AASLD序贯治疗替诺加干扰素提高树突状细胞和CD8+ T细胞的S

StephenW

序贯治疗替诺福韦加干扰素提高树突状细胞和CD8 + T细胞的功能,显着减少 PD-1,
相比
替诺福韦单药治疗
*TITLE: *Sequential Therapy with Tenofovir plus Peg Interferon Improves Dendritic Cell and CD8 T cell Functions by Significant Reduction in PD-1 Compared with Tenofovir Monotherapy in Chronic Hepatitis B (CHB) Patients

*AUTHORS (FIRST NAME, LAST NAME): *_Nirupma Trehanpati_^1 , Arshi Khanam^1 , Tarandeep Singh^1 , Ankit Bhardwaj^1 , Ankur Jindal^2 , Syed Hissar^1 , Shiv K. Sarin^1, 2

*Institutional Author(s): *

*INSTITUTIONS (ALL): *1. Research, Institute of liver and biliary sciences, New Delhi, India.
2. Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.

*ABSTRACT BODY: *Background: Dendritic cells (DCs) are antigen presenting cells, responsible for initiating antiviral immunity and induction of T cell mediated response. Functional defects have been observed in DCs of CHB patients. Reduction in HBV viral load alone or followed by addition of interferon (sequential therapy) to enhance immune modulation are logical strategies to achieve rapid and effective HBV clearance.
Aim: To investigate relative functional restoration of DCs in HBeAg+ve CHB patients, receiving Tenofovir mono-therapy and tenofovir plus pegylated interferon (Peg-IFN) sequential therapy.
Methods: Sixty histologically proven CHB patients were recruited and randomly divided into two groups; Group1(n=36) received Tenofovir 300mg/day monotherapy for the 48 weeks and Group 2 (n=24) received Tenofovir alone till week 12, followed by Tenofovir+ Peg-IFN till week 36 and subsequently tenofovir till week 48. PBMCs were isolated from patients at baseline and 24 week. Frequency of circulating myeloid (mDCs) and plasmacytoid dendritic cells (pDCs), costimulatory molecules CD80, CD83, toll like receptor TLR7,TLR 9 and CCR7 was analysed on DCs by flow cytometery. In vitro generated immature DCs were stimulated with resiquimod (TLR7/8 agonist) and CPG oligonucleotide (TLR9 agonist) and IFN-alpha and TNF-alpha level was measured. Phagocytic assay was performed to analyse antigen uptake by DCs. Results: More than 2 Log HBV DNA reductions was observed in both groups at week 24. No difference in frequencies of mDCs and pDCs was observed at baseline and 24 week. Sequential therapy significantly increased the frequency of CD8 T cells (p=0.02), memory T cells (CD8+CD127+) (p=0.03) and decreased programmed death-1(PD1) expression on CD8 T cells (p=0.03) compared with tenofovir monotherapy in CHB patients. CD80 and 83 expression was increased in both groups.CCR7 expression on mDCs and HLA- DR expression required for antigen presentation was upregulated in both groups at 24 weeks compared to baseline (p<0.05). Significant (<0.05) increase in TLR9 but not TLR7 expression on mDCs was observed in group 2. Phagocytic activity of DCs was enhanced from baseline in group 1 (9.5%vs61.4% p= 0.05) and 2 (8.9%vs.21.6% p= 0.08). IFN-alpha and TNF-alpha production by mDCs and pDCs improved at week 24 in both groups.
Conclusion: Improved functionality of dendritic cells with tenofovir monotherapy as well as sequential therapy is related to reduction in HBV DNA levels. Sequential therapy using PEG IFN was significantly superior in restoring CD8 T cell mediated immunity and TLR9 functions on DCs. Our results support the role of immune restoration and modulation in HBV clearance using sequential therapy.

StephenW

背景：树突状细胞（DCs）的抗原递呈细胞，负责启动抗病毒免疫和诱导T细胞介导的​​反应。已观察到的CHB患者的DC功能缺陷。减少HBV病毒载量或之后加入干扰素序贯治疗，以提高免疫功能的调节是合乎逻辑的策略，以达到快速和有效的病毒清除。
相对区议会功能恢复的
目的：研究在HBeAg + CHB患者，接受替诺福韦单药和替诺福韦加聚乙二醇干扰素（PEG-IFN）序贯治疗。
招募和方法：60例病理证实为慢性乙型肝炎患者，随机分为两组，1组（n = 36）接受替诺福韦的300mg/day单药治疗48周和第2组（n = 24）替诺福韦单独直到第12周，其次是替诺福韦+ PEG-IFN至第36周，随后替诺福韦至48周。从在基线和24周患者分离PBMCs。频率的流通髓细胞性（MDCS），和浆细胞样树突状细胞（PDC）的共刺激分子CD80，CD83，Toll样TLR受体TLR7，9和CCR7的DC，流式细胞仪分析。在体外培养产生的未成熟的DC刺激resiquimod（TLR7 / 8激动剂）和CPG寡核苷酸（TLR9激动剂）和IFN-a和TN-a水平测量。吞噬试验区议会进行分析抗原的吸收。结果：超过2登录HBV DNA减少观察24周时，在这两个群体。无差异的mDC和的pDCs频率观察在基线和24周。序贯疗法显著增加的CD8Ť细胞（p = 0.02），记忆性T细胞（CD8 + CD127 +）（p = 0.03）的频率和减少程序性死亡，1（PD1）表达CD8Ť细胞（P = 0.03）相比，替诺福韦单药治疗慢性乙型肝炎患者。 MDCS和HLA-DR的表达上调所需的抗原递呈到基线水平（P <0.05），两组在24周都groups.CCR7表达CD80和83的表达增加。显著（<0.05）增加TLR9的，但在第2组中没有观察TLR7的表达上的mDC。加强区议会的吞噬活性，从基线第1组（9.5％vs61.4％，P = 0.05）和2例（8.9％vs.21.6％，P = 0.08）。干扰素 - a和TNF-a MDC，并PDCS生产改善了24周时，在这两个群体。
结论：替诺福韦单药治疗和序贯治疗的树突状细胞的功能改进相关的HBV DNA水平降低。使用PEG IFN序贯疗法明显优于恢复CD8 + T细胞介导的​​免疫力和TLR9区议会功能。我们的研究结果支持免疫恢复及调制在HBV间隙使用序贯治疗的作用。