髓样抑制细胞在慢性HBV感染的具有高水平乙型肝炎表面抗原

StephenW

Aliment Pharmacol Ther. 2019 Apr 15. doi: 10.1111/apt.15226. [Epub ahead of print]
Myeloid-derived suppressor cells induce regulatory T cells in chronically HBV infected patients with high levels of hepatitis B surface antigen and persist after antiviral therapy.
Pal S1, Nandi M1, Dey D1, Chakraborty BC1, Shil A1, Ghosh S2, Banerjee S1, Santra A1, Ahammed SKM3, Chowdhury A3, Datta S1.
Author information

1
    Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
2
    Human Genetics Unit, Indian Statistical Institute, Kolkata, India.
3
    Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.

Abstract
BACKGROUND:

CD4+ regulatory T-cells (Tregs) expand during chronic hepatitis B virus (HBV) infection and inhibit antiviral immunity, although the underlying mechanism remains largely elusive. Myeloid-derived suppressor cells (MDSC) have been linked with T-cell dysfunction but questions remain regarding their persistence/profile/function in chronically HBV infected patients.
AIM:

To characterise MDSC in different phases of chronic HBV infection namely, immune-tolerant (IT), hepatitis B e-antigen-positive chronic hepatitis B (EP-CHB), inactive carriers (IC) and hepatitis B e-antigen-negative chronic hepatitis B (EN-CHB), to investigate their role in Treg induction and evaluate the effect of anti-viral therapy on these cells.
METHODS:

Multiparametric flow cytometry, cell-sorting and co-culture assays were performed along with longitudinal immune monitoring of CHB patients receiving tenofovir.
RESULTS:

HLA-DR- CD11b+ CD33hi -Monocytic-MDSC (M-MDSC) were enhanced in IT, EP-CHB and EN-CHB compared with IC, and this was related to increasing hepatitis B surface antigen (HBsAg) concentration. IT and EP-/EN-CHB displayed elevated frequency of CD4+ CD25+ FOXP3+ Treg that positively correlated with that of M-MDSC. However, both M-MDSC and HLA-DR- CD11b+ CD33low -granulocytic-MDSC from IT and EP-/EN-CHB expressed high transforming growth factor beta (TGF-β) and interleukin-10 (IL-10). Co-culture of sorted HLA-DR- CD33+ -MDSC with autologous MDSC depleted-PBMC from IT and CHB but not from IC, increased CD4+ CD25+ FOXP3+ -iTreg and CD4+ FOXP3- IL-10+ -Tr1-cells through a cell-contact independent mechanism. While MDSC-derived TGF-β and IL-10 promoted development of iTreg, only IL-10 appeared to be crucial for Tr1 induction. One year of tenofovir treatment failed to normalise MDSC frequency/function or reduce Treg percentage and serum HBsAg levels, despite reduction in viral load.
CONCLUSIONS:

We established a previously unrecognised role of MDSC in Treg development in IT and EP-/EN-CHB via TGF-β/IL-10-dependent pathways and both cell-types persisted after anti-viral therapy. Hence, therapeutic targeting of MDSC or reducing circulating HBsAg level together with tenofovir-therapy might be more effective in restricting HBV persistence and disease progression.

© 2019 John Wiley & Sons Ltd.

PMID:
    30982998
DOI:
    10.1111/apt.15226

StephenW

Aliment Pharmacol Ther。 2019年4月15日.doi：10.1111 / apt.15226。 [印刷前的电子版]
髓样抑制细胞在慢性HBV感染的具有高水平乙型肝炎表面抗原的患者中诱导调节性T细胞，并且在抗病毒治疗后持续存在。
Pal S1，Nandi M1，Dey D1，Chakraborty BC1，Shil A1，Ghosh S2，Banerjee S1，Santra A1，Ahammed SKM3，Chowdhury A3，Datta S1。
作者信息

1
    印度加尔各答研究生医学教育与研究所肝脏研究中心，消化和肝病学院。
2
    人类遗传学部，印度统计研究所，印度加尔各答。
3
    印度加尔各答研究生医学教育与研究所消化和肝病学院肝病学系。

抽象
背景：

CD4 +调节性T细胞（Tregs）在慢性乙型肝炎病毒（HBV）感染期间扩增并抑制抗病毒免疫，尽管潜在的机制仍然很难实现。髓样抑制细胞（MDSC）与T细胞功能障碍有关，但长期HBV感染患者的持续性/特征/功能仍有疑问。
目标：

在慢性HBV感染的不同阶段表征MDSC，即免疫耐受（IT），乙型肝炎e抗原阳性慢性乙型肝炎（EP-CHB），非活动性携带者（IC）和乙型肝炎e抗原阴性慢性肝炎B（EN-CHB），研究它们在Treg诱导中的作用并评估抗病毒疗法对这些细胞的作用。
方法：

进行多参数流式细胞术，细胞分选和共培养测定以及接受替诺福韦的CHB患者的纵向免疫监测。
结果：

与IC相比，HLA-DR-CD11b + CD33hi -Monocytic-MDSC（M-MDSC）在IT，EP-CHB和EN-CHB中增强，这与增加的乙型肝炎表面抗原（HBsAg）浓度有关。 IT和EP- / EN-CHB显示CD4 + CD25 + FOXP3 + Treg的频率升高，其与M-MDSC的频率正相关。然而，来自IT和EP- / EN-CHB的M-MDSC和HLA-DR-CD11b + CD33low-粒细胞-MDSC均表达高转化生长因子β（TGF-β）和白细胞介素-10（IL-10）。分选的HLA-DR-CD33 + -MDSC与来自IT和CHB但不来自IC的自体MDSC耗尽的PBMC共培养，通过细胞接触增加CD4 + CD25 + FOXP3 + -iTreg和CD4 + FOXP3-IL-10 + -Tr1-细胞独立机制。虽然MDSC衍生的TGF-β和IL-10促进iTreg的发展，但只有IL-10似乎对Tr1诱导至关重要。尽管病毒载量减少，但是一年的替诺福韦治疗未能使MDSC频率/功能正常化或降低Treg百分比和血清HBsAg水平。
结论：

我们通过TGF-β/ IL-10依赖性途径在IT和EP- / EN-CHB中建立了MDSC在Treg发展中的先前未被认识的作用，并且两种细胞类型在抗病毒治疗后持续存在。因此，MDSC的治疗靶向或降低循环HBsAg水平与替诺福韦治疗可能在限制HBV持续性和疾病进展方面更有效。

©2019 John Wiley＆Sons Ltd.

结论：
    30982998
DOI：
    10.1111 / apt.15226