BACKGROUND & AIMS: The antiviral function of peripheral hepatitis B virus (HBV)-specific T cells can be increased in patients with chronic hepatitis B by blocking the interaction of programmed death (PD)-1 with its ligand PD-L1. However, no information is available about the effects of this blockade on intrahepatic lymphocytes. We studied T-cell exhaustion and the effects of PD-1/PD-L1 blockade on intrahepatic and circulating HBV-specific T cells in patients with chronic hepatitis B. METHODS: A total of 42 patients with chronic HBV infection who underwent liver biopsy were studied. The ex vivo phenotype of peripheral and intrahepatic HBVspecific CD8_ T cells was assessed by flow cytometry with class I tetramers and antibodies to T-cell differentiation molecules. Functional recovery was evaluated by analyzing expansion and production of interferon (IFN)-_ and interleukin (IL)-2 after short-term incubation of T cells with HBV peptides in the presence of anti-PD-L1 or control antibodies. RESULTS: Intrahepatic HBV-specific CD8_ cells expressed higher levels of PD-1 and lower levels of CD127 than their peripheral counterparts. Blockade of PD-1/PD-L1 interaction increased CD8_ cell proliferation and IFN-_ and IL-2 production by circulating intrahepatic lymphocytes, even though anti-PD-L1 had a stronger effect on intrahepatic compared with peripheral T cells. CONCLUSIONS: T-cell exhaustion by high antigen concentrations promotes HBV-specific T-cell dysfunction by affecting phenotype and function of peripheral and intrahepatic T cells. By restoring antiviral T-cell functions, not only in peripheral but also in intrahepatic lymphocytes, anti-PD-L1 might be a good therapeutic candidate for chronic HBV infection.

Anti-Viral Intrahepatic T-Cell Responses can be Restored by Blocking Programmed Death-1 Pathway in Chronic Hepatitis B / P. Fisicaro; C. Valdatta; M. Massari; E. Loggi; E. Biasini; L. Sacchelli; MC. Cavallo; EM. Silini; P. Andreone; G. Missale; C. Ferrari. - In: GASTROENTEROLOGY. - ISSN 0892-1601. - 138(2010), pp. 682-693. [10.1053/j.gastro.2009.09.052]

Anti-Viral Intrahepatic T-Cell Responses can be Restored by Blocking Programmed Death-1 Pathway in Chronic Hepatitis B

SILINI, Enrico Maria;G. Missale;FERRARI, Carlo
2010

Abstract

BACKGROUND & AIMS: The antiviral function of peripheral hepatitis B virus (HBV)-specific T cells can be increased in patients with chronic hepatitis B by blocking the interaction of programmed death (PD)-1 with its ligand PD-L1. However, no information is available about the effects of this blockade on intrahepatic lymphocytes. We studied T-cell exhaustion and the effects of PD-1/PD-L1 blockade on intrahepatic and circulating HBV-specific T cells in patients with chronic hepatitis B. METHODS: A total of 42 patients with chronic HBV infection who underwent liver biopsy were studied. The ex vivo phenotype of peripheral and intrahepatic HBVspecific CD8_ T cells was assessed by flow cytometry with class I tetramers and antibodies to T-cell differentiation molecules. Functional recovery was evaluated by analyzing expansion and production of interferon (IFN)-_ and interleukin (IL)-2 after short-term incubation of T cells with HBV peptides in the presence of anti-PD-L1 or control antibodies. RESULTS: Intrahepatic HBV-specific CD8_ cells expressed higher levels of PD-1 and lower levels of CD127 than their peripheral counterparts. Blockade of PD-1/PD-L1 interaction increased CD8_ cell proliferation and IFN-_ and IL-2 production by circulating intrahepatic lymphocytes, even though anti-PD-L1 had a stronger effect on intrahepatic compared with peripheral T cells. CONCLUSIONS: T-cell exhaustion by high antigen concentrations promotes HBV-specific T-cell dysfunction by affecting phenotype and function of peripheral and intrahepatic T cells. By restoring antiviral T-cell functions, not only in peripheral but also in intrahepatic lymphocytes, anti-PD-L1 might be a good therapeutic candidate for chronic HBV infection.
Anti-Viral Intrahepatic T-Cell Responses can be Restored by Blocking Programmed Death-1 Pathway in Chronic Hepatitis B / P. Fisicaro; C. Valdatta; M. Massari; E. Loggi; E. Biasini; L. Sacchelli; MC. Cavallo; EM. Silini; P. Andreone; G. Missale; C. Ferrari. - In: GASTROENTEROLOGY. - ISSN 0892-1601. - 138(2010), pp. 682-693. [10.1053/j.gastro.2009.09.052]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2331539
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