疏肝健脾固髓方治疗多发性硬化的临床及机制的初步研究
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摘要
目的：研究多发性硬化患者外周血T细胞亚群的变化规律,探讨T细胞亚群作为多发性硬化病情变化指标和治疗依据的可能性。通过EAE模型探讨疏肝健脾固髓方治疗多发性硬化的机制。
方法：将MS患者按照疾病分期进行分类,统计各病期外周血T细胞亚群的变化。运用聚类分析,探讨多发性硬化的证候特点。疏肝健脾固髓方治疗多发性硬化动物模型后检测其外周血炎症细胞因子蛋白的表达情况并观察病理改变。
结果：1.临床研究
1.1多发性硬化病人在激素治疗期的CD4+T细胞亚群与病程发病早期、激素影响期、稳定期相比比例增高,差异有显著意义(P<0.05)；激素治疗后CD3+CD19-T细胞与激素治疗期相比比例降低,差异有显著意义(P<0.05)。其余各T细胞亚群在各病期的比较均无显著性差异(P>0.05)。
1.2临床症状研究中大部分病人中均有不同程度的肝郁脾虚证候特点,如情绪低落(50.8%)、两胁不适(22.2%)、胸闷(31.7%)、心烦(41.3%)、神疲乏力(65.1%)、纳少(28.6%)、恶心(12.7%)、呃逆(12.7%)、嗳气(14.3%)、腹胀(22.2%)、胃脘痞满(28.6%)。聚类分析症状,分为三类：第一类：第一簇的症候表现为水饮、第二簇为痰浊、第三簇为脾虚。第二类：第一簇为心肾阴虚、第二簇为阴虚火旺。第三类为阳虚证的表现。第四类为阴阳两虚。
2.实验研究
2.1采用MOG35-55免疫C57BL小鼠建立EAE的慢性迁延型模型,发现小鼠首次发病时间在免疫后的14-17天,临床评分为1分左右。发病的高峰期一般在19-29天,临床评分在1-2.5分之间。随后进入慢性迁延期,临床评分维持在1-2分。个别小鼠发现了复发缓解的现象,并且随着时间的延长,复发的频率和症状评分逐渐降低,在3个月左右的时间后可能也与慢性迁延期的小鼠一样会达到一个平台期。
2.2疏肝健脾固髓方治疗多发性硬化的机制探讨
2.2.1在C57BL小鼠EAE模型显示,IL-21、IL-17F均为致炎性因子,呈现先升高后降低的变化规律,表明2者在疾病的早期发挥作用。激素组2者的升高不明显,中药组IL-17F则为下降趋势。
2.2.2在EAE中TNF-α主要作用是致炎性的,表现为逐渐升高,但在激素组和中药组则为先下降后升高,尤其在4周时下降较为明显。
IFN-γ为致炎性因子,在EAE中呈现逐渐升高的趋势,但在激素组和中药组呈现先下降后略微升高的趋势,且在第4周下降最为明显。
提示激素和中药可能在疾病发作前期发挥抗炎作用,而急性发作后期抗炎作用逐渐减退。
2.2.3IL-10和IL-4均为抑炎性因子,在EAE中呈现逐渐升高的趋势,在中药组亦表现升高,尤其在8周时IL-10升高更加明显,激素组则没有升高趋势。提示随着病程进展,EAE在急性期炎症损害髓鞘的同时,也启动了抗炎机制。激素在抗炎的同时也抑制了抑炎性的细胞因子的产生,而中药保护了抑制炎性的内源性积极因素,对于后期的修复和减少复发有利。
2.2.4动物病理切片显示,EAE组脑组织和脊髓组织切片均可见炎症细胞浸润,血管增生等炎症表现。而在正常组脑组织切片中血管很少增生,未见炎症细胞浸润。
结论：
1.多发性硬化发作期总T细胞和CD4+T细胞相对较高,T细胞的这一规律可能为成为多发性硬化病情变化的指标。
2.疏肝健脾固髓方治疗多发性硬化的机制可能是降低了致炎性细胞因子的表达,并保护抑炎性细胞因子的表达达到控制炎症的作用。虽然抑制炎症细胞因子的作用不及皮质激素,但对于抑炎细胞因子具有保护作用为其特点,这似可以对疏肝健脾固髓方控制急性期症状作用不如激素,而具有减少多发性硬化复发作用的临床现象的解释。
3.小鼠EAE模型可作为多发性硬化药物抗炎作用靶点筛选模型,TNF-α、IFN-γ、 IL-21、IL-17F和IL-10、IL-4等指标较为敏感,可以用于药物筛选和判断疗效。为进一步的MS药物治疗和药物筛选提供了实验依据。
4.在采用MOG35-55免疫C57BL小鼠建立的EAE慢性迁延型模型中出现的个别复发缓解现象,提示小鼠自身免疫情况可能存在较大的差异,在应用EAE这一经典模型时仍需要注意到可能对急性发作期药物筛选造成干扰。相反,而这一现象有可能为复发缓解型模型的来源提供新的研究思路。
Objective Studing the correlativity of peripheral blood T cells subsets in patients with multiple sclerosis of and the stage of disease.Investigate the possibilities of T-cell subs ets as indicators of multiple sclerosis changes in condition and foudation of treatment. Explore the mechanism of Shuganjianpi Gusui Recipe treat MS by EAE modal.
Methods
MS patients wound be classified according to the stage of disease, statistics variation of peripheral blood T cell subsets in differate stage. Using of cluster analysis to explore the characteristics of the syndrome of multiple sclerosis. Shuganjianpi Gusui Recipe treats animal model of multiple sclerosis, detected its peripheral inflammatory cytokine protein expression and observed the pathological changes.
Results
1. Clinical Research:
1.1CD4+T cells subsets of MS in hormone treatment stage is higher than early onset desease, period of influence hormones, stable period, difference had statistical significance (P<0.05). There was significant difference while CD3+CD19-T subsets after hormone treatment is significantly lower than hormone treatment stage (.P<0.05). The rest of the T cell subsets in each stage of disease showed no significant difference(P>0.05).
1.2In clinical studies, most MS patients with varying degrees of liver and spleen deficiency syndrome characteristics. For example, depression (50.8%), two flank discomfort (22.2%), tightness in the chest(31.7%), irritability (41.3%), lassitude (65.1%), decreased appetite(28.6%), nausea (12.7%), hiccups (12.7%), belching (14.3%), abdominal distension (22.2%), epigastric fullness (28.6%).Cluster analysis of symptoms is divided into three categories:the first category:the first cluster of symptoms manifested as shuiyin, the second cluster of phlegm, and the third cluster as spleen deficiency. The second category:the first cluster of the heart and kidney yin deficiency, the second cluster of yin difiency huowang. The third category is the yang deficiency. The fourth category is the yin and yang deficiency.
2. Experimental Research:
2.1MOG35-55immunization of C57BL mice obtained EAE chronic persistent model. Found that the mice first time of onset14-17days after immunization, clinical score for about1. The peak incidence on19-29days, it's clinical score between1and2.5. Subsequently moved to a chronic stage which having clinical score remained1to2. Few mice were found having relapse phenomenon, the frequency of recurrence and symptom scores decreased with time, in about three months the relapse-remitte mouse reached the same plateau with chronic mouse.
2.2Mechanisms of Shuganjianpi Gusui Recipe animal model for multiple sclerosis:
2.2.1In EAE model, IL-21, IL-17F as inflammatory cytokines, increased firstly and then decreased, indicating that they play a role early in the disease. In hormone group they elevated were not obvious, in the TCM group IL-17F was a downward trend.
2.2.2In EAE, TNF-a as an inflammatory cytokine gradually increased, But in the hormone group and TCM group was first decreased and then increased, especially at4week was more evident. IFN-y as pro-inflammatory cytokines in EAE was gradually increased, but in the hormone group and TCM group decreased at first and then slightly rising, and the most significant decline at4weeks.
Indicating TCM group and hormones group may play a role in inhibiting inflammatory at early onset of the disease and anti-inflammatory effect gradually diminishes at late stage.
2.2.3IL-10and IL-4as the anti-inflammatory cytokines in EAE gradually increased, so do the same in TCM group.The increase in the TCM group more obvious, especially at8weeks, but the hormone group does not show this trend. Point to EAE showed myelin damage in the acute phase of inflammation, but also launched anti-inflammatory mechanism as progression of desease.
Hormones inhibited inflammatory cytokine production, also inhibited the anti-inflammatory cytokine production. TCM protected the endogenous positive factors of anti-inflammatory cytokine, did favor for the repair and reduce recurrence late.
2.2.4Animal Pathology revealed, EAE brain tissue and spinal cord tissue slices showed obvious inflammatory cell infiltration, vascular proliferation. Normal brain tissue slices showed little inflammatory cell proliferation, few vascular angiogenesis.
Conclusion
1. Total T cells and CD4+T cells is higher on exacerbation of Multiple sclerosis than other stage of MS, as this rule, T cells may be to be an indicator of condition changes in multiple sclerosis.
2. The mechanism of Shuganjianpi Gusui Recipe treat multiple sclerosis may be reduces the expression of pro-inflammatory cytokines, and protection anti-inflammatory cytokines to control inflammation. Although inhibition of pro-inflammatory cytokines is less than hormones, but for anti-inflammatory cytokines have a protective effect as its features of TCM. This seems to be explain that Shuganjianpi Gusui Recipe control of acute symptoms weeker than hormones, which have a reduced role in multiple sclerosis clinical recurrence.
3. EAE mouse model can be used as screening target of anti-inflammatory drugs model of multiple sclerosis, TNF-a, IFN-y, IL-21, IL-17F and IL-10, IL-4are more sensible, can be used to screening drugs and determine the drugs'efficacy, provides an experimental basis for further study in MS drug therapy and drug screening.
4. MOG35-55immunization of C57BL mice obtained EAE chronic persistent model. Few mice were found having relapse phenomenon, point to there may be a big difference in murine autoimmune conditions. In the application of this classic model of EAE is still aware that the possibility of causing interference for drug screening of acute exacerbation.
方法：将MS患者按照疾病分期进行分类,统计各病期外周血T细胞亚群的变化。运用聚类分析,探讨多发性硬化的证候特点。疏肝健脾固髓方治疗多发性硬化动物模型后检测其外周血炎症细胞因子蛋白的表达情况并观察病理改变。
结果：1.临床研究
1.1多发性硬化病人在激素治疗期的CD4+T细胞亚群与病程发病早期、激素影响期、稳定期相比比例增高,差异有显著意义(P<0.05)；激素治疗后CD3+CD19-T细胞与激素治疗期相比比例降低,差异有显著意义(P<0.05)。其余各T细胞亚群在各病期的比较均无显著性差异(P>0.05)。
1.2临床症状研究中大部分病人中均有不同程度的肝郁脾虚证候特点,如情绪低落(50.8%)、两胁不适(22.2%)、胸闷(31.7%)、心烦(41.3%)、神疲乏力(65.1%)、纳少(28.6%)、恶心(12.7%)、呃逆(12.7%)、嗳气(14.3%)、腹胀(22.2%)、胃脘痞满(28.6%)。聚类分析症状,分为三类：第一类：第一簇的症候表现为水饮、第二簇为痰浊、第三簇为脾虚。第二类：第一簇为心肾阴虚、第二簇为阴虚火旺。第三类为阳虚证的表现。第四类为阴阳两虚。
2.实验研究
2.1采用MOG35-55免疫C57BL小鼠建立EAE的慢性迁延型模型,发现小鼠首次发病时间在免疫后的14-17天,临床评分为1分左右。发病的高峰期一般在19-29天,临床评分在1-2.5分之间。随后进入慢性迁延期,临床评分维持在1-2分。个别小鼠发现了复发缓解的现象,并且随着时间的延长,复发的频率和症状评分逐渐降低,在3个月左右的时间后可能也与慢性迁延期的小鼠一样会达到一个平台期。
2.2疏肝健脾固髓方治疗多发性硬化的机制探讨
2.2.1在C57BL小鼠EAE模型显示,IL-21、IL-17F均为致炎性因子,呈现先升高后降低的变化规律,表明2者在疾病的早期发挥作用。激素组2者的升高不明显,中药组IL-17F则为下降趋势。
2.2.2在EAE中TNF-α主要作用是致炎性的,表现为逐渐升高,但在激素组和中药组则为先下降后升高,尤其在4周时下降较为明显。
IFN-γ为致炎性因子,在EAE中呈现逐渐升高的趋势,但在激素组和中药组呈现先下降后略微升高的趋势,且在第4周下降最为明显。
提示激素和中药可能在疾病发作前期发挥抗炎作用,而急性发作后期抗炎作用逐渐减退。
2.2.3IL-10和IL-4均为抑炎性因子,在EAE中呈现逐渐升高的趋势,在中药组亦表现升高,尤其在8周时IL-10升高更加明显,激素组则没有升高趋势。提示随着病程进展,EAE在急性期炎症损害髓鞘的同时,也启动了抗炎机制。激素在抗炎的同时也抑制了抑炎性的细胞因子的产生,而中药保护了抑制炎性的内源性积极因素,对于后期的修复和减少复发有利。
2.2.4动物病理切片显示,EAE组脑组织和脊髓组织切片均可见炎症细胞浸润,血管增生等炎症表现。而在正常组脑组织切片中血管很少增生,未见炎症细胞浸润。
结论：
1.多发性硬化发作期总T细胞和CD4+T细胞相对较高,T细胞的这一规律可能为成为多发性硬化病情变化的指标。
2.疏肝健脾固髓方治疗多发性硬化的机制可能是降低了致炎性细胞因子的表达,并保护抑炎性细胞因子的表达达到控制炎症的作用。虽然抑制炎症细胞因子的作用不及皮质激素,但对于抑炎细胞因子具有保护作用为其特点,这似可以对疏肝健脾固髓方控制急性期症状作用不如激素,而具有减少多发性硬化复发作用的临床现象的解释。
3.小鼠EAE模型可作为多发性硬化药物抗炎作用靶点筛选模型,TNF-α、IFN-γ、 IL-21、IL-17F和IL-10、IL-4等指标较为敏感,可以用于药物筛选和判断疗效。为进一步的MS药物治疗和药物筛选提供了实验依据。
4.在采用MOG35-55免疫C57BL小鼠建立的EAE慢性迁延型模型中出现的个别复发缓解现象,提示小鼠自身免疫情况可能存在较大的差异,在应用EAE这一经典模型时仍需要注意到可能对急性发作期药物筛选造成干扰。相反,而这一现象有可能为复发缓解型模型的来源提供新的研究思路。
Objective Studing the correlativity of peripheral blood T cells subsets in patients with multiple sclerosis of and the stage of disease.Investigate the possibilities of T-cell subs ets as indicators of multiple sclerosis changes in condition and foudation of treatment. Explore the mechanism of Shuganjianpi Gusui Recipe treat MS by EAE modal.
Methods
MS patients wound be classified according to the stage of disease, statistics variation of peripheral blood T cell subsets in differate stage. Using of cluster analysis to explore the characteristics of the syndrome of multiple sclerosis. Shuganjianpi Gusui Recipe treats animal model of multiple sclerosis, detected its peripheral inflammatory cytokine protein expression and observed the pathological changes.
Results
1. Clinical Research:
1.1CD4+T cells subsets of MS in hormone treatment stage is higher than early onset desease, period of influence hormones, stable period, difference had statistical significance (P<0.05). There was significant difference while CD3+CD19-T subsets after hormone treatment is significantly lower than hormone treatment stage (.P<0.05). The rest of the T cell subsets in each stage of disease showed no significant difference(P>0.05).
1.2In clinical studies, most MS patients with varying degrees of liver and spleen deficiency syndrome characteristics. For example, depression (50.8%), two flank discomfort (22.2%), tightness in the chest(31.7%), irritability (41.3%), lassitude (65.1%), decreased appetite(28.6%), nausea (12.7%), hiccups (12.7%), belching (14.3%), abdominal distension (22.2%), epigastric fullness (28.6%).Cluster analysis of symptoms is divided into three categories:the first category:the first cluster of symptoms manifested as shuiyin, the second cluster of phlegm, and the third cluster as spleen deficiency. The second category:the first cluster of the heart and kidney yin deficiency, the second cluster of yin difiency huowang. The third category is the yang deficiency. The fourth category is the yin and yang deficiency.
2. Experimental Research:
2.1MOG35-55immunization of C57BL mice obtained EAE chronic persistent model. Found that the mice first time of onset14-17days after immunization, clinical score for about1. The peak incidence on19-29days, it's clinical score between1and2.5. Subsequently moved to a chronic stage which having clinical score remained1to2. Few mice were found having relapse phenomenon, the frequency of recurrence and symptom scores decreased with time, in about three months the relapse-remitte mouse reached the same plateau with chronic mouse.
2.2Mechanisms of Shuganjianpi Gusui Recipe animal model for multiple sclerosis:
2.2.1In EAE model, IL-21, IL-17F as inflammatory cytokines, increased firstly and then decreased, indicating that they play a role early in the disease. In hormone group they elevated were not obvious, in the TCM group IL-17F was a downward trend.
2.2.2In EAE, TNF-a as an inflammatory cytokine gradually increased, But in the hormone group and TCM group was first decreased and then increased, especially at4week was more evident. IFN-y as pro-inflammatory cytokines in EAE was gradually increased, but in the hormone group and TCM group decreased at first and then slightly rising, and the most significant decline at4weeks.
Indicating TCM group and hormones group may play a role in inhibiting inflammatory at early onset of the disease and anti-inflammatory effect gradually diminishes at late stage.
2.2.3IL-10and IL-4as the anti-inflammatory cytokines in EAE gradually increased, so do the same in TCM group.The increase in the TCM group more obvious, especially at8weeks, but the hormone group does not show this trend. Point to EAE showed myelin damage in the acute phase of inflammation, but also launched anti-inflammatory mechanism as progression of desease.
Hormones inhibited inflammatory cytokine production, also inhibited the anti-inflammatory cytokine production. TCM protected the endogenous positive factors of anti-inflammatory cytokine, did favor for the repair and reduce recurrence late.
2.2.4Animal Pathology revealed, EAE brain tissue and spinal cord tissue slices showed obvious inflammatory cell infiltration, vascular proliferation. Normal brain tissue slices showed little inflammatory cell proliferation, few vascular angiogenesis.
Conclusion
1. Total T cells and CD4+T cells is higher on exacerbation of Multiple sclerosis than other stage of MS, as this rule, T cells may be to be an indicator of condition changes in multiple sclerosis.
2. The mechanism of Shuganjianpi Gusui Recipe treat multiple sclerosis may be reduces the expression of pro-inflammatory cytokines, and protection anti-inflammatory cytokines to control inflammation. Although inhibition of pro-inflammatory cytokines is less than hormones, but for anti-inflammatory cytokines have a protective effect as its features of TCM. This seems to be explain that Shuganjianpi Gusui Recipe control of acute symptoms weeker than hormones, which have a reduced role in multiple sclerosis clinical recurrence.
3. EAE mouse model can be used as screening target of anti-inflammatory drugs model of multiple sclerosis, TNF-a, IFN-y, IL-21, IL-17F and IL-10, IL-4are more sensible, can be used to screening drugs and determine the drugs'efficacy, provides an experimental basis for further study in MS drug therapy and drug screening.
4. MOG35-55immunization of C57BL mice obtained EAE chronic persistent model. Few mice were found having relapse phenomenon, point to there may be a big difference in murine autoimmune conditions. In the application of this classic model of EAE is still aware that the possibility of causing interference for drug screening of acute exacerbation.
引文
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