Telbivudine therapy may shape CD4+ T-cell response to prevent liver fibrosis in patients with chronic hepatitis B
Telbivudine therapy may shape CD4+ T-cell response to prevent liver fibrosis in patients with chronic hepatitis B
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DOI：
10.1111/liv.12589
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发表时间：
2015-03-01
影响因子：
6.7
通讯作者：
Jiang, Wei
中科院分区：
文献类型：
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作者：
Li, Jing;Jia, Minglei;Jiang, Wei
背景与目的：核苷（酸）类似物（NAs）可通过抑制病毒复制间接恢复宿主针对乙型肝炎病毒（HBV）的免疫功能。我们旨在探究替比夫定是否能通过影响CD4 + T细胞应答来阻止HBV相关的肝纤维化进展。
方法：36例HBeAg阳性的慢性乙型肝炎（CHB）患者入组接受为期52周的替比夫定单药治疗，并在治疗第0周、第4周、第12周、第24周和第52周进行随访。至治疗第52周时，患者被分为完全应答组（CR，n = 10），即HBV - DNA和HBeAg均为阴性；部分应答组（PR，n = 11），仅HBV - DNA阴性；无应答组（NR，n = 15），HBV - DNA仍为阳性。制备外周血单个核细胞（PBMCs）用于进一步的流式细胞术和实时荧光定量PCR分析，同时也用于与原代肝星状细胞（HSCs）进行体外实验。
结果：在周围血中，所有慢性HBV感染者均表现出CD4 + T细胞应答的参与，其中非活动性携带者（IC）以Th1（CD4 + IFN + ）为主，CHB患者以Th17（CD4 + IL - 17 + ）为主，而免疫耐受（IT）者以Treg（CD4 + CD25高表达Foxp3 + ）为主。此外，我们发现对替比夫定的治疗应答尤其与Th1和Th17的上调以及Treg的下调相关。再者，与CR组的CD4 + 细胞相比，NR组的CD4 + 细胞在体外可显著加剧HSCs的细胞活化、增殖和细胞因子产生，这部分由IL - 4和TGF - 1介导。
结论：替比夫定可能通过恢复针对HBV的CD4 + T细胞应答来减缓HBV相关的肝纤维化进展。
Background & AimsNucleos(t)ide analogues (NAs) can indirectly restore host immunity against hepatitis B virus (HBV) by inhibiting virus replication. We aimed to investigate whether telbivudine could prevent HBV-related fibrosis progression by their influence on CD4(+) T-cell response.MethodsThirty-six HBeAg-positive patients with chronic hepatitis B (CHB) were enrolled for 52-week telbivudine monotherapy and were followed at treatment week (TW)-0, 4, 12, 24 and 52. By TW-52, the patients were classified into a complete-response group (CR, n=10) with both negative HBV-DNA and HBeAg, or a part-response group (PR, n=11) only with negative DNA, or a non-response group (NR, n=15) still with positive DNA. The peripheral blood mononuclear cells (PBMCs) were prepared for further flow cytometric and real-time PCR analyses, and also for the in vitro experiments with primary hepatic stellate cells (HSCs).ResultsPeripherally, all chronic HBV-infected subjects showed the involvement of CD4(+) T-cell responses, among whom the inactive carriers (IC) had Th1 (CD4(+)IFN(+)) dominated, CHB had Th17 (CD4(+)IL-17(+)) dominated, while the immune tolerant (IT) subjects had Treg (CD4(+)CD25(high)Foxp3(+)) dominated. Besides, we found the therapeutic responses to telbivudine were especially associated with up-regulation of Th1 and Th17, and down-regulation of Treg. Furthermore, compared to CD4(+) cells from CR, those from NR could in vitro significantly exacerbate cell activation, proliferation and cytokine production of HSCs, which were partly mediated by IL-4 and TGF-1.ConclusionsTelbivudine might slow down HBV-related liver fibrosis progression by restoring CD4(+) T-cell responses against HBV.