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. 作者: StephenW 时间: 2014-8-20 13:10