艾滋病免疫功能重建不全机制研究
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摘要
[目的]：研究艾滋病患者经有效抗病毒治疗后出现不同免疫学应答的特征,并进一步探讨艾滋病免疫功能重建不全的机制。
[方法]：从2003年10月至2009年4月于北京协和医院艾滋病诊疗中心规律随诊的患者55名,这些患者规律随诊,经抗病毒治疗2年以上,自基线、1月、3月、6月、9月、12月、18月、24月、30月、36月规律随访,检测血浆病毒载量、并采用流式细胞术技术检测外周血B细胞计数(CD19+)、NK细胞计数(CD16+CD56+)、CD4/CD8+T淋巴细胞计数(CD3+CD4+、CD3+CD8+)、CD4+T淋巴细胞纯真(CD4+CD45RA+CD62L+)、记忆亚群计数(CD4+CD45RA-)、CD8+T淋巴细胞激活亚群比例(CD8+CD38+/CD8、CD8+HLA-DR+/CD8+),并留取PBMC冻存待用。选取抗病毒治疗后血浆病毒载量维持在50copies／ml以下一年以上的患者,根据其是否存在免疫学应答进一步划分为免疫学应答组(n=15)、免疫学无应答组(n=11)。对两组患者自治疗前基线水平、治疗后6月、12月、24月、36月各随访点进行纵向研究。复苏冻存的PBMC采用流式细胞术技术,对外周血CD4+T淋巴细胞激活亚群比例(CD4+CD38+/CD4+、CD4+HLA-DR+/CD4+); CD4+T淋巴细胞胸腺新生纯真亚群比例(CD4+CD45RA+CD31+/CD4+)及CD4+T淋巴细胞早期凋亡亚群比例(CD4+AnnexinV+PI-/CD4+);调节性CD4+T淋巴细胞比例(CD4+CD25+FoxP3+/CD4+);记忆CD4+T淋巴细胞早期(CD27+CCR7+)中期(CD27-CCR7+)晚期(CD27-CCR7-)不同分化成熟阶段比例进行检测。评价两组艾滋病患者在免疫学应答特征的差异,进而分析免疫学无应答的发生机制。
[结果]：
1.基线水平,免疫学无应答组CD4+T淋巴细胞计数为37±36／ul与免疫学应答组172±87／ul比较有显著性差异(P<0.01)；免疫学应答组胸腺新生纯真CD4+比例为11.9±7.0%,显著高于免疫学无应答组2.6±1.5%(P=0.023)。基线免疫学无应答组患者CD4+T淋巴细胞早期凋亡比例为9.5±4.3%,显著高于免疫应答组的4.1±3.3%的比例(P<0.01)；免疫学无应答组调节性CD4+T淋巴细胞的比例为6.9±3.5%,免疫学应答组为3.7±2.2%,健康对照组为2.5±0.8%,免疫学无应答组较其它两组均有显著增高(P<0.01)；两组患者CD4+/CD8+T淋巴细胞激活亚群在基线水平无差异；
2.两组患者经抗病毒治疗后NK细胞、B细胞计数都有逐步增高,在抗病毒治疗初期增高更显著。B细胞增长在两组中存在差异,免疫学无应答组患者增长快于免疫学应答组；
3.经36月抗逆转录病毒治疗后,记忆表型CD4+T淋巴细胞在免疫学应答组平均增长128+61／ul,在免疫学无应答组平均增长118+67／ul；而纯真表型CD4+T淋巴细胞在免疫学应答组平均增长107+82／ul,在免疫学无应答组平均增长46±18／ul。两组间CD4+T淋巴细胞计数增长的差异主要在纯真CD4+T淋巴细胞部分(P<0.01)。
4.两组艾滋病患者CD4+／CD8+T淋巴细胞激活亚群在基线水平无显著差异,但均显著高于健康对照组。在抗病毒治疗6月时免疫学应答组患者CD8+CD38+/CD8+较基线下降比例显著高于免疫学无应答组(p<0.05)；
5.免疫应答组治疗后6月、12月、24月、36月时CCR7+CD27+记忆CD4+T细胞亚群比例显著高于免疫无应答组(p<0.05)；在治疗后36月时两组早期记忆CD4+T淋巴细胞比例为：INR组51.0±5.3%,IR组62.9±10.0%；
6.CD4+T淋巴细胞早期凋亡亚群比例与CD8+CD38+激活比例(r=0.225,p=0.016)、CD8+HLA-DR+激活比例(r=0.229,p=0.014)之间呈正相关；CD4+T淋巴细胞早期凋亡亚群比例与调节性CD4+T淋巴细胞比例也存在正相关(r=0.205,p=0.029)。
[结论]：
1.经抗病毒治疗后,CD4+T淋巴细胞计数的增长可分为两期,早期快速增长以记忆表型CD4+T淋巴细胞为主；后期主要为纯真细胞的持久增长。至抗病毒治疗后36月,免疫学无应答组患者CD4+T淋巴细胞增长水平较免疫学应答组水平低主要在于纯真CD4+T淋巴细胞计数增长低。两组患者NK细胞数量增长相似,而B细胞在免疫学无应答组增长较显著。
2.在基线水平,CD4+T淋巴细胞计数显著减低、胸腺新生CD4+T淋巴细胞比例显著下降、CD4+T淋巴细胞早期凋亡比例显著的增高、调节性T淋巴细胞比例的异常增高都是患者发生免疫学无应答的预警因素；开始治疗后,CD8+T淋巴细胞表达CD38的激活亚群降低的速度慢,预示患者可能将出现免疫学无应答；
3.CD8+T淋巴细胞异常激活比例与CD4+T淋巴细胞早期凋亡存在正相关；调节性CD4+T淋巴细胞比例与CD4+T淋巴细胞早期凋亡比例存在正相关。
[Objective]:Our study aims to analyse the characteristics of the immune reconstitution of HIV/AIDS patients after HAART and the pathogenesis of immune non-response.
[Methods]:Erollment began in 2003. All 55 adult patients coming from HIV/AIDS research center of Peking Union Medical Collage Hospital (PUMCH) were followed in an identical manner at the out-patient department. They were followed from baseline to month 36(M36). T cell subset and plasma viral load will done in baseline, Ml, M3, M6, M9, M12, M18, M24, M30, M36. Lymphcyte subsets include B cell count (CD 19+), NK cell count (CD16+CD56+), CD4 and CD8+T cell count(CD3+CD4+, CD3+CD8+), naive CD4+T cell count(CD4+CD45RA+CD62L+), memory CD4+T cell count(CD4+CD45RA-), the percentage of CD8+T cell actived subset(CD8+CD38+/CD8+, CD8+HLA-DR+/CD8+). PBMCs were isolated and cryopreserved. If the treated patient's plasma viral load was undetectable for over 1 year, the subject would be further divided into immune response group (IR) (n=15) or immune non-response group (INR) (n=11). The PBMC of baseline,6M,12M,24M, 36M were thawed for FCM analysis. The FCM analysis included the percentage of CD4+T cell actived subset(CD8+CD38+/CD8+, CD8+HLA-DR+/CD8+), the recent thymic emigrants of CD4+T cell percentage (CD4+CD45RA+CD31+/CD4+), the early apoptosis CD4+T cell percentage (CD4+Annexin V+PI-/CD4+), the CD4+regulatory T cell percentage (CD4+CD25+FoxP3+/CD4+), and the differentiation subset of CD4+memory cells expression of CCR7 and CD27.
[Results]:
1. At baseline, the mean CD4+T cell count was 37±36/ul in INR group which was significantly higher than the mean CD4+T cell count of IR group (172±87/ul) (P < 0.01). The recent thymic emigrants of CD4+T cell percentage was 11.9±7.0% in IR group, which was significantly higher than those of INR group(P=0.023). The early apoptosis CD4+T cell percentage was 4.1±3.3% in IR group which was significantly lower than those of INR group(P< 0.01). The CD4+regulatory T cell percentage was 6.9±3.5% in INR group, much higher than that of IR goup(P<0.01).
2. NK cell count, B cell count was increased after HAART in both groups. This increase was more significant in the early phase of treatment. The increase of the mean B cell count was more significant in INR group than in IR gorup.
3. After 36-month-treatment, the increase of memory CD4+T cell count was 128±61/ul in IR group and 118±67/ul in INR group; the increase of naive CD4+T cell count was 107±82/ul in IR group and 46±18/ul in INR group(P< 0.01). The difference of CD4+T cell count after HAART was mainly occurred in naive CD4+T cells.
4. The percentages of CD8+T cell actived subsets were similar in both AIDS patients groups in baseline. But after threatment, the pesentage of CD8+CD38+/CD8+ decreased more rapidly in IR group than in INR group.
5. After 6-month-treatment, the early differentiation subset of memory CD4+T cell (CD4+CD45RA-CCR7+CD27+/CD4+CD45RA-) was much higher in IR group than in INR group.
6. The percentage of early apoptosis CD4+T cell subset was positively corelated with the percentage of both CD8+T cell actived subsets(CD8+CD38+, r=0.225, p=0.016; CD8+HLA-DR+, r=0.229, p=0.014); The percentage of early apoptosis CD4+T cell subset was positively corelated with the CD4+regulatory T cell percentage (r=0.205, p=0.029).
[Conclusions]:
1. After HAART, CD4+T cell was increased rapidly in the early phase. This early phase increase reflected the memory CD4+T cell redistribution. After the early phase, the second phase increase reflected the slow and significant increase of the naive CD4+T cell count. After 36-month-treatment, the discrepancy of CD4+T cell count increase of the two groups was mainly occurred in naive CD4+T cell subset. The increase of NK cell count was similar in both groups. The increase of B cell count was more significant in INR group than in IR group.
2. The lower baseline CD4+T cell count, the lower percentage of recent thymic emigrants CD4+T cell, the higher early apoptosis CD4+T cell percentage, the higher CD4+regulatory T cell percentage were the presentiment of immune non-response. After treatment, the slower decrease of CD8+CD38+activated subset of CD8+T cell was also indicate the immune non-response.
3. The percentage of active subset of CD8+T cell was positively correlated with the early apoptosis CD4+T cell percentage. The CD4+regulatory T cell percentage was positively correlated with the early apoptosis CD4+T cell percentage.
[方法]：从2003年10月至2009年4月于北京协和医院艾滋病诊疗中心规律随诊的患者55名,这些患者规律随诊,经抗病毒治疗2年以上,自基线、1月、3月、6月、9月、12月、18月、24月、30月、36月规律随访,检测血浆病毒载量、并采用流式细胞术技术检测外周血B细胞计数(CD19+)、NK细胞计数(CD16+CD56+)、CD4/CD8+T淋巴细胞计数(CD3+CD4+、CD3+CD8+)、CD4+T淋巴细胞纯真(CD4+CD45RA+CD62L+)、记忆亚群计数(CD4+CD45RA-)、CD8+T淋巴细胞激活亚群比例(CD8+CD38+/CD8、CD8+HLA-DR+/CD8+),并留取PBMC冻存待用。选取抗病毒治疗后血浆病毒载量维持在50copies／ml以下一年以上的患者,根据其是否存在免疫学应答进一步划分为免疫学应答组(n=15)、免疫学无应答组(n=11)。对两组患者自治疗前基线水平、治疗后6月、12月、24月、36月各随访点进行纵向研究。复苏冻存的PBMC采用流式细胞术技术,对外周血CD4+T淋巴细胞激活亚群比例(CD4+CD38+/CD4+、CD4+HLA-DR+/CD4+); CD4+T淋巴细胞胸腺新生纯真亚群比例(CD4+CD45RA+CD31+/CD4+)及CD4+T淋巴细胞早期凋亡亚群比例(CD4+AnnexinV+PI-/CD4+);调节性CD4+T淋巴细胞比例(CD4+CD25+FoxP3+/CD4+);记忆CD4+T淋巴细胞早期(CD27+CCR7+)中期(CD27-CCR7+)晚期(CD27-CCR7-)不同分化成熟阶段比例进行检测。评价两组艾滋病患者在免疫学应答特征的差异,进而分析免疫学无应答的发生机制。
[结果]：
1.基线水平,免疫学无应答组CD4+T淋巴细胞计数为37±36／ul与免疫学应答组172±87／ul比较有显著性差异(P<0.01)；免疫学应答组胸腺新生纯真CD4+比例为11.9±7.0%,显著高于免疫学无应答组2.6±1.5%(P=0.023)。基线免疫学无应答组患者CD4+T淋巴细胞早期凋亡比例为9.5±4.3%,显著高于免疫应答组的4.1±3.3%的比例(P<0.01)；免疫学无应答组调节性CD4+T淋巴细胞的比例为6.9±3.5%,免疫学应答组为3.7±2.2%,健康对照组为2.5±0.8%,免疫学无应答组较其它两组均有显著增高(P<0.01)；两组患者CD4+/CD8+T淋巴细胞激活亚群在基线水平无差异；
2.两组患者经抗病毒治疗后NK细胞、B细胞计数都有逐步增高,在抗病毒治疗初期增高更显著。B细胞增长在两组中存在差异,免疫学无应答组患者增长快于免疫学应答组；
3.经36月抗逆转录病毒治疗后,记忆表型CD4+T淋巴细胞在免疫学应答组平均增长128+61／ul,在免疫学无应答组平均增长118+67／ul；而纯真表型CD4+T淋巴细胞在免疫学应答组平均增长107+82／ul,在免疫学无应答组平均增长46±18／ul。两组间CD4+T淋巴细胞计数增长的差异主要在纯真CD4+T淋巴细胞部分(P<0.01)。
4.两组艾滋病患者CD4+／CD8+T淋巴细胞激活亚群在基线水平无显著差异,但均显著高于健康对照组。在抗病毒治疗6月时免疫学应答组患者CD8+CD38+/CD8+较基线下降比例显著高于免疫学无应答组(p<0.05)；
5.免疫应答组治疗后6月、12月、24月、36月时CCR7+CD27+记忆CD4+T细胞亚群比例显著高于免疫无应答组(p<0.05)；在治疗后36月时两组早期记忆CD4+T淋巴细胞比例为：INR组51.0±5.3%,IR组62.9±10.0%；
6.CD4+T淋巴细胞早期凋亡亚群比例与CD8+CD38+激活比例(r=0.225,p=0.016)、CD8+HLA-DR+激活比例(r=0.229,p=0.014)之间呈正相关；CD4+T淋巴细胞早期凋亡亚群比例与调节性CD4+T淋巴细胞比例也存在正相关(r=0.205,p=0.029)。
[结论]：
1.经抗病毒治疗后,CD4+T淋巴细胞计数的增长可分为两期,早期快速增长以记忆表型CD4+T淋巴细胞为主；后期主要为纯真细胞的持久增长。至抗病毒治疗后36月,免疫学无应答组患者CD4+T淋巴细胞增长水平较免疫学应答组水平低主要在于纯真CD4+T淋巴细胞计数增长低。两组患者NK细胞数量增长相似,而B细胞在免疫学无应答组增长较显著。
2.在基线水平,CD4+T淋巴细胞计数显著减低、胸腺新生CD4+T淋巴细胞比例显著下降、CD4+T淋巴细胞早期凋亡比例显著的增高、调节性T淋巴细胞比例的异常增高都是患者发生免疫学无应答的预警因素；开始治疗后,CD8+T淋巴细胞表达CD38的激活亚群降低的速度慢,预示患者可能将出现免疫学无应答；
3.CD8+T淋巴细胞异常激活比例与CD4+T淋巴细胞早期凋亡存在正相关；调节性CD4+T淋巴细胞比例与CD4+T淋巴细胞早期凋亡比例存在正相关。
[Objective]:Our study aims to analyse the characteristics of the immune reconstitution of HIV/AIDS patients after HAART and the pathogenesis of immune non-response.
[Methods]:Erollment began in 2003. All 55 adult patients coming from HIV/AIDS research center of Peking Union Medical Collage Hospital (PUMCH) were followed in an identical manner at the out-patient department. They were followed from baseline to month 36(M36). T cell subset and plasma viral load will done in baseline, Ml, M3, M6, M9, M12, M18, M24, M30, M36. Lymphcyte subsets include B cell count (CD 19+), NK cell count (CD16+CD56+), CD4 and CD8+T cell count(CD3+CD4+, CD3+CD8+), naive CD4+T cell count(CD4+CD45RA+CD62L+), memory CD4+T cell count(CD4+CD45RA-), the percentage of CD8+T cell actived subset(CD8+CD38+/CD8+, CD8+HLA-DR+/CD8+). PBMCs were isolated and cryopreserved. If the treated patient's plasma viral load was undetectable for over 1 year, the subject would be further divided into immune response group (IR) (n=15) or immune non-response group (INR) (n=11). The PBMC of baseline,6M,12M,24M, 36M were thawed for FCM analysis. The FCM analysis included the percentage of CD4+T cell actived subset(CD8+CD38+/CD8+, CD8+HLA-DR+/CD8+), the recent thymic emigrants of CD4+T cell percentage (CD4+CD45RA+CD31+/CD4+), the early apoptosis CD4+T cell percentage (CD4+Annexin V+PI-/CD4+), the CD4+regulatory T cell percentage (CD4+CD25+FoxP3+/CD4+), and the differentiation subset of CD4+memory cells expression of CCR7 and CD27.
[Results]:
1. At baseline, the mean CD4+T cell count was 37±36/ul in INR group which was significantly higher than the mean CD4+T cell count of IR group (172±87/ul) (P < 0.01). The recent thymic emigrants of CD4+T cell percentage was 11.9±7.0% in IR group, which was significantly higher than those of INR group(P=0.023). The early apoptosis CD4+T cell percentage was 4.1±3.3% in IR group which was significantly lower than those of INR group(P< 0.01). The CD4+regulatory T cell percentage was 6.9±3.5% in INR group, much higher than that of IR goup(P<0.01).
2. NK cell count, B cell count was increased after HAART in both groups. This increase was more significant in the early phase of treatment. The increase of the mean B cell count was more significant in INR group than in IR gorup.
3. After 36-month-treatment, the increase of memory CD4+T cell count was 128±61/ul in IR group and 118±67/ul in INR group; the increase of naive CD4+T cell count was 107±82/ul in IR group and 46±18/ul in INR group(P< 0.01). The difference of CD4+T cell count after HAART was mainly occurred in naive CD4+T cells.
4. The percentages of CD8+T cell actived subsets were similar in both AIDS patients groups in baseline. But after threatment, the pesentage of CD8+CD38+/CD8+ decreased more rapidly in IR group than in INR group.
5. After 6-month-treatment, the early differentiation subset of memory CD4+T cell (CD4+CD45RA-CCR7+CD27+/CD4+CD45RA-) was much higher in IR group than in INR group.
6. The percentage of early apoptosis CD4+T cell subset was positively corelated with the percentage of both CD8+T cell actived subsets(CD8+CD38+, r=0.225, p=0.016; CD8+HLA-DR+, r=0.229, p=0.014); The percentage of early apoptosis CD4+T cell subset was positively corelated with the CD4+regulatory T cell percentage (r=0.205, p=0.029).
[Conclusions]:
1. After HAART, CD4+T cell was increased rapidly in the early phase. This early phase increase reflected the memory CD4+T cell redistribution. After the early phase, the second phase increase reflected the slow and significant increase of the naive CD4+T cell count. After 36-month-treatment, the discrepancy of CD4+T cell count increase of the two groups was mainly occurred in naive CD4+T cell subset. The increase of NK cell count was similar in both groups. The increase of B cell count was more significant in INR group than in IR group.
2. The lower baseline CD4+T cell count, the lower percentage of recent thymic emigrants CD4+T cell, the higher early apoptosis CD4+T cell percentage, the higher CD4+regulatory T cell percentage were the presentiment of immune non-response. After treatment, the slower decrease of CD8+CD38+activated subset of CD8+T cell was also indicate the immune non-response.
3. The percentage of active subset of CD8+T cell was positively correlated with the early apoptosis CD4+T cell percentage. The CD4+regulatory T cell percentage was positively correlated with the early apoptosis CD4+T cell percentage.
引文
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