复治及耐多药结核病患者的Th1/Th2细胞状态变化的研究
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摘要
结核病是由结核分枝杆菌(mycobacterium tuberculosis,MTB)引起的一种感染性疾病,机体正常的免疫功能可以帮助及时清除感染的结核菌,从而阻止发展成为结核病,免疫系统正常功能的运行依赖于多种细胞间、细胞与细胞外基质间的粘附作用,以及多种粘附分子及配体的相互作用。MTB作为一种胞内寄生菌,机体的抗结核免疫主要依赖于特异性的细胞免疫,多种细胞因子参与免疫反应,所以结核病的发展与转归与细胞免疫功能有密切关系。临床绝大多数结核病患者经治疗顺利痊愈,但有少数复治及耐药患者治疗困难,效果差。对此类患者进行病原学研究得较多,而对患者免疫功能研究较少。本课题对复治及耐药患者的细胞免疫功能进行研究。
目的:观察复治及耐药肺结核患者免疫功能指标的变化。对此类患者的免疫功能进行评价。从而在免疫学角度寻找致病原因,并为临床医生提供免疫治疗的实验室依据,最大限度的提高临床疗效。
方法:符合入选标准的健康组、初治肺结核组、复治肺结核组及耐多药肺结核组的患者均静脉采血用酶联免疫吸附法(ELISA)分别进行IFN-γ、IL-2、IL-4及IL-10检测;流式细胞仪(FCM)进行CD3+、CD4+、CD8+、CD4+/CD8+检测。用配对t检验和秩和检验。评价复治及耐药肺结核患者免疫功能的变化。
结果:符合研究标准的各组患者,健康组、初治组、复治组、耐多药组的细胞因子检验结果显示:1、血清IFN-γ:各组间受试者差异均无显著性(P＞0.05),2、IL-2:健康组与初治组、复治组与耐多药组的浓度无显著性差异(P＞0.05);健康组与复治组及耐多药组、初治组与复治组、初治组与耐多药组的浓度差异有非常显著性(P＜0.01)。3、IL-4及IL-10:健康组与初治组、健康组与复治组、健康组与耐多药组、初治组与耐多药组、初治组与复治组的浓度差异有非常显著性(P＜0.01)。复治组与耐多药组的浓度无显著性差异(P＞0.05)。健康组、初治组、复治组、耐多药组的各组间受试者血清CD3+的百分比差异均无显著性(P＞0.05);健康组与各结核组的CD4+、CD8+的百分比CD4+/CD8+差异均有非常显著性(P＜0.01),初治组与复治组及耐多药组的CD8+百分比差异有非常显著性(P＜0.01);初治组与耐多药组的CD4+/CD8+差异有非常显著性(P＜0.01);初治组与复治组的CD4+、CD4+/CD8+的百分比差异均有显著性(P＜0.05)。复治组与耐多药组的CD4+、CD8+、CD4+/CD8+的百分比均无显著性差异(P＞0.05)。
结论:结核病患者细胞免疫功能均下降,表现为CD4+T淋巴细胞百分比降低,CD8+T淋巴细胞百分比升高,CD4+/CD8+比值降低甚至倒置,增强抗结核免疫反应的淋巴因子IFN-γ、IL-2浓度降低而抑制此反应的淋巴因子IL-4及IL-10浓度升高。但其中复治及耐多药结核病患者较初治患者的细胞免疫功能进一步下降,表现为上述变化更加显著,使病情表现更加复杂及增加了治疗难度。
Tuberculosis is a disease caused by a facultative intracellular pathogen mycobacterium tuberculosis(MTB).Normal immunity can help human body erase mycobacterium tuberculosis in order to inhibit it develop into tuberculosis.Normal function of immune system depends on adherence among cells and cell-extracellular matrix,as well as functions among cell adhesion molecules and its mate.Immunity against MTB which is intercellular bacteria depends on specific cellular immunity which involves many cell factors.Specific cellular immunity plays an important role in fighting with tuberculosis.Most of tuberculosis patients can be cured by clinical treatment,but there are still some patients who have difficult in treating because of drug-resistance and other reasons.We have much pathogenic research in such patients, but few in their immunity.
Objectives:To observe and value changes of immunity in retreatment and multiple-drug-resistance(MDR) TB patients.Thereby to help oncologist to adopt immune therapy,obtain maximum clinical efficacy,in tuberculosis.
Methods:The patients' blood in accord with the selective standard is collected,and then IFN-r,,IL-2,IL-4及IL-10 is measured with enzyme-labeled immunosorbent assay(ELISA) CD3+,CD4+,CD8+,CD4+/CD8+ is measured with flow cytometry. Data were analyzed with T-test and rank sum test,The changes of the patients immune function can be evaluated.
Results:a The statistic analytic results of cytokine IFN-r,,IL-2,IL-4 and IL-10 in healthy group,initial treatment group,retreatment group and MDR group show 1,The results of IFN-rin each group are not significant(P＞0.05).2,IL-2 between healthy group and initial treatment group are not significant(P＞0.05),the same result between retreatment group and MDR group.The result between healthy group and retreatment group;healthy group and MDR group;initial treatment group and retreatment group; initial treatment group and MDR group are significant(P＜0.01).3,IL-4 and IL-10 in each two group are significant(P＜0.01) except that it is not significant(P＞0.05) between retreatment group and MDR group.。The results of CD3+ in each group are not significant(P＞0.05).The results of CD4+,CD8+ and CD4+/CD8+ between healthy group and each TB group are significant(P＜0.01).CD8+ between initial treatment group and retreatment group,initial treatment group and MDR group are significant(P＜0.01).CD4+/CD8+ between initial treatment group and MDR group are significant(P＜0.01),CD4+,CD4+/CD8+ between initial treatment group and retreatment group are significant(P＜0.01),CD4+,CD8+,CD4+/CD8+ between retreatment group and MDR group are not significant(P＞0.05).
Conclusion:The cellular immunity of TB patients decrease.It shows that the percent of CD4+T lymphocyte decrease while the percent of CD8+ T lymphocyte increase,CD4+/CD8+ decrease.Cytokines of IFN-r,and IL-2 which enhance the immunity against tuberculosis decrease while cytokines of IL-4 and IL-10 which inhibit the immunity against tuberculosis increase.Compared with initial treatment group,the immunity of retreatment group and MDR group are even worse,which can cause difficulty in treating.
目的:观察复治及耐药肺结核患者免疫功能指标的变化。对此类患者的免疫功能进行评价。从而在免疫学角度寻找致病原因,并为临床医生提供免疫治疗的实验室依据,最大限度的提高临床疗效。
方法:符合入选标准的健康组、初治肺结核组、复治肺结核组及耐多药肺结核组的患者均静脉采血用酶联免疫吸附法(ELISA)分别进行IFN-γ、IL-2、IL-4及IL-10检测;流式细胞仪(FCM)进行CD3+、CD4+、CD8+、CD4+/CD8+检测。用配对t检验和秩和检验。评价复治及耐药肺结核患者免疫功能的变化。
结果:符合研究标准的各组患者,健康组、初治组、复治组、耐多药组的细胞因子检验结果显示:1、血清IFN-γ:各组间受试者差异均无显著性(P＞0.05),2、IL-2:健康组与初治组、复治组与耐多药组的浓度无显著性差异(P＞0.05);健康组与复治组及耐多药组、初治组与复治组、初治组与耐多药组的浓度差异有非常显著性(P＜0.01)。3、IL-4及IL-10:健康组与初治组、健康组与复治组、健康组与耐多药组、初治组与耐多药组、初治组与复治组的浓度差异有非常显著性(P＜0.01)。复治组与耐多药组的浓度无显著性差异(P＞0.05)。健康组、初治组、复治组、耐多药组的各组间受试者血清CD3+的百分比差异均无显著性(P＞0.05);健康组与各结核组的CD4+、CD8+的百分比CD4+/CD8+差异均有非常显著性(P＜0.01),初治组与复治组及耐多药组的CD8+百分比差异有非常显著性(P＜0.01);初治组与耐多药组的CD4+/CD8+差异有非常显著性(P＜0.01);初治组与复治组的CD4+、CD4+/CD8+的百分比差异均有显著性(P＜0.05)。复治组与耐多药组的CD4+、CD8+、CD4+/CD8+的百分比均无显著性差异(P＞0.05)。
结论:结核病患者细胞免疫功能均下降,表现为CD4+T淋巴细胞百分比降低,CD8+T淋巴细胞百分比升高,CD4+/CD8+比值降低甚至倒置,增强抗结核免疫反应的淋巴因子IFN-γ、IL-2浓度降低而抑制此反应的淋巴因子IL-4及IL-10浓度升高。但其中复治及耐多药结核病患者较初治患者的细胞免疫功能进一步下降,表现为上述变化更加显著,使病情表现更加复杂及增加了治疗难度。
Tuberculosis is a disease caused by a facultative intracellular pathogen mycobacterium tuberculosis(MTB).Normal immunity can help human body erase mycobacterium tuberculosis in order to inhibit it develop into tuberculosis.Normal function of immune system depends on adherence among cells and cell-extracellular matrix,as well as functions among cell adhesion molecules and its mate.Immunity against MTB which is intercellular bacteria depends on specific cellular immunity which involves many cell factors.Specific cellular immunity plays an important role in fighting with tuberculosis.Most of tuberculosis patients can be cured by clinical treatment,but there are still some patients who have difficult in treating because of drug-resistance and other reasons.We have much pathogenic research in such patients, but few in their immunity.
Objectives:To observe and value changes of immunity in retreatment and multiple-drug-resistance(MDR) TB patients.Thereby to help oncologist to adopt immune therapy,obtain maximum clinical efficacy,in tuberculosis.
Methods:The patients' blood in accord with the selective standard is collected,and then IFN-r,,IL-2,IL-4及IL-10 is measured with enzyme-labeled immunosorbent assay(ELISA) CD3+,CD4+,CD8+,CD4+/CD8+ is measured with flow cytometry. Data were analyzed with T-test and rank sum test,The changes of the patients immune function can be evaluated.
Results:a The statistic analytic results of cytokine IFN-r,,IL-2,IL-4 and IL-10 in healthy group,initial treatment group,retreatment group and MDR group show 1,The results of IFN-rin each group are not significant(P＞0.05).2,IL-2 between healthy group and initial treatment group are not significant(P＞0.05),the same result between retreatment group and MDR group.The result between healthy group and retreatment group;healthy group and MDR group;initial treatment group and retreatment group; initial treatment group and MDR group are significant(P＜0.01).3,IL-4 and IL-10 in each two group are significant(P＜0.01) except that it is not significant(P＞0.05) between retreatment group and MDR group.。The results of CD3+ in each group are not significant(P＞0.05).The results of CD4+,CD8+ and CD4+/CD8+ between healthy group and each TB group are significant(P＜0.01).CD8+ between initial treatment group and retreatment group,initial treatment group and MDR group are significant(P＜0.01).CD4+/CD8+ between initial treatment group and MDR group are significant(P＜0.01),CD4+,CD4+/CD8+ between initial treatment group and retreatment group are significant(P＜0.01),CD4+,CD8+,CD4+/CD8+ between retreatment group and MDR group are not significant(P＞0.05).
Conclusion:The cellular immunity of TB patients decrease.It shows that the percent of CD4+T lymphocyte decrease while the percent of CD8+ T lymphocyte increase,CD4+/CD8+ decrease.Cytokines of IFN-r,and IL-2 which enhance the immunity against tuberculosis decrease while cytokines of IL-4 and IL-10 which inhibit the immunity against tuberculosis increase.Compared with initial treatment group,the immunity of retreatment group and MDR group are even worse,which can cause difficulty in treating.
引文
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[6]Ordway DJ,Pinto L,Martins M,et al.Gammadelta T cell responsesassociated with the development of tuberculosis in health care workers[J].FEMS Immunol.Med Microbiol,2005,43(3):339-350
[7]Tobian AA,Canaday DH,Harding CV.Bacterial heat shock proteinspeptides to CD4+T cells[J].J Immunol,2004,173(8):5130-5137
[8]Kamath AB,Alt J,Debbabi H,et al.The major histocompatibilitycomplex haplotype affects T-cell recognition of mycobacterial antigensbut not resistance toMycobacteriumtuberculosis in C3Hmice[J].Infectlmmun,2004,72(12):6790-6798
[9]Avgustin B,Kotnik V,Skoberne M.CD69 expression on CD4+T lymphocytes after stimulation with tuberculosis is an indicator of immunesensitization againstmycobacteriumtuberculosis antigens[J].Clin DiagnLab Immumol,2005,12(1): 101-106
[10]Cowley SC,Elkins KL.CD4+ T cells mediate IFN-gamma-independent control of Mycobacterium tuberculosis infection both in vitro andin vivo[J].J Immunol,2003,171(9):4689-4699
[11]Tamura T,ArigaH,Kinashi T.The role of antigenic peptide in CD4+Thelper phenotype development in a T cell receptor transgenic model[J].Int Immunol,2004,16(12):1691-1699
[12]Wang J,SantosuossoM,Ngai P.Activation of CD8Tcellsbymycobacterial vaccination protects against pulmonary tuberculosis in the absenceof CD4 T cells[J].J Immunol,2004,173(7):4590-4597
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