Gastroenterology

Gastroenterology

Volume 138, Issue 2, February 2010, Pages 682-693.e4
Gastroenterology

Basic—Liver, Pancreas, and Biliary Tract
Antiviral Intrahepatic T-Cell Responses Can Be Restored by Blocking Programmed Death-1 Pathway in Chronic Hepatitis B

https://doi.org/10.1053/j.gastro.2009.09.052Get rights and content

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 HBV-specific 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)-γ 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-γ 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.

Section snippets

Study Subjects

A total of 42 patients with chronic hepatitis B were enrolled at the Unit of Infectious Diseases and Hepatology of the Azienda Ospedaliero-Universitaria of Parma, Parma, Italy, and at the Department of Clinical Medicine of the University of Bologna, Bologna, Italy. Diagnosis of chronic hepatitis B was based on the detection of alanine aminotransferase (ALT) elevation lasting for more than 6 months, associated with positive hepatitis B surface antigen (HBsAg), antibody to hepatitis B core

Frequency of HBV-Specific CD8 T Cells

To compare the ex vivo frequency and phenotype of HBV-specific CD8 T cells from liver and peripheral blood, 17 HLA-A2- positive patients with chronic hepatitis B were studied with a panel of 6 major histocompatibility complex (MHC) class I tetramers containing frequently detected HBV epitopes (core AA, 18–27; envelope AA, 183–191, AA 335–343, and AA 348–357; and polymerase, AA 575–583 and AA 816–824). Because of limitations in the number of cells available from liver biopsies, staining of LIL

Discussion

Studies in animal models of virus infections show that persistent exposure to high antigen concentrations can affect the antiviral T-cell function by causing different degrees of functional impairment, up to physical T-cell deletion, as a function of the quantity of antigen to which T cells are exposed.29, 30 T-cell exhaustion by this mechanism may play an important role in the pathogenesis of the HBV-specific T-cell hyporesponsiveness of chronic HBV infection because high antigen

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by the VIRGIL EC grant QLK2-CT-2002-00700; by Fondazione Cassa Risparmio di Parma, Parma, Italy; by grant 85/2007, Ricerca Finalizzata, Progetto Ordinario, Ministry of Health, Italy; and by Fondo per gli Investimenti della Ricerca di Base (grant No. RBNE013PMJ); and by the Ministry of Instruction, University and Research, Italy.

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