艾滋病HAART治疗免疫重建炎性综合征的免疫机制初步研究

目的 为探讨我国艾滋病病人(AIDS)启动高效抗反转录病毒治疗(HAART)后,发生免疫重建炎性综合征(IRIS)的免疫学发病机制,在前瞻性研究队列中对启动HAART的AIDS病人部分淋巴细胞亚群、调节性T细胞和部分Th1和Th2细胞因子等进行追踪分析.方法 将接受HAART初始治疗的238例AIDS病人建立前瞻性研究队列,分为在24周内发生IRIS的47例病人(IRIS组)和未发生IRIS的191例病人(非IRIS组).在HAART的0周、12周和24周采集两组血标本,对47例IRIS病例及随机选择的50例非IRIS病例进行免疫机制的研究分析,检测HIV病毒载量和CD4+细胞计数;使用流式细胞术检测部分淋巴细胞亚群和调节性T细胞(CD4+CD25+Foxp3+).在HAART的0周、4周、12周、24周及发生IRIS时分别采集全部238例患者的血标本,使用ELISA法测定血浆细胞因子IL-2、IFN-γ、IL-4、IL-10以及IL-7水平.结果 两组感染者的CD4+、CD8+纯真细胞和记忆细胞比例在0周、12周、24周及发生IRIS时比较差异均无统计学意义,但CD4+记忆细胞和CD8+记忆细胞比例在启动HAART后均明显上升.两组感染者CD4+CD38+活化细胞和CD8+CD38+活化细胞比例在基线时均较正常值明显升高,治疗后均有下降趋势.在0周、12周、24周及发生IRIS时CD4+CD25+Foxp3+调节性T细胞在IRIS组中均较非IRIS组要低.两组IL-2及IFN-γ在HAART后均呈上升趋势,且IRIS组在4周及发生IRIS时更明显高于非IRIS组;两组IL-4及IL-10在HAART后均呈下降趋势,IRIS组中IL-10在4周及发生IRIS时更明显低于非IRIS组.IL-7在两组中基线时均较正常值升高,并随HAART进程逐渐降低,其中IRIS组在各随访点IL-7均要高于非IRIS组.结论 接受HAART治疗者早期即出现记忆T细胞快速上升,在IRIS炎症反应中可能起重要作用.IL-2、IL-10和IFN-γ在发生IRIS时的水平差别,提示IRIS的发生与炎性细胞因子大量增加,炎性抑制因子相对不足有一定关系.IL-7也可能参与到IRIS的发病机制中.

Abstract：

Objective To investigate the immunological pathogenesis of immune reconstitution inflammatory syndrome (IRIS) during highly active antiretroviral therapy( HAART), in this prospective cohort study we analyzed the lymphocyte subsets, lymphocyte activation, changes in regulatory T cells, and levels of Th1 and Th2 cytokines in both IRIS and non-IRIS groups. Methods Two hundred and thirty-eight AIDS patients received HAART and participated prospective research cohort for 24 weeks follow-up. Forty-seven IRIS cases and 191 non-IRIS cases were enrolled in the IRIS group or non-IRIS group respectively. Blood samples were collected in both groups at pre- and post-HAART 12 weeks, 24 weeks. Using flow cytometer to detect the immunophenotypes of lymphocyte subsets (CD4 + CD45RA+ CD62L+, CD8+ CD45RA+ CD62L+naive T cells; CD4+ CD45RO+, CD8+ CD45RO+ memory T cells), activated T lymphocytes (CD4+CD38 +, CD8 + CD38 + cells), and regulatory T cell ( CD4 + CD25 + Foxp3 + ). Blood samples collected at pre-and post-HAART4 weeks, 12 weeks, 24 weeks and used ELISA to detect IL-2, IFN-γ, IL-4, IL-10and IL-7 cytokine serum levels. Results The percentages of CD4 + and CD8 + naive T cells and mlemory T cells exhibited no significant differences at the baseline, 12 weeks, 24 weeks of HAART initiation between both groups, but CD4 + and CD8 + memory T cells were demonstrated a trend towards to increase while compared to baseline during HAART. The percentages of CD4 + and CD8 + activated T cells are significantly higher at the baseline while compared to normal control and demonstrated a downward trend, but between both groups showed no significant difference. The percentages of CD4 + regulatory T cell was lower in IRIS group than non-IRIS group at the baseline, 12 weeks, 24 weeks and the onset of IRIS. Th1 cytokines, IL-2 and IFN-γshowed an upward trend during HAART at the levels of IRIS group had significantly increased at 4 weeks and the onset of IRIS. Th2 cytokines, IL-4 and IL-10 showed a downward trend during HAART,and the levels of IL-10 in IRIS group had significantly decreased at 4 weeks and the onset of IRIS. IL-7 was higher than normal control at the baseline in two groups and showed a downward trend during HAART. The level of IL-7 was higher than non-IRIS group at all follow-up points. Conclusion Memory T cells appear rapid increase in the early stage of HAART and may play a significant role in the inflammatory response of IRIS. CD4 + and CD8 + naive T cells, memory T cells and activated T cells showed no significant difference between IRIS and non-IRIS group within 24 weeks after HAART started. There was a significant reduction in the frequency of regulatory T cells in IRIS group without obvious upward trend during HAART, suggesting that the immune suppression function of regulatory T cells in IRIS was impaired. IL-2 and IFN-γ significantly increased while IL-10 significantly decreased at 4 weeks post-HAART initiation and onset of IRIS in IRISgroup than non-IRIS group, suggested that IRIS was related to cytokines environment disorder. That is, a significant increase in inflammatory cytokines, while the relative lack of non-inflammatory cytokines. The level of IL-7 decreased gradually after HAART started, and it was higher in IRIS group when compared to non-IRIS group in the first 24 weeks after HAART started. Also IL-7 may play a role in the pathogenesis of IRIS.

Study on immune mechanisms of HAART associated immune reconstitution inflammatory syndrome in AIDS

Objective To investigate the immunological pathogenesis of immune reconstitution inflammatory syndrome (IRIS) during highly active antiretroviral therapy( HAART), in this prospective cohort study we analyzed the lymphocyte subsets, lymphocyte activation, changes in regulatory T cells, and levels of Th1 and Th2 cytokines in both IRIS and non-IRIS groups. Methods Two hundred and thirty-eight AIDS patients received HAART and participated prospective research cohort for 24 weeks follow-up. Forty-seven IRIS cases and 191 non-IRIS cases were enrolled in the IRIS group or non-IRIS group respectively. Blood samples were collected in both groups at pre- and post-HAART 12 weeks, 24 weeks. Using flow cytometer to detect the immunophenotypes of lymphocyte subsets (CD4 + CD45RA+ CD62L+, CD8+ CD45RA+ CD62L+naive T cells; CD4+ CD45RO+, CD8+ CD45RO+ memory T cells), activated T lymphocytes (CD4+CD38 +, CD8 + CD38 + cells), and regulatory T cell ( CD4 + CD25 + Foxp3 + ). Blood samples collected at pre-and post-HAART4 weeks, 12 weeks, 24 weeks and used ELISA to detect IL-2, IFN-γ, IL-4, IL-10and IL-7 cytokine serum levels. Results The percentages of CD4 + and CD8 + naive T cells and mlemory T cells exhibited no significant differences at the baseline, 12 weeks, 24 weeks of HAART initiation between both groups, but CD4 + and CD8 + memory T cells were demonstrated a trend towards to increase while compared to baseline during HAART. The percentages of CD4 + and CD8 + activated T cells are significantly higher at the baseline while compared to normal control and demonstrated a downward trend, but between both groups showed no significant difference. The percentages of CD4 + regulatory T cell was lower in IRIS group than non-IRIS group at the baseline, 12 weeks, 24 weeks and the onset of IRIS. Th1 cytokines, IL-2 and IFN-γshowed an upward trend during HAART at the levels of IRIS group had significantly increased at 4 weeks and the onset of IRIS. Th2 cytokines, IL-4 and IL-10 showed a downward trend during HAART,and the levels of IL-10 in IRIS group had significantly decreased at 4 weeks and the onset of IRIS. IL-7 was higher than normal control at the baseline in two groups and showed a downward trend during HAART. The level of IL-7 was higher than non-IRIS group at all follow-up points. Conclusion Memory T cells appear rapid increase in the early stage of HAART and may play a significant role in the inflammatory response of IRIS. CD4 + and CD8 + naive T cells, memory T cells and activated T cells showed no significant difference between IRIS and non-IRIS group within 24 weeks after HAART started. There was a significant reduction in the frequency of regulatory T cells in IRIS group without obvious upward trend during HAART, suggesting that the immune suppression function of regulatory T cells in IRIS was impaired. IL-2 and IFN-γ significantly increased while IL-10 significantly decreased at 4 weeks post-HAART initiation and onset of IRIS in IRISgroup than non-IRIS group, suggested that IRIS was related to cytokines environment disorder. That is, a significant increase in inflammatory cytokines, while the relative lack of non-inflammatory cytokines. The level of IL-7 decreased gradually after HAART started, and it was higher in IRIS group when compared to non-IRIS group in the first 24 weeks after HAART started. Also IL-7 may play a role in the pathogenesis of IRIS.