猴AIDS模型外周血免疫病毒学指标动态变化及艾可清治疗猴AIDS模型的研究
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摘要
截至2009年10月底,累计报告艾滋病病毒感染者和病人319 877例,其中艾滋病病人102 323例；报告死亡49 845例。卫生部与联合国艾滋病规划署和世界卫生组织联合对中国2009年艾滋病疫情进行了评估。结果显示,截至2009年底,估计中国目前存活艾滋病病毒感染者和病人(HIV/AIDS)约74万人,其中,艾滋病病人为10.5万人；估计2009年当年新发艾滋病病毒感染者4.8万人。目前我国艾滋病传播途径已由以前的吸毒为主要途径转变为性接触占70%以上。
我国近年来非常重视艾滋病的防治,积极发挥各方面的力量和手段,包括重视研究用中医来治疗艾滋病。在对中医药治疗艾滋病试点工作项目进行总结后,发现中医药治疗艾滋病在调节免疫功能、改善临床症状、提高生存质量、延缓病情进展等方面有较好疗效。然而也有很多问题需要解决,比如如何客观准确的评估中医在艾滋病治疗中的作用?如果使中医治疗艾滋病的疗效有所突破,不断进步?中医治疗艾滋病所起的疗效的机制何在?
本论文检测了用SIV感染恒河猴造成猴艾滋病模型外周血的免疫学指标、病毒学指标的变化情况,然后观察了中药复方艾可清对SIV感染前后变化明显的免疫学和病毒学指标的影响。
1SIV感染猴模型病毒、免疫指标的动态变化
用SIVmac239感染36只恒河猴,观察外周血指标检测包括血常规、CD4+T细胞、CDS+T细胞计数、血浆病毒载量；外周血PBMC免疫共刺激分子mRNA量,这些免疫共刺激分子包括：CTLA-4、FOXP3、PD-1、IDO、HLA-DR、ICOS、CD28。
实验结果显示,WBC计数在SIV感染之后并未出现明显变化；CD4+T细胞比例和计数在SIV感染1周后均升高,SIV感染2周时又下降,此后几周有所波动,但都维持在低水平；其中CD4+T细胞比例保持基本稳定,但CD4+T细胞计数有逐渐降低的趋势。CD8+T细胞比例和计数在SIV感染后第]周和第2周均较SIV感染前逐渐升高,至第3周开始下降,第4周降至最低(但仍高于SIV感染前),第5周又有所上升,此后保持基本稳定。CD4/CD8比例在SIV感染后1、2周开始下降,第2周降至最低,然后第3周开始回升,至第4周继续上升,但仍低于第2周；第5周又开始下降,此后保持基本稳定。
SIV感染猴的病毒载量则与文献报道基本一致,第二周上升达到最高,其后回落,开始波动,第5周后基本保持稳定的波动。
从这些实验结果可以看出,SIV感染猴的CD4+T细胞计数的下降与感染前比较其下降程度并不大,这可能是因为SIV感染导致的CD4+T细胞减少需要一个比较长的时间,在数周内并不能迅速降低。
实验结果显示,SIV感染后免疫共刺激分子CTLA-4、FOXP3、PD-1、IDO、HLA-DR、ICOS、CD28的mRNA量出现了不同程的升高,各个免疫共刺激分子mRNA的峰值出现在不同的时间点,只有HLA-DR的峰值出现在SIV感染后第二周,其它免疫共刺激分子mRNA量的峰值均出现在SIV感染第5周之后。
这些结果说明,本实验所检测的7个免疫共刺激分子均与SIV感染的结果有着密切的关系,这些与AIDS疾病进展密切相关的分子表达的变化规律可能受到多种因素的复杂影响,其表达规律可能反映着疾病的进展规律。2中药复方艾可清对SIV感染猴免疫学、病理改变及病毒载量的影响
用SIVmac239感染12只恒河猴造成猴艾滋病模型,于感染第71天开始给药,分为模型对照组、艾可清高剂量组、艾可清低剂量组。艾可清高剂量组的给药剂量为0.4455g/kg.天,低剂量组给药剂量为：0.1485g/kg.天,灌胃给药。检测外周血CD4+、CD8+T细胞计数、病毒载量、免疫共刺激分子mRNA变化及浅表淋巴结病理变化。
结果显示,艾可清高剂量组在给药期间的时间点,CD4+T细胞计数较给药前明显上升,但停药后时间点呈下降趋势；说明艾可清对猴艾滋病模型外周血CD4+T细胞计数具有一定的改善作用。
在外周血SIV病毒载量方面,艾可清高、低剂量组均在给药8周时使SIV病毒载量明显下降；而在停药后各时间点则均有所回升。这说明艾可清高、低剂量组均对病毒载量有一定的抑制作用。
在外周浅表淋巴结病理检测方面,高剂量组的淋巴结病理结构在给药期间“好转”和“转坏”各半,在停药后保持稳定。
本研究检测了7种免疫共刺激分子mRNA量,结果显示,艾可清给药后能显著降低PD-1、IDO、HLA-DRmRNA的表达量。PD-1是促进免疫的重要免疫共刺激分子,IDO则在SIV感染猴血浆及内脏组织中显著升高,且与病毒载量有关:HLA-DR则是免疫活化的指标。因此艾可清降低这几种免疫共刺激分子的mRNA表达说明艾可清可能减轻了SIV导致的免疫激活的程度,从而改善SIV感染导致的免疫病理。全文结论
1SIV感染猴外周血CD4+T细胞、CD8+T细胞比例及细胞计数、CD4/CD8比值、SIV病毒载量在感染前后均出现明显变化。
2SIV感染猴外周血PBMC表达免疫共刺激分子CTLA-4、FOXP3、PD-1、IDO、HLA-DR、1COS、CD28的mRNA量出现了不同程的升高,各个免疫共刺激分子mRNA的峰值出现在不同的时间点,
3中药复方艾可清对猴艾滋病模型外周血CD4+T细胞计数具有一定的升高作用；对病毒载量有一定的降低作用,能够一定程度上改善猴艾滋病模型浅表淋巴结的病理表现。
4中药复方艾可清对猴艾滋病模型外周血PBMC分泌的PD-1、IDO及HLA-DRmRNA有显著降低作用。
There were 319 877 cases of HIV infected people and AIDS patients in China before October 31,2009. The AIDS patients are 102 323 cases in all of the people infected by HIV. The dead cases is up to 49 845. The AIDS epidemic of 2009 in China was evaluated by Ministry of health of P.R.C and UNAIDS combined with WHO. The results showed that Before the end of 2009, It is evaluated that there are 740,000 HIV infected cases (HIV/AIDS), the AIDS patients is up to 1050000. The de novo HIV infected cases up to 48000 cases. At present, the route of HIV transmission had changed from Drug abuse to 70% more through sexual transmission.
China had put much emphasis on the prevention and treatment of HIV/AIDS. All sorts of methods include Chinese Medicine were employed to treat the HIV/AIDS. The pilot programme of Chinese Medicine to treat HIV/AIDS was summarized and the results showed that Chinese Medicine have the favourable effect of immune modulation, clinical symptom improvement, quality of survive improvement and delayed the progression of disease. But there were also some problem to be face and solve. For example, How to objectively evaluate the effects of Chinese Medicine to treat HIV/AIDS? How to make a significant progress in the effects of Chinese Medicine to treat HIV/AIDS? What are the mechanism of the effects of Chinese Medicine to treat HIV/AIDS?
This research tests the immunological and virological items in peripheral blood in rhesus monkeys infected with SIV. The effects of the herb complex Ai Ke Qing to the immunological and virological items was observed.
1 The dynamic changes of immunological and virological items in peripheral blood in rhesus monkeys infected with SIV.
36 rhesus monkeys were infected with SIVmac239, blood routine, CD4+T cell counts and CD8+T cell counts in the peripheral blood, plasma viral load, PBMC costimulatory molecule mRNA quantity include CTLA-4、FOXP3、PD-1、IDC、HLA-DR、ICOS、CD28。
The results showed that the WBC counts did not significantly change before and after SIV infection. Both the CD4+T cell ratio and counts are up-regulated one week after SIV infection, but down-regulated two weeks after SIV infection, then fluctuate and maintained in a low level. The CD4+T cell ratio remained stable. But the CD4+T cell counts are tend to decrease gradually. The CD8+T cell ratio and counts are both up-regulated
in the second week after SIV infection, but down-regulated from three weeks after SIV infection. The lowest level occurred at 4 weeks after SIV infection but higher than the level before SIV infection. The CD8+T cell ratio and counts are a bit up at fifth week after SIV infection and then remained stable. The CD4/CD8 is down-regulated after one week after SIV infection and reached lowest level at the second week. Then the CD4/CD8 is up-regulate in third and forth week after SIV infection. But it is lower than the level of second week. The CD4/CD8 down-regulate again at fifth week and then remained stable.
The dynamic changes of plasma viral load are similar to the previous report. The summit occurred at second week after SIV infection and then decreased and fluctuate stable.
From these results we can conclude that the down-regulation extent of CD4+T cell counts is not very big compared with the level before infection. This may be because the down-regulation of CD4+T cell counts need a long time. Several weeks are insufficient for significantly down-regulation.
The results also showed that the mRNA levels of PBMC costimulatory molecule mRNA include TLA-4、FOXP3、PD-1、IDO、HLA-DR、ICOS、CD28 are significantly get up in different extent. The summits of these mRNA levels occurred in different time point. Only the mRNA summit level of HLA-DR is occurred in second week after SIV infection, all the others are occurred fifth week after SIV infection.
From the above experiments we can conclude that all of the seven costimulatory molecules are closely related to the SIV infection results. The expression rule of these costimulatory molecules may affected by complex factors. The rule of its expression may manifest the rule of HIV disease progression. 2The effects of Chinese herb complex Ai Ke Qing to the immunological, pathological changes and viral load of rhesus monkeys infected with SIV
12 rhesus monkeys infected with SIVmac239. After 71 days of SIV infection, the 12 monkeys were randomly divided into 3 groups, namely model control group, Ai Ke Qing high dose group and Ai Ke Qing low dose group and start intragastric administration according to the group. The high dose of Ai Ke Qing is 0.4455g/kg.d; The low dose of Ai Ke Qing is 0.1485g/kg.d. The CD4-T cell counts and CD8+T cell counts in the peripheral blood, plasma viral load, PBMC costimulatory molecule mRNA quantity and pathological changes in superficial lymph nodes.
The results showed that the CD4+T cell counts are increased in the time points during drug administration compared with the level before drug administration. But it tend to get down after drug withdrawal. So the Ai Ke Qing herb complex may have some effect on relief the CD4+T cell counts.
The plasma viral load of both the Ai Ke Qing high and low dose groups are significantly get down at the time point of eighth week after drug administration. But it back up at time points of drug cessation. These results revealed that both the Ai Ke Qing high and low dose group can inhibit the plasma viral load in some extent.
To the pathological changes in superficial lymph nodes, The high dose group showed 2 monkeys improved and 2 monkeys deteriorated during drug administration. Then the pathological changes remained stable after drug cessation.
This experiment tested 7 costimulatory molecule mRNA. The results showed that the mRNA levels of PD-1、IDO and HLA-DR are significantly inhibited by Ai Ke Qing herb complex.PD-1 is an important costimulatory molecule that can promote immune activation. But the IDO is increased in plasma and internal organ tissues and mainly related to plasma viral load. HLA-DR is a marker of immune activation. From these experiments we can conclude that the Ai Ke Qing herb complex may relief the immune activation state because it can inhibit the immune activation costimulatory molecule expression. So results in the improvement of immune pathological changes caused by SIV infection.
Conclusion
1 The CD4+T cell, CD8+T cell ratio and counts, CD4/CD8 in blood, SIV plasma viral load showed significant change in SIV infected rhesus monkeys.
2 The costimulatory molecules mRNA of CTLA-4、FOXP3、PD-1、IDO、HLA-DR、ICOS、CD28 are up-regulated in different extent. The summit levels of them are occurred in different time points.
3 The CD4+T cell counts can up-regulate in some extent through Ai Ke Qing administration; Ai Ke Qing also can decrease SIV plasma viral load and can improve the pathological changes in superficial lymph nodes in some extent.
4 The Ai Ke Qing herb complex can significantly decrease the mRNA levels of PD-1、IDO and HLA-DR in PBMC of rhesus monkeys infected with SIV.
我国近年来非常重视艾滋病的防治,积极发挥各方面的力量和手段,包括重视研究用中医来治疗艾滋病。在对中医药治疗艾滋病试点工作项目进行总结后,发现中医药治疗艾滋病在调节免疫功能、改善临床症状、提高生存质量、延缓病情进展等方面有较好疗效。然而也有很多问题需要解决,比如如何客观准确的评估中医在艾滋病治疗中的作用?如果使中医治疗艾滋病的疗效有所突破,不断进步?中医治疗艾滋病所起的疗效的机制何在?
本论文检测了用SIV感染恒河猴造成猴艾滋病模型外周血的免疫学指标、病毒学指标的变化情况,然后观察了中药复方艾可清对SIV感染前后变化明显的免疫学和病毒学指标的影响。
1SIV感染猴模型病毒、免疫指标的动态变化
用SIVmac239感染36只恒河猴,观察外周血指标检测包括血常规、CD4+T细胞、CDS+T细胞计数、血浆病毒载量；外周血PBMC免疫共刺激分子mRNA量,这些免疫共刺激分子包括：CTLA-4、FOXP3、PD-1、IDO、HLA-DR、ICOS、CD28。
实验结果显示,WBC计数在SIV感染之后并未出现明显变化；CD4+T细胞比例和计数在SIV感染1周后均升高,SIV感染2周时又下降,此后几周有所波动,但都维持在低水平；其中CD4+T细胞比例保持基本稳定,但CD4+T细胞计数有逐渐降低的趋势。CD8+T细胞比例和计数在SIV感染后第]周和第2周均较SIV感染前逐渐升高,至第3周开始下降,第4周降至最低(但仍高于SIV感染前),第5周又有所上升,此后保持基本稳定。CD4/CD8比例在SIV感染后1、2周开始下降,第2周降至最低,然后第3周开始回升,至第4周继续上升,但仍低于第2周；第5周又开始下降,此后保持基本稳定。
SIV感染猴的病毒载量则与文献报道基本一致,第二周上升达到最高,其后回落,开始波动,第5周后基本保持稳定的波动。
从这些实验结果可以看出,SIV感染猴的CD4+T细胞计数的下降与感染前比较其下降程度并不大,这可能是因为SIV感染导致的CD4+T细胞减少需要一个比较长的时间,在数周内并不能迅速降低。
实验结果显示,SIV感染后免疫共刺激分子CTLA-4、FOXP3、PD-1、IDO、HLA-DR、ICOS、CD28的mRNA量出现了不同程的升高,各个免疫共刺激分子mRNA的峰值出现在不同的时间点,只有HLA-DR的峰值出现在SIV感染后第二周,其它免疫共刺激分子mRNA量的峰值均出现在SIV感染第5周之后。
这些结果说明,本实验所检测的7个免疫共刺激分子均与SIV感染的结果有着密切的关系,这些与AIDS疾病进展密切相关的分子表达的变化规律可能受到多种因素的复杂影响,其表达规律可能反映着疾病的进展规律。2中药复方艾可清对SIV感染猴免疫学、病理改变及病毒载量的影响
用SIVmac239感染12只恒河猴造成猴艾滋病模型,于感染第71天开始给药,分为模型对照组、艾可清高剂量组、艾可清低剂量组。艾可清高剂量组的给药剂量为0.4455g/kg.天,低剂量组给药剂量为：0.1485g/kg.天,灌胃给药。检测外周血CD4+、CD8+T细胞计数、病毒载量、免疫共刺激分子mRNA变化及浅表淋巴结病理变化。
结果显示,艾可清高剂量组在给药期间的时间点,CD4+T细胞计数较给药前明显上升,但停药后时间点呈下降趋势；说明艾可清对猴艾滋病模型外周血CD4+T细胞计数具有一定的改善作用。
在外周血SIV病毒载量方面,艾可清高、低剂量组均在给药8周时使SIV病毒载量明显下降；而在停药后各时间点则均有所回升。这说明艾可清高、低剂量组均对病毒载量有一定的抑制作用。
在外周浅表淋巴结病理检测方面,高剂量组的淋巴结病理结构在给药期间“好转”和“转坏”各半,在停药后保持稳定。
本研究检测了7种免疫共刺激分子mRNA量,结果显示,艾可清给药后能显著降低PD-1、IDO、HLA-DRmRNA的表达量。PD-1是促进免疫的重要免疫共刺激分子,IDO则在SIV感染猴血浆及内脏组织中显著升高,且与病毒载量有关:HLA-DR则是免疫活化的指标。因此艾可清降低这几种免疫共刺激分子的mRNA表达说明艾可清可能减轻了SIV导致的免疫激活的程度,从而改善SIV感染导致的免疫病理。全文结论
1SIV感染猴外周血CD4+T细胞、CD8+T细胞比例及细胞计数、CD4/CD8比值、SIV病毒载量在感染前后均出现明显变化。
2SIV感染猴外周血PBMC表达免疫共刺激分子CTLA-4、FOXP3、PD-1、IDO、HLA-DR、1COS、CD28的mRNA量出现了不同程的升高,各个免疫共刺激分子mRNA的峰值出现在不同的时间点,
3中药复方艾可清对猴艾滋病模型外周血CD4+T细胞计数具有一定的升高作用；对病毒载量有一定的降低作用,能够一定程度上改善猴艾滋病模型浅表淋巴结的病理表现。
4中药复方艾可清对猴艾滋病模型外周血PBMC分泌的PD-1、IDO及HLA-DRmRNA有显著降低作用。
There were 319 877 cases of HIV infected people and AIDS patients in China before October 31,2009. The AIDS patients are 102 323 cases in all of the people infected by HIV. The dead cases is up to 49 845. The AIDS epidemic of 2009 in China was evaluated by Ministry of health of P.R.C and UNAIDS combined with WHO. The results showed that Before the end of 2009, It is evaluated that there are 740,000 HIV infected cases (HIV/AIDS), the AIDS patients is up to 1050000. The de novo HIV infected cases up to 48000 cases. At present, the route of HIV transmission had changed from Drug abuse to 70% more through sexual transmission.
China had put much emphasis on the prevention and treatment of HIV/AIDS. All sorts of methods include Chinese Medicine were employed to treat the HIV/AIDS. The pilot programme of Chinese Medicine to treat HIV/AIDS was summarized and the results showed that Chinese Medicine have the favourable effect of immune modulation, clinical symptom improvement, quality of survive improvement and delayed the progression of disease. But there were also some problem to be face and solve. For example, How to objectively evaluate the effects of Chinese Medicine to treat HIV/AIDS? How to make a significant progress in the effects of Chinese Medicine to treat HIV/AIDS? What are the mechanism of the effects of Chinese Medicine to treat HIV/AIDS?
This research tests the immunological and virological items in peripheral blood in rhesus monkeys infected with SIV. The effects of the herb complex Ai Ke Qing to the immunological and virological items was observed.
1 The dynamic changes of immunological and virological items in peripheral blood in rhesus monkeys infected with SIV.
36 rhesus monkeys were infected with SIVmac239, blood routine, CD4+T cell counts and CD8+T cell counts in the peripheral blood, plasma viral load, PBMC costimulatory molecule mRNA quantity include CTLA-4、FOXP3、PD-1、IDC、HLA-DR、ICOS、CD28。
The results showed that the WBC counts did not significantly change before and after SIV infection. Both the CD4+T cell ratio and counts are up-regulated one week after SIV infection, but down-regulated two weeks after SIV infection, then fluctuate and maintained in a low level. The CD4+T cell ratio remained stable. But the CD4+T cell counts are tend to decrease gradually. The CD8+T cell ratio and counts are both up-regulated
in the second week after SIV infection, but down-regulated from three weeks after SIV infection. The lowest level occurred at 4 weeks after SIV infection but higher than the level before SIV infection. The CD8+T cell ratio and counts are a bit up at fifth week after SIV infection and then remained stable. The CD4/CD8 is down-regulated after one week after SIV infection and reached lowest level at the second week. Then the CD4/CD8 is up-regulate in third and forth week after SIV infection. But it is lower than the level of second week. The CD4/CD8 down-regulate again at fifth week and then remained stable.
The dynamic changes of plasma viral load are similar to the previous report. The summit occurred at second week after SIV infection and then decreased and fluctuate stable.
From these results we can conclude that the down-regulation extent of CD4+T cell counts is not very big compared with the level before infection. This may be because the down-regulation of CD4+T cell counts need a long time. Several weeks are insufficient for significantly down-regulation.
The results also showed that the mRNA levels of PBMC costimulatory molecule mRNA include TLA-4、FOXP3、PD-1、IDO、HLA-DR、ICOS、CD28 are significantly get up in different extent. The summits of these mRNA levels occurred in different time point. Only the mRNA summit level of HLA-DR is occurred in second week after SIV infection, all the others are occurred fifth week after SIV infection.
From the above experiments we can conclude that all of the seven costimulatory molecules are closely related to the SIV infection results. The expression rule of these costimulatory molecules may affected by complex factors. The rule of its expression may manifest the rule of HIV disease progression. 2The effects of Chinese herb complex Ai Ke Qing to the immunological, pathological changes and viral load of rhesus monkeys infected with SIV
12 rhesus monkeys infected with SIVmac239. After 71 days of SIV infection, the 12 monkeys were randomly divided into 3 groups, namely model control group, Ai Ke Qing high dose group and Ai Ke Qing low dose group and start intragastric administration according to the group. The high dose of Ai Ke Qing is 0.4455g/kg.d; The low dose of Ai Ke Qing is 0.1485g/kg.d. The CD4-T cell counts and CD8+T cell counts in the peripheral blood, plasma viral load, PBMC costimulatory molecule mRNA quantity and pathological changes in superficial lymph nodes.
The results showed that the CD4+T cell counts are increased in the time points during drug administration compared with the level before drug administration. But it tend to get down after drug withdrawal. So the Ai Ke Qing herb complex may have some effect on relief the CD4+T cell counts.
The plasma viral load of both the Ai Ke Qing high and low dose groups are significantly get down at the time point of eighth week after drug administration. But it back up at time points of drug cessation. These results revealed that both the Ai Ke Qing high and low dose group can inhibit the plasma viral load in some extent.
To the pathological changes in superficial lymph nodes, The high dose group showed 2 monkeys improved and 2 monkeys deteriorated during drug administration. Then the pathological changes remained stable after drug cessation.
This experiment tested 7 costimulatory molecule mRNA. The results showed that the mRNA levels of PD-1、IDO and HLA-DR are significantly inhibited by Ai Ke Qing herb complex.PD-1 is an important costimulatory molecule that can promote immune activation. But the IDO is increased in plasma and internal organ tissues and mainly related to plasma viral load. HLA-DR is a marker of immune activation. From these experiments we can conclude that the Ai Ke Qing herb complex may relief the immune activation state because it can inhibit the immune activation costimulatory molecule expression. So results in the improvement of immune pathological changes caused by SIV infection.
Conclusion
1 The CD4+T cell, CD8+T cell ratio and counts, CD4/CD8 in blood, SIV plasma viral load showed significant change in SIV infected rhesus monkeys.
2 The costimulatory molecules mRNA of CTLA-4、FOXP3、PD-1、IDO、HLA-DR、ICOS、CD28 are up-regulated in different extent. The summit levels of them are occurred in different time points.
3 The CD4+T cell counts can up-regulate in some extent through Ai Ke Qing administration; Ai Ke Qing also can decrease SIV plasma viral load and can improve the pathological changes in superficial lymph nodes in some extent.
4 The Ai Ke Qing herb complex can significantly decrease the mRNA levels of PD-1、IDO and HLA-DR in PBMC of rhesus monkeys infected with SIV.
引文
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