Circulating Tregs Correlate with Viral Load Reduction in Chronic HBV-Treated Patients with Tenofovir Disoproxil Fumarate
Circulating Tregs Correlate with Viral Load Reduction in Chronic HBV-Treated Patients with Tenofovir Disoproxil Fumarate
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DOI：
10.1007/s10875-011-9509-7
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发表时间：
2011-06-01
影响因子：
9.1
通讯作者：
Sarin, Shiv Kumar
中科院分区：
文献类型：
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作者：
TrehanPati, Nirupma;Kotillil, Shyam;Sarin, Shiv Kumar
目前对乙肝病毒药物的反应有限可能是由于宿主细胞毒性细胞反应不足所致。循环中的Tregs已被证明与乙肝病毒感染的慢性化有关，但其在抗病毒治疗中的分布尚未被研究。分析了替诺福韦300 mg/d治疗的35例慢性乙型病毒性肝炎EAG-Ve和EAG+Ve细胞免疫应答的频率及其对细胞免疫应答的影响。检测外周血单个核细胞(PBMCs)在无Tregs或无Tregs的情况下，经HBcAg或HBcAg刺激及阻断PD-1/PDL-1后，Tregs在细胞因子分泌细胞中的频率及其调节作用。治疗前，EAG患者HBVDNA水平降低，CD8T细胞减少，Tregs增加，T细胞表达PD1。治疗12周后，两组均可观察到~gt；2log乙肝病毒的减少，同时两组EAG患者的CD8T细胞频率增加，趋化因子受体/Toll样受体的表达增加。治疗过程中两组患者PBMCs CD8细胞上PD-1表达均降低，而Tregs上PD-1表达无明显变化。EAG-VE组Tregs持续升高至12周，24周时下降。在两组患者中，24周后，去除PBMC中的CD_4(+)CD_(25)(+)Tregs可增强乙肝病毒特异性T细胞应答，阻断PD-1/PDL_1通路对EAG+VE患者的促炎细胞因子的产生有促进作用，但对EAG-VE患者无影响。我们的结论是，在EAG病患者体内，由乙肝病毒复制诱导的Tregs更多地扩大。替诺福韦降低HBVDNA部分恢复了获得性免疫反应，也减少了Tregs。在EAG+VE患者中，PD-1/PDL1被阻断，细胞因子的产生增加，而在EAG-VE患者中则没有，提示EAG+VE和EAG-VE患者参与了明显不同的免疫机制。
Limited response to current hepatitis B virus (HBV) drugs is possibly due to inadequate host cytotoxic cellular responses. Circulating Tregs have been shown to be associated with chronicity of HBV infection, but their profile during antiviral therapy has not been studied. We analyzed the frequency and effect of Tregs on cellular immune responses against HBV in 35 chronic hepatitis B eAg-ve and eAg+ve patients treated with tenofovir 300 mg/day. Frequency of Tregs and their modulatory role in cytokine-secreting cells were determined after stimulation with HBsAg or HBcAg in the absence or presence of Tregs and after blockage of PD-1/PDL-1 in peripheral blood mononuclear cells (PBMCs). Prior to therapy, eAg-ve patients had lower HBV DNA levels, reduced CD8 T cells, increased Tregs, and T cells expressing PD1. After 12 weeks of therapy, > 2 log HBV viral reduction was observed in both groups, along with an increase frequencies of CD8 T cells in eAg-ve patients and increased expression of chemokine receptors/Toll-like receptors in both groups. PD-1 expression on CD8 cells in PBMCs was decreased in both groups during therapy but not on Tregs. In eAg-ve group, sustained increase of Tregs was observed till week 12, which declined at week 24. In both groups, after 24 weeks, depletion of CD4(+)CD25(+) Tregs from PBMCs enhanced HBV-specific T cell responses, and blockage of PD-1/PDL1 pathway did enhance pro-inflammatory cytokine production in eAg+ve patients but not in eAg-ve. We conclude that Tregs induced by HBV replication in vivo are expanded in eAg-ve patients more. Reduction in HBV DNA by tenofovir partially restored adaptive immune responses and also reduced the Tregs. Blockage of PD-1/PDL1, enhanced cytokine production in eAg+ve patients but not in eAg-ve, suggests that distinctly different immunologic mechanisms are involved in eAg+ve and eAg-ve patients.