CD8+T细胞向CD4+或CD8+成熟T细胞的分化发育延缓；2、低菌组的肠粘膜IL-12(主要由DC分泌)、IL-10(调节性细胞因子)的mRNA以及IFN-γ/IL-4(Thl／Th2)比值均下调,血浆IL-4分泌增多,PBMCs体外刺激后IFN-γ表达降低；增菌组的肠粘膜IL-12、IFN-γ、IL-10mRNA以及IFN-γ/IL-4均上调,PBMCs的IFN-γ表达增高；3、低菌组体外培养的PBMCs合成抗体IgM减少,增菌组则升高。
结论生后早期,肠道定植的双歧杆菌能够：1、促进PP结中DC的成熟及对IL-12的表达,对肠外DC的作用则不明显；2、影响着T细胞在中枢免疫器官胸腺中的发育成熟；3、诱导局部和全身的辅助性T细胞应答向Thl方向偏倚,有助于机体Thl／Th2平衡的实现；同时促进局部肠道调节性T细胞免疫应答的发育；4、增强PBMCs合成抗体的能力,进而促进全身性的体液免疫应答。
Appropriate nutritional level is an important guarantee for the normal physiological function and continuous development of the children's immune system. The nutritional intervention for children in reality has two major cases:to correct the impaired function and blocked development of the immune-system caused by nutrient unbalance, rehabilitating the body's defensive quality to diseases; through constructing a good nutritional environment, promote the development of the immune system and enhance the immunity in childhood, thereby preventing diseases and promoting long-term health. In this paper, we discussed the mechanism of vitamin A modulation of the intestinal mucosal immunity, as well as the role of bifidobacteria on the development of both the gut and systemic immunity, to enrich the knowledge about the relationship between children's nutrition and immunity in these two aspects.
Objectives In order to clarify the mechanism of vitamin A (VA) modulation of intestinal mucosal immunity, we investigated the effects and approaches of retinoic acid (RA), an active metabolite of VA, on the number, maturation and cytokine production of intestinal dendritic cells (DCs), to probe into its role at the initial step of immune response.
Methods Peyer's patches (PPs) from the healthy adult SD rats were cultured in vitro, with all-trans retinoic acid (at-RA) or/and Ro 41-5253 (RO), a specific antagonist for retinoic acid receptor a were added into the culture. The tissues were harvested 24 h and 48 h later for the following analysis.1. Surface marker expressions on DCs were assessed using direct immunofluorescent antibodies and flow cytometer to evaluate the effect of RA on the number (the percentage of OX-62 positive cells) and maturation (fluorescence intensity of OX6 and CD86) of DCs in cultured PPs.2. By using RT-quantitative PCR, the effect of RA on the gene expression of cytokines and RARa in PPs were examined.
Results 1. After culture for both 24 h and 48 h, the number of DCs in PPs showed no significant difference among the RA, RA+RO, and control group, but treated with at-RA promoted the maturation of DCs, with the effect most notable at 24 h of culture; 2. at-RA treatment led to reduced IL-12 (mainly secreted by DCs) and IFN-γ(Thl cytokine) but increased IL-10 (regulatory cytokine) gene expression in PPs, whereas there was no significant difference in IL-4 (Th2 cytokine) mRNA compared with the control. Moreover, RARa gene expression in PPs was up-regulated by at-RA; 3. All the actions of at-RA described above were reversed when cultured along with Ro 41-5253.
Conclusion 1.Retinoic acid could promote the maturation of DCs in cultured PPs, and make immune response bias to regulatory T cell, thus be potent in maintaining homeostasis of the gut immunity, and preventing the emergence of a harmful inflammatory state; 2. RARa plays a very important role in the regulation of mucosal immunity by retinoic acid.
Objectives We established an animal model, the rat with intestinal bifidobacteria minimisation or extra colonization, to explore how intestinal bifidobacteria affect the development of both the gut and systemic immunity in early life, especially its modulation on the differentiation, maturation and function of DCs, the type of T-cell responses and immunoglobulin synthesis, providing theoretical and experimental basis for the proper usage of probiotics in children in reality.
Methods Neonatal SD rats housed under strict barrier systems were fed from birth with sufficient antibiotics (bifidobacteria minimisation group) or supplemented daily with live Bifidobacterium longum (bifidobacteria supplementation group). The role of intestinal bifidobacteria on the following immune-development indices was determined at one, three and six weeks old respectively:1. By use of flow cytometry, the number (the percentage of OX-62 positive cells) and maturation (fluorescence intensity of CD86) of DCs, the proportion of each T-cell subset in PPs, spleen and peripheral blood were detected, as well as the development of T cells in thymus.2. The mRNA levels of cytokines in intestinal mucosa and cultured peripheral blood mononuclear cells (PBMCs) were measured by RT-PCR, and production of these cytokines in plasma was determined by ELISA.3. The secretion of IgG and IgM by PBMCs were detected by ELISA.
Results 1. Minimisation of the intestinal bifidobacteria delayed maturation of DCs in PPs, whereas supplementation with bifidobacteria promoted DC maturation in PPs. Besides, in bifidobacteria minimisation group, the differentiation of immature CD4+CD8+T cell to mature CD4+or CD8+T cell was delayed in thymus; 2. Bifidobacteria minimisation down-regulated IL-12, IL-10 mRNA and the IFN-y/IL-4 (Thl/Th2) mRNA ratio in intestinal mucosa, increased IL-4 secretion in the plasma, decreased IFN-y mRNA in cultured PBMCs; bifidobacteria supplementation up-regulated IL-12, IFN-y, IL-10 mRNA and the IFN-y/IL-4 ratio in intestinal mucosa, increased IFN-y gene expression in PBMCs; 3. Bifidobacteria minimisation group had a decreased production of IgM by cultured PBMCs, whereas bifidobacteria supplementation group had an increased secretion of it.
Conclusion In early life, intestinal bifidobacteria colonisation could:1. promote DC maturation and its espression of IL-12 in PPs; 2. influence the development of T cells in thymus; 3. favour the T-helper cell response of the body in a Thl type and meanwhile ensure the development of regulatory T cell response in the gut; 4. enhance antibody synthesis by PBMCs, thereby having a potential role in strengthening the humoral immunity.
目的通过研究维生素A在体内的活性代谢产物—视黄酸(retinoic acid, RA)对肠粘膜树突状细胞(dedritic cell, DC)的数量、成熟分化和细胞因子产生的影响,及其作用的途径,从免疫应答的初始环节探讨维生素A调节肠粘膜免疫的作用及其机制,为临床正确应用维生素A营养防治疾病提供理论和实验依据。
方法大鼠肠粘膜的集合淋巴结(Peyer's patches, PP结)体外培养,分为：对照组；RA组,加入全反式视黄酸(at-RA); RA+RO组,同时加入RA和视黄酸受体RARα特异性拮抗剂(Ro 41-5253)。于培养24h、48h收获组织块后,1、采用流式细胞仪检测大鼠DC表面分化标志,观察RA对PP结DC数目(OX62阳性细胞百分比)和成熟分化(OX6、CD86荧光强度)的影响；2、采用荧光定量PCR的方法,观察RA对PP结细胞因子基因转录水平的影响,以及RARαmRNA表达水平的相应变化。
结果1、培养24h和48h,三组PP结DC数目均无显著差异,但RA处理后DC的成熟度明显升高,该作用于培养24h显著；2、RA处理使得PP结细胞因子IL-12(主要由DC分泌)和IFN-γ(Thl细胞因子)的mRNA水平下调,调节性细胞因子IL-10的mRNA表达升高,而Th2细胞因子IL-4的产生无明显变化。此外,加入RA后可使RARα在PP结的基因表达上调；3、当Ro同时加入时,则可逆转RA的上述作用。
结论1、视黄酸可促进体外培养的PP结中DC的成熟,并使后续的免疫应答反应向调节性T细胞的方向偏倚,有利于粘膜免疫稳态的维持,防止局部过度炎症反应的发生；2、RARα参与了视黄酸对肠粘膜免疫的调节作用。
目的通过建立生后早期肠道双歧杆菌减灭或额外定植的动物模型,研究在免疫发育过程中,双歧杆菌对DC数量、成熟分化和功能的作用,以及对T细胞应答类型的调节、对抗体生成的影响,从抗原提呈、细胞免疫和体液免疫三方面,探讨双歧杆菌促进免疫系统发育的作用途径与机制,为在儿童中科学合理应用益生菌提供理论和实验依据。
方法饲养在严格屏障环境的新生大鼠从出生起每天给予大剂量抗生素肠道灭菌(低菌组)或口服接种长双歧杆菌(增菌组),分别于生后1W、3W和6W观察以下免疫发育指标：1、应用流式细胞术,了解双歧杆菌对PP结、脾脏和外周血中DC数目(OX62阳性细胞百分比)和成熟度(CD86荧光强度)、T细胞亚群分布,以及胸腺中T细胞发育成熟的影响；2、采用荧光定量PCR和ELISA的方法,了解双歧杆菌对肠粘膜和血浆细胞因子表达水平,以及体外培养的外周血单个核细胞(peripheral blood mononuclear cells, PBMCs)细胞因子基因转录水平的影响；3、应用ELISA的方法,了解双歧杆菌对PBMCs生成抗体(IgG和IgM)能力的影响。
结果1、低菌组PP结中DC的成熟度降低,增菌组则增高；低菌组胸腺中未成熟的CD4+CD8+T细胞向CD4+或CD8+成熟T细胞的分化发育延缓；2、低菌组的肠粘膜IL-12(主要由DC分泌)、IL-10(调节性细胞因子)的mRNA以及IFN-γ/IL-4(Thl／Th2)比值均下调,血浆IL-4分泌增多,PBMCs体外刺激后IFN-γ表达降低；增菌组的肠粘膜IL-12、IFN-γ、IL-10mRNA以及IFN-γ/IL-4均上调,PBMCs的IFN-γ表达增高；3、低菌组体外培养的PBMCs合成抗体IgM减少,增菌组则升高。
结论生后早期,肠道定植的双歧杆菌能够：1、促进PP结中DC的成熟及对IL-12的表达,对肠外DC的作用则不明显；2、影响着T细胞在中枢免疫器官胸腺中的发育成熟；3、诱导局部和全身的辅助性T细胞应答向Thl方向偏倚,有助于机体Thl／Th2平衡的实现；同时促进局部肠道调节性T细胞免疫应答的发育；4、增强PBMCs合成抗体的能力,进而促进全身性的体液免疫应答。
Appropriate nutritional level is an important guarantee for the normal physiological function and continuous development of the children's immune system. The nutritional intervention for children in reality has two major cases:to correct the impaired function and blocked development of the immune-system caused by nutrient unbalance, rehabilitating the body's defensive quality to diseases; through constructing a good nutritional environment, promote the development of the immune system and enhance the immunity in childhood, thereby preventing diseases and promoting long-term health. In this paper, we discussed the mechanism of vitamin A modulation of the intestinal mucosal immunity, as well as the role of bifidobacteria on the development of both the gut and systemic immunity, to enrich the knowledge about the relationship between children's nutrition and immunity in these two aspects.
Objectives In order to clarify the mechanism of vitamin A (VA) modulation of intestinal mucosal immunity, we investigated the effects and approaches of retinoic acid (RA), an active metabolite of VA, on the number, maturation and cytokine production of intestinal dendritic cells (DCs), to probe into its role at the initial step of immune response.
Methods Peyer's patches (PPs) from the healthy adult SD rats were cultured in vitro, with all-trans retinoic acid (at-RA) or/and Ro 41-5253 (RO), a specific antagonist for retinoic acid receptor a were added into the culture. The tissues were harvested 24 h and 48 h later for the following analysis.1. Surface marker expressions on DCs were assessed using direct immunofluorescent antibodies and flow cytometer to evaluate the effect of RA on the number (the percentage of OX-62 positive cells) and maturation (fluorescence intensity of OX6 and CD86) of DCs in cultured PPs.2. By using RT-quantitative PCR, the effect of RA on the gene expression of cytokines and RARa in PPs were examined.
Results 1. After culture for both 24 h and 48 h, the number of DCs in PPs showed no significant difference among the RA, RA+RO, and control group, but treated with at-RA promoted the maturation of DCs, with the effect most notable at 24 h of culture; 2. at-RA treatment led to reduced IL-12 (mainly secreted by DCs) and IFN-γ(Thl cytokine) but increased IL-10 (regulatory cytokine) gene expression in PPs, whereas there was no significant difference in IL-4 (Th2 cytokine) mRNA compared with the control. Moreover, RARa gene expression in PPs was up-regulated by at-RA; 3. All the actions of at-RA described above were reversed when cultured along with Ro 41-5253.
Conclusion 1.Retinoic acid could promote the maturation of DCs in cultured PPs, and make immune response bias to regulatory T cell, thus be potent in maintaining homeostasis of the gut immunity, and preventing the emergence of a harmful inflammatory state; 2. RARa plays a very important role in the regulation of mucosal immunity by retinoic acid.
Objectives We established an animal model, the rat with intestinal bifidobacteria minimisation or extra colonization, to explore how intestinal bifidobacteria affect the development of both the gut and systemic immunity in early life, especially its modulation on the differentiation, maturation and function of DCs, the type of T-cell responses and immunoglobulin synthesis, providing theoretical and experimental basis for the proper usage of probiotics in children in reality.
Methods Neonatal SD rats housed under strict barrier systems were fed from birth with sufficient antibiotics (bifidobacteria minimisation group) or supplemented daily with live Bifidobacterium longum (bifidobacteria supplementation group). The role of intestinal bifidobacteria on the following immune-development indices was determined at one, three and six weeks old respectively:1. By use of flow cytometry, the number (the percentage of OX-62 positive cells) and maturation (fluorescence intensity of CD86) of DCs, the proportion of each T-cell subset in PPs, spleen and peripheral blood were detected, as well as the development of T cells in thymus.2. The mRNA levels of cytokines in intestinal mucosa and cultured peripheral blood mononuclear cells (PBMCs) were measured by RT-PCR, and production of these cytokines in plasma was determined by ELISA.3. The secretion of IgG and IgM by PBMCs were detected by ELISA.
Results 1. Minimisation of the intestinal bifidobacteria delayed maturation of DCs in PPs, whereas supplementation with bifidobacteria promoted DC maturation in PPs. Besides, in bifidobacteria minimisation group, the differentiation of immature CD4+CD8+T cell to mature CD4+or CD8+T cell was delayed in thymus; 2. Bifidobacteria minimisation down-regulated IL-12, IL-10 mRNA and the IFN-y/IL-4 (Thl/Th2) mRNA ratio in intestinal mucosa, increased IL-4 secretion in the plasma, decreased IFN-y mRNA in cultured PBMCs; bifidobacteria supplementation up-regulated IL-12, IFN-y, IL-10 mRNA and the IFN-y/IL-4 ratio in intestinal mucosa, increased IFN-y gene expression in PBMCs; 3. Bifidobacteria minimisation group had a decreased production of IgM by cultured PBMCs, whereas bifidobacteria supplementation group had an increased secretion of it.
Conclusion In early life, intestinal bifidobacteria colonisation could:1. promote DC maturation and its espression of IL-12 in PPs; 2. influence the development of T cells in thymus; 3. favour the T-helper cell response of the body in a Thl type and meanwhile ensure the development of regulatory T cell response in the gut; 4. enhance antibody synthesis by PBMCs, thereby having a potential role in strengthening the humoral immunity.
引文
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