PD-1阻断 - HBV特异性CD8 + T细胞的功能恢复

StephenW

Source: J Hepatol  |  Posted 1 week ago
Restoration of HBV-specific CD8+ T-cell function by PD-1 blockade in inactive carrier patients is linked to T-cell differentiation; Bengsch B, Martin B, Thimme R; Journal of Hepatology (Jul 2014)

   
BACKGROUND & AIMS The up-regulation 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 analyzed 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.

CONCLUSIONS Despite the expression of multiple inhibitory receptors by HBV-specific CD8+ T-cells, expression and response to blockade was dominated by PD-1. However, PD-1 expression did not predict response to blockade. Rather, response to blockade was associated with intermediate T-cell differentiation. These findings have important implications for our understanding of inhibitory receptor blockade as a novel therapeutic strategy.

StephenW

资料来源：肝脏病学杂志|发表于1周前
的HBV特异性CD8 + T细胞的功能由PD-1阻断在被连接到T细胞分化惰性载体的病人的恢复; Bengsch B，马丁B，Thimme R等中华肝脏病杂志（2014年7月）

   
背景与目的的上调几种抑制信号转导途径通过耗尽的HBV特异性CD8 + T细胞在慢性感染被认为有助于病毒的持久性。抑制性受体的阻断重振疲惫的T细胞的功能是一种很有前途的新的治疗方法。然而，小的信息是可用的关于个体抑制通路对HBV特异性CD8 + T细胞衰竭和相对贡献的抑制性受体阻断对恢复T细胞功能在慢性HBV的影响。

方法98 HLA-A2 +的慢性感染患者进行分析体外对HBV特异性CD8 + T细胞应答，多种抑制性受体和T细胞分化标记物的表达。的抑制性受体阻断靶向PD-1，2B4，添-3，CTLA-4和BTLA的影响进行了评估体外。

结果在我们的研究中，离体HBV特异性CD8 + T细胞应答优先确定在HBeAg-的患者低ALT和低病毒载量（不活动载波）。我们观察到的PD-1为主的抑制性受体表达的清晰的层次结构。为抑制性受体阻滞剂的反应是异类。相比其他抑制性受体的阻断，在PD-1通路阻断导致强劲的增长函数。值得注意的是，对PD-1阻断了积极的作用与中间的T细胞的分化。

结论尽管多种抑制性受体的由HBV特异性CD8 + T细胞，表达和响应于封锁的表达主要是由PD-1。然而，PD-1的表达并没有预测对封锁。相反，应对封锁了中间的T细胞分化有关。这些发现对我们的抑制性受体阻滞剂作为一种新的治疗策略的理解具有重要意义。

lgs1

虽然看不懂
但还是觉得你真勤快

StephenW

回复 lgs1 的帖子

科学家们希望能够恢复T细胞免疫, 通过PD-1的阻断(PD-1 blockade). 看来不是那么简单.