CD4^+调节性T细胞在再生障碍性贫血免疫发病中的作用

Role of CD4^+T regulatory in immune pathophysiology of aplastic anemia

目的探讨CD4+调节性T细胞(Tregul atory,Treg)在再生障碍性贫血(aplasticanemia,AA)免疫发病机制中的作用。方法对2005年7月至2006年3月苏州大学附属第一医院23例发病期AA患者、10例恢复期AA患者及15名正常对照者测定骨髓中CD4+CD25+Treg、CD4+CTLA-4+Treg、CD4+PD-1+Treg、CD3+CD8-IL-10+Treg、CD3+CD8-TGF-β1+Treg、CD3+CD8-IL-4+Treg变化,分析其与免疫启动因素CD28及免疫效应因素干扰素-γ(IFN-γ)的关系。结果AA发病期、恢复期及正常对照组CD4+CD25+Treg数比较差异无显著性意义;AA发病期CD4+CTLA-4+Treg表达较对照组明显下降,PD-1与对照组比较差异无显著性意义;AA恢复期CD4+CT-LA-4+Treg及PD-1表达均较发病期明显升高,与对照组相当;AA恢复期患者IFN-γ较发病期明显下降(P=0.021),与正常对照组相当(P=0.402),IL-4、TGF-β及IL-10与AA发病组及对照组比较差异均无显著性意义;AA发病期患者骨髓CD3+CD4+T淋巴细胞膜表面CD28表达较正常对照组明显增加;AA恢复期患者的CD28表达率较发病期显著降低,亦低于正常对照组(P=0.048)。AA发病期CD4+CTLA-4+Treg明显下降,其余Treg无显著变化;AA恢复期CD4+CTLA-4+Treg、CD4+PD-1+Treg升高显著。CD28/CTLA-4、CD28/PD-1发病期与对照组比,均显著升高;AA恢复期为明显低于发病期,与对照组相当。IFN-γ+/IL-4+、IFN-γ+/TGF-β+及IFN-γ+/IL-10+发病期较对照组均显著升高;AA恢复期明显低于发病期,而与对照组相当。结论在免疫应答起始阶段或效应阶段,AA正性调控共刺激因子表达增加,而负性调控共刺激因子表达减少或无变化,使免疫平衡向持续增强偏移,调节性因素增高利于造血恢复;对于增强的免疫应答,AA的CD4+Treg呈下降趋势,可能与发病有关。

Objective To explore the possible immune pathophysiology of CD4 ^＋T regulatory（ CD4 ^＋ Treg）in acquired aplastic anemia（AA）. Methods The levels of CD4 ^＋ CD25 ^＋ Treg, CD4 ^＋ CTLA-4^＋ Treg,CD4^＋ PD-1^＋ Treg、CD3 ^＋ CD8^ - IL-10^＋ Treg ,CD3 ^＋ CD8^ - TGF-β1^＋ Treg,CD3^＋ CD8^ - IL-4 ^＋ Treg in the bone marrow of 23 cases of AA at active phase, 10 cases of AA at recovery phase and 15 normal controls were measured, and the relationship between CD4 ^＋ Treg and priming immune factor-CD28 or effective immune factor-IFN-γ was also evaluated respectively. Results Contrast to normal controls, while CD4^＋ CTLA-4 ^＋ Treg of AA at active phase decreased markedly, levels of other CD4 ^＋ Treg ： CD4 ^＋ CD25^＋ Treg, CD4 ^＋ PD-1 ^＋ Treg, CD3 ^＋ CD8 ^- IL-10 ^＋ Treg, CD3 ^＋ CD8 ^- TGF-β1^＋ Treg and CD3^ ＋ CD8 ^- IL-4 ^＋ Treg did not change significantly. Contrast to normal controls, the ratio of membrance costimulatory of CD28/CTLA-4 and CD28/PD-1 were all increases significantly in AA at active phase;the ratio of cytokines in cell plasma of IFN-γ/IL-4, IFN-γ/TGF-β, and IFN-γ/IL-10 were also increased significantly. Conclusion In AA, not only at priming stage but also at effective stage, the positive costimulatory increased while the negative regulatory costimulatory decreases or dose not change, which shifted the immune balance to intensification. That the CD4^＋ Treg does not expand to control the intensified immune reaction might be one of immunopathgenesis of AA.