共刺激分子CTLA_4-Ig对支气管哮喘治疗作用的实验研究
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摘要
支气管哮喘是气道慢性变态反应性炎症性疾病。现代研究已证实，支气管哮喘的病理基础为气管变应性炎症（AAI）。在变应原的刺激下，多种炎症细胞（以嗜酸粒细胞为主），自气道趋化，聚集并激活，释放出多种炎性介质，破坏气道上皮，从而造成AAI和气道高反应性。气道炎症学说认为：哮喘是一种涉及多种炎性细胞及炎症介质相互作用的一种慢性气道炎症疾病。气道炎症是气道高反应性（哮喘病理生理学特征）的病理基础。
目前，众多学者认为哮喘的发病与CD4过度活化、CD4/CD8失衡有密切关系，并提出将CD4作为哮喘免疫调节的靶点。CD4+ T细胞可分为Th1和Th2亚群，当Th2亚群多优势时易发生高IgE血症和嗜酸细胞增多。Th1亚群主要分泌IFN-γ、IL-2和IL-12，而Th2亚群分泌IL-4、IL-5和IL-13等细胞因子。
近十年的研究发现，无论哮喘病人Th1/Th2比例向Th2方向极化，还是IL-4、IL-5、IL-13等细胞的分泌亢进，共刺激分子都起了重要作用。CD28是表达于T细胞表面并接受协同刺激信号的受体，与之相匹配的表达于APC表面的B7-1和B7-2分子。细胞毒性T淋巴细胞相关蛋白-4（CTLA-4即CTLA4）也表达于T细胞表面，其结构与CD28相同，亦能与CD80和CD86分子相结合。但CTLA4与它们的亲和能力较CD28大20倍。CTLA4在静止的T细胞不表达，在刚活化的T细胞表达水平也较低。T细胞活化后24h才有少量CTLA4表达，48h达高峰，96h恢复原来水平。共刺激信号受抑制能阻止T细胞激活，并能
使T细胞处于长期无应答状态甚至凋亡。对于T细胞的激活起上调作用的CTLA4能抑制T细胞的增殖。促进抗原特异性凋亡，并能抑制Th1和Th2细胞产生的细胞因子。CTLA-4Ig是CTLA4位于细胞外的结构部分和IgG的Fc段融合的可溶性蛋白，所以也能与CD80和CD86结合。在抗原诱导的气道炎症的鼠模型中，用CTLA-4Ig阻断CD80和/或CD86共刺激途径可以抑制T细胞的激活。近年应用单克隆抗体发现一组新的细胞膜表面分子，命名为CD45分子。CD45分子的异构体（isoforms）常限定在某些T细胞表面表达，故称之为CD45R。应用这种异构体分子可将T细胞分为二个新亚群。凡未经抗原刺激的T细胞可称之为原始T细胞（naive T cell, Tn）为CD45RA+T细胞群，而经抗原刺激分化为记忆T细胞（memory T cell, Tm）为CD45RO+细胞群。二者在细胞因子分泌和对B细胞辅助方面存在差别。记忆性T细胞分泌Th1和Th2样淋巴因子如IL-4、IL-6、IFN-r、IL-13、和少量IL-2，并对B细胞产生免疫球蛋白有辅助作用。
1、共刺激分子CTLA4-Ig对哮喘病人T细胞表达IL-13的影响
以16例哮喘病人为研究对象，12例健康人为对照，分别取外周静脉血6ml，进行PBMC的分离并培养，然后进行PHA及CTLA4-Ig适宜刺激浓度的摸索，PHA最适刺激浓度为20μg/ml，CTLA4-Ig最适刺激浓度为1μg/ml，每个病人和正常人的PBMC分为4组，分别给予不同刺激：（1）未给予任何刺激，为单纯培养组。（2）加入PHA20μg/ml，为刺激组。（3）加入PHA（20μg/ml）和CTLA4Ig（1μg/ml）培养36h后进行细胞总RNA提取，然后逆转录，所得cDNA进行PCR扩增。结果显示，正常对照组不同的刺激条件下，IL-13表达始终测不出。哮喘组PHA作用下，T细胞IL-13表达量有所增高，P＜0.01。同在PHA刺激情况下，CTLA4-Ig使IL-13表达量明显下降，P＜0.01。对正常人PHA刺激后IL-13表达测不出是具有一定合理性的，正常人IL-13表达不应该很活跃，另外，我们测定IL-13mRNA表达时或者超过了T细胞活化后细胞因子的表达时间，或者正常人对PHA不存在过敏现象。在哮喘组中
给与PHA刺激后，IL-13基因表达增多P＜0.01，可能与哮喘病人针对特异抗原PHA的记忆性淋巴细胞数量较多有关。在哮喘病人体内IL-13mRNA始终达到测量水平反应了该病IL-13的升高情况。同在抗原特异性刺激下，CTLA4-Ig明显抑制了哮喘病人PBMC中IL-13的表达，从而可以作为治疗哮喘的一个手段。
2、共刺激分子CTLA4-Ig对支气管哮喘病人CD4+CD45RO+T细胞功能的影响
以18例哮喘病人为研究对象，10例健康人为对照，先进行外周血单个核细胞的分离，然后用尼龙棉柱法分离T、B细胞，用免疫磁性微珠分离法分离CD4+细胞培养。将分离出的T细胞培养，加入鼠抗人CD8抗体，洗涤除去未反应的抗体，用兔抗鼠IgG磁珠与上述悬液培养交放入磁场5min后吸出悬浮细胞即为CD4+T细胞，免疫磁性微珠分离法分离CD4+CD45RO+T细胞，将分离的CD4+CD45RO+T与B细胞混合，每个正常人和病人PBMC分3组，分组刺激：（1）单纯培养组。（2）PHA组。（3）PHA+CTLA4-Ig组，培养36h，收集上清，用酶联免疫吸附测定（ILISA）法检测上清中IL-4、IL-13（按试剂盒说明书操作）结果正常对照组单独加入PHA，IL-4分泌较不加刺激原时增加（P<0.01），同时加入PHA和CTLA4-Ig后，IL-4分泌较单独PHA刺激时明显减少（P<0.01）；哮喘病人组单独加入PHA，IL-4分泌较不加刺激原时增加（P<0.01），同时加入PHA和CTLA4-Ig后，IL-4分泌较单独PHA刺激时明显减少（P<0.01），正常组和哮喘组CD4+CD45RO+T细胞分泌IL-13情况同IL-4。哮喘组和正常对照组CD4+CD45RO+T细胞分泌IL-4存在组间差异：不加任何刺激，单独加入PHA，同时加入PHA和CTLA4-Ig三
Bronchial asthma is a kind of chronic allergic inflammatory disease of airway. Studies have verified that the pathologic foundation of asthma is allergic airway inflammation (AAI). With the stimulation of allergen, Many kinds of inflammatory cells, relied mainly on easinophilia, trend and assemble to the airway to be activccted, and release many kinds of inflammatory factors to destroy the epithelium of the airway, which cause AAI and airway hyper responsiveness. The theory of airway inflammation thinks that the asthma is a kind of chronic airway inflammatory disease, which involves the interactive of many inflammatory cells and factors. Airway inflammation is the pathologic foundation of airway hyperten siveness, which is the patho physiologic character of the asthma.
Nowadays, many scholars think that the onset of asthma has close relation with excessively activation of CD4 and the out of 13alance of CD4/CD8, and they propose regarding CD4 as the target of immunoregulation of asthma. CD4+T cells can be divided into subgroups of Th1 and Th2. when the subgroup of Th2 is preponderant, it is easy for the increase of 1gE in blood and so eosinophilia to take place. The subgroup of Th1 mainly secrete IFN-r, and IL-12, however, the subgroup of Th2 secrete IL-4, IL-5, IL-13 and other cellular factors.
Studies in recent ten years have mediated that no matter whether the proportion of Th1/Th2 polarizing to Th2 in patients of asthma or the excessively secreting of IL-4, IL-5, IL-13, etc, the costimulatory molecules play an important role. CD28 is a receptor expressed on the surface of T cell and recepting costimulatory signal, which is matched by the molecules of BT-1 and BT-2 expressed on the surface of APC. CTLA4 which has the same structure with CD28 and can also be combined with the molecules of CD80 and CD86, is also expressed on the surface of T cell, however the CTLA4 is so times the affinity to them of CD28. CTLA4 is not expressed in static T cell, and just expressed with a lower level in fresh activated T cell. The expression of CTLA4 is just in a lower level in 24hs after the activation of T cell and reaches the peak in 48h and resumes to the original level in 96 hours. The inhibition (suppression) of costimulatory signal can prevent the activation of T cell, and can make T cell in a strode of no response for a long time or apoptosis. CTLA4 that promotes the activation of T cell can inhibit the increase of T cell, promote the peculiar apoptosis of antigen, and inhibit Th1 and Th2 cell producing cellular factors. CTLA-4Ig, which is a structure part of CTLA4 out of cell, is a kind of soluble protein that can merge with the Fc segment of IgG, so it can combine with CD80 and CD86 too. In the mouse model of antigen-induced airway inflammation mouse, blocking the costimulatory way of CD80 and /or CD86 with CTLA-4Ig, can suppress the activation of T cell. Recently, a group of new molecules named as CD45 are found on the surface of cell membrane with the using of monoclonal antibody. The isoforms of CD45 are called as CD45R, as they are normally expressed on the surface of certain cells limitedly. T cells can be divided into two subgroups with this isoforms. The T cell without the stimulation of antigen is called naive T cell (Tn), which belongs to the group of CD45RA+T cell. However, The T cell with the strangulation of antigen is called memory T cell (Tm) which
belongs to the group of CD45RO+cell. There are difference in the effect of secreting cellular factors and in allxiliary effect to B cell between the two. Tm secretes kinds of Th1. and Th2 lymph factors, such as IL-4, IL-6, IFN-r, IL-13, and a little IL-2, and has auxiliary function to produce Ig on B cell.
1. The influence of costimulatory molecules CTLA4-Ig on the expression of IL-13 by T cell in the patients of asthma.
Using 16 cases of asthmatic patients as the research objects, 12 healthy persons as contrast, fetching peripheral veinal blood 6ml respectively, carrying on the separation and culture of PBMC, The PBMC of ea
目前，众多学者认为哮喘的发病与CD4过度活化、CD4/CD8失衡有密切关系，并提出将CD4作为哮喘免疫调节的靶点。CD4+ T细胞可分为Th1和Th2亚群，当Th2亚群多优势时易发生高IgE血症和嗜酸细胞增多。Th1亚群主要分泌IFN-γ、IL-2和IL-12，而Th2亚群分泌IL-4、IL-5和IL-13等细胞因子。
近十年的研究发现，无论哮喘病人Th1/Th2比例向Th2方向极化，还是IL-4、IL-5、IL-13等细胞的分泌亢进，共刺激分子都起了重要作用。CD28是表达于T细胞表面并接受协同刺激信号的受体，与之相匹配的表达于APC表面的B7-1和B7-2分子。细胞毒性T淋巴细胞相关蛋白-4（CTLA-4即CTLA4）也表达于T细胞表面，其结构与CD28相同，亦能与CD80和CD86分子相结合。但CTLA4与它们的亲和能力较CD28大20倍。CTLA4在静止的T细胞不表达，在刚活化的T细胞表达水平也较低。T细胞活化后24h才有少量CTLA4表达，48h达高峰，96h恢复原来水平。共刺激信号受抑制能阻止T细胞激活，并能
使T细胞处于长期无应答状态甚至凋亡。对于T细胞的激活起上调作用的CTLA4能抑制T细胞的增殖。促进抗原特异性凋亡，并能抑制Th1和Th2细胞产生的细胞因子。CTLA-4Ig是CTLA4位于细胞外的结构部分和IgG的Fc段融合的可溶性蛋白，所以也能与CD80和CD86结合。在抗原诱导的气道炎症的鼠模型中，用CTLA-4Ig阻断CD80和/或CD86共刺激途径可以抑制T细胞的激活。近年应用单克隆抗体发现一组新的细胞膜表面分子，命名为CD45分子。CD45分子的异构体（isoforms）常限定在某些T细胞表面表达，故称之为CD45R。应用这种异构体分子可将T细胞分为二个新亚群。凡未经抗原刺激的T细胞可称之为原始T细胞（naive T cell, Tn）为CD45RA+T细胞群，而经抗原刺激分化为记忆T细胞（memory T cell, Tm）为CD45RO+细胞群。二者在细胞因子分泌和对B细胞辅助方面存在差别。记忆性T细胞分泌Th1和Th2样淋巴因子如IL-4、IL-6、IFN-r、IL-13、和少量IL-2，并对B细胞产生免疫球蛋白有辅助作用。
1、共刺激分子CTLA4-Ig对哮喘病人T细胞表达IL-13的影响
以16例哮喘病人为研究对象，12例健康人为对照，分别取外周静脉血6ml，进行PBMC的分离并培养，然后进行PHA及CTLA4-Ig适宜刺激浓度的摸索，PHA最适刺激浓度为20μg/ml，CTLA4-Ig最适刺激浓度为1μg/ml，每个病人和正常人的PBMC分为4组，分别给予不同刺激：（1）未给予任何刺激，为单纯培养组。（2）加入PHA20μg/ml，为刺激组。（3）加入PHA（20μg/ml）和CTLA4Ig（1μg/ml）培养36h后进行细胞总RNA提取，然后逆转录，所得cDNA进行PCR扩增。结果显示，正常对照组不同的刺激条件下，IL-13表达始终测不出。哮喘组PHA作用下，T细胞IL-13表达量有所增高，P＜0.01。同在PHA刺激情况下，CTLA4-Ig使IL-13表达量明显下降，P＜0.01。对正常人PHA刺激后IL-13表达测不出是具有一定合理性的，正常人IL-13表达不应该很活跃，另外，我们测定IL-13mRNA表达时或者超过了T细胞活化后细胞因子的表达时间，或者正常人对PHA不存在过敏现象。在哮喘组中
给与PHA刺激后，IL-13基因表达增多P＜0.01，可能与哮喘病人针对特异抗原PHA的记忆性淋巴细胞数量较多有关。在哮喘病人体内IL-13mRNA始终达到测量水平反应了该病IL-13的升高情况。同在抗原特异性刺激下，CTLA4-Ig明显抑制了哮喘病人PBMC中IL-13的表达，从而可以作为治疗哮喘的一个手段。
2、共刺激分子CTLA4-Ig对支气管哮喘病人CD4+CD45RO+T细胞功能的影响
以18例哮喘病人为研究对象，10例健康人为对照，先进行外周血单个核细胞的分离，然后用尼龙棉柱法分离T、B细胞，用免疫磁性微珠分离法分离CD4+细胞培养。将分离出的T细胞培养，加入鼠抗人CD8抗体，洗涤除去未反应的抗体，用兔抗鼠IgG磁珠与上述悬液培养交放入磁场5min后吸出悬浮细胞即为CD4+T细胞，免疫磁性微珠分离法分离CD4+CD45RO+T细胞，将分离的CD4+CD45RO+T与B细胞混合，每个正常人和病人PBMC分3组，分组刺激：（1）单纯培养组。（2）PHA组。（3）PHA+CTLA4-Ig组，培养36h，收集上清，用酶联免疫吸附测定（ILISA）法检测上清中IL-4、IL-13（按试剂盒说明书操作）结果正常对照组单独加入PHA，IL-4分泌较不加刺激原时增加（P<0.01），同时加入PHA和CTLA4-Ig后，IL-4分泌较单独PHA刺激时明显减少（P<0.01）；哮喘病人组单独加入PHA，IL-4分泌较不加刺激原时增加（P<0.01），同时加入PHA和CTLA4-Ig后，IL-4分泌较单独PHA刺激时明显减少（P<0.01），正常组和哮喘组CD4+CD45RO+T细胞分泌IL-13情况同IL-4。哮喘组和正常对照组CD4+CD45RO+T细胞分泌IL-4存在组间差异：不加任何刺激，单独加入PHA，同时加入PHA和CTLA4-Ig三
Bronchial asthma is a kind of chronic allergic inflammatory disease of airway. Studies have verified that the pathologic foundation of asthma is allergic airway inflammation (AAI). With the stimulation of allergen, Many kinds of inflammatory cells, relied mainly on easinophilia, trend and assemble to the airway to be activccted, and release many kinds of inflammatory factors to destroy the epithelium of the airway, which cause AAI and airway hyper responsiveness. The theory of airway inflammation thinks that the asthma is a kind of chronic airway inflammatory disease, which involves the interactive of many inflammatory cells and factors. Airway inflammation is the pathologic foundation of airway hyperten siveness, which is the patho physiologic character of the asthma.
Nowadays, many scholars think that the onset of asthma has close relation with excessively activation of CD4 and the out of 13alance of CD4/CD8, and they propose regarding CD4 as the target of immunoregulation of asthma. CD4+T cells can be divided into subgroups of Th1 and Th2. when the subgroup of Th2 is preponderant, it is easy for the increase of 1gE in blood and so eosinophilia to take place. The subgroup of Th1 mainly secrete IFN-r, and IL-12, however, the subgroup of Th2 secrete IL-4, IL-5, IL-13 and other cellular factors.
Studies in recent ten years have mediated that no matter whether the proportion of Th1/Th2 polarizing to Th2 in patients of asthma or the excessively secreting of IL-4, IL-5, IL-13, etc, the costimulatory molecules play an important role. CD28 is a receptor expressed on the surface of T cell and recepting costimulatory signal, which is matched by the molecules of BT-1 and BT-2 expressed on the surface of APC. CTLA4 which has the same structure with CD28 and can also be combined with the molecules of CD80 and CD86, is also expressed on the surface of T cell, however the CTLA4 is so times the affinity to them of CD28. CTLA4 is not expressed in static T cell, and just expressed with a lower level in fresh activated T cell. The expression of CTLA4 is just in a lower level in 24hs after the activation of T cell and reaches the peak in 48h and resumes to the original level in 96 hours. The inhibition (suppression) of costimulatory signal can prevent the activation of T cell, and can make T cell in a strode of no response for a long time or apoptosis. CTLA4 that promotes the activation of T cell can inhibit the increase of T cell, promote the peculiar apoptosis of antigen, and inhibit Th1 and Th2 cell producing cellular factors. CTLA-4Ig, which is a structure part of CTLA4 out of cell, is a kind of soluble protein that can merge with the Fc segment of IgG, so it can combine with CD80 and CD86 too. In the mouse model of antigen-induced airway inflammation mouse, blocking the costimulatory way of CD80 and /or CD86 with CTLA-4Ig, can suppress the activation of T cell. Recently, a group of new molecules named as CD45 are found on the surface of cell membrane with the using of monoclonal antibody. The isoforms of CD45 are called as CD45R, as they are normally expressed on the surface of certain cells limitedly. T cells can be divided into two subgroups with this isoforms. The T cell without the stimulation of antigen is called naive T cell (Tn), which belongs to the group of CD45RA+T cell. However, The T cell with the strangulation of antigen is called memory T cell (Tm) which
belongs to the group of CD45RO+cell. There are difference in the effect of secreting cellular factors and in allxiliary effect to B cell between the two. Tm secretes kinds of Th1. and Th2 lymph factors, such as IL-4, IL-6, IFN-r, IL-13, and a little IL-2, and has auxiliary function to produce Ig on B cell.
1. The influence of costimulatory molecules CTLA4-Ig on the expression of IL-13 by T cell in the patients of asthma.
Using 16 cases of asthmatic patients as the research objects, 12 healthy persons as contrast, fetching peripheral veinal blood 6ml respectively, carrying on the separation and culture of PBMC, The PBMC of ea
引文
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