还是来点最新的资讯吧。阻断PD-1逆转HBV的耐受

大鹏鸟

http://journals.plos.org/plosone ... ournal.pone.0039179PD-1 Blockage Reverses Immune Dysfunction and Hepatitis B Viral Persistence in a Mouse Animal Model
Abstract

Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Recent studies in animal models of viral infection indicate that the interaction between the inhibitory receptor, programmed death (PD)-1, on lymphocytes and its ligand (PD-L1) play a critical role in T-cell exhaustion by inducing T-cell inactivation. High PD-1 expression levels by peripheral T-lymphocytes and the possibility of improving T-cell function by blocking PD-1-mediated signaling confirm the importance of this inhibitory pathway in inducing T-cell exhaustion. We studied T-cell exhaustion and the effects of PD-1 and PD-L1 blockade on intrahepatic infiltrating T-cells in our recently developed mouse model of HBV persistence. In this mouse animal model, we demonstrated that there were increased intrahepatic PD-1-expressing CD8+ and CD4+ T cells in mice with HBV persistence, but PD-1 upregulation was resolved in mice which had cleared HBV. The Intrahepatic CD8+ T-cells expressed higher levels of PD-1 and lower levels of CD127 in mice with HBV persistence. Blockade of PD-1/PD-L1 interactions increased HBcAg-specific interferon (IFN)-γ production in intrahepatic T lymphocytes. Furthermore, blocking the interaction of PD-1 with PD-L1 by an anti-PD-1 monoclonal antibody (mAb) reversed the exhausted phenotype in intrahepatic T lymphocytes and viral persistence to clearance of HBV in vivo. Our results indicated that PD-1 blockage reverses immune dysfunction and viral persistence of HBV infection in a mouse animal model, suggesting that the anti-PD-1 mAb might be a good therapeutic candidate for chronic HBV infection.

乙型肝炎病毒感染导致慢性肝炎、肝硬化和肝细胞癌。最近在病毒感染的动物模型研究表明，抑制性受体之间的相互作用，淋巴细胞表面程序性死亡受体PD-1及其配体（PD-L1）诱导T细胞失活的T细胞耗竭发挥关键作用。外周血T淋巴细胞PD-1表达水平高的阻断pd-1-mediated信号诱导T细胞耗竭证实这一抑制性通路的重要性提高T细胞功能的可能性。我们研究了T细胞耗竭和PD-1和我们最近开发的小鼠模型肝内浸润的T细胞对HBV持续PD-L1阻断作用。在这种小鼠动物模型，我们表明，有增加肝内pd-1-expressing CD8+和持续感染小鼠的CD4 + T细胞PD-1的表达上调，但在有清除HBV小鼠分辨。肝内CD8+T细胞PD-1表达水平较高和较低水平的HBV持续性小鼠CD4~+CD25~+调节性T细胞。PD-1/PD-L1互动封锁HBcAg特异性干扰素（IFN）增加在肝内T淋巴细胞γ生产。此外，阻断由一个抗PD-1单克隆抗体（mAb）PD-L1 PD-1的作用逆转精疲力竭的表型在肝内T淋巴细胞和病毒持续存在于体内HBV的清除。我们的研究结果表明，PD-1阻断逆转免疫功能紊乱与HBV感染的病毒持续在小鼠动物模型，表明抗PD-1单克隆抗体可能是慢性HBV感染有良好的治疗候选者。

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http://www.sciencedirect.com/sci ... i/S0168827814004735

Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation

Background & Aims

The upregulation of several inhibitory signalling pathways by exhausted HBV-specific CD8+ T cells in chronic infection is thought to contribute to viral persistence. Blockade of inhibitory receptors to reinvigorate exhausted T cell function is a promising novel therapeutic approach. However, little information is available regarding the relative contribution of individual inhibitory pathways to HBV-specific CD8+ T cell failure and the impact of inhibitory receptor blockade on restoration of T cell function in chronic HBV.

Methods

98 HLA-A2+ chronically infected patients were analysed ex vivo for HBV-specific CD8+ T cell responses, the expression of multiple inhibitory receptors and T cell differentiation markers. The effects of inhibitory receptor blockade targeting PD-1, 2B4, Tim-3, CTLA-4, and BTLA were assessed in vitro.

Results

In our cohort, ex vivo HBV-specific CD8+ T cell responses were identified preferentially in HBeAg patients with low ALT and low viral load (inactive carriers). We observed a clear hierarchy of inhibitory receptor expression dominated by PD-1. The response to inhibitory receptor blockade was heterogeneous. Compared to the blockade of other inhibitory receptors, blockade of the PD-1 pathway resulted in the strongest increase in function. Of note, a positive effect of PD-1 blockade was linked to intermediate T cell differentiation.

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