Antiviral Intrahepatic T-Cell Responses Can Be Restored by Blocking Programmed Death-1 Pathway in Chronic Hepatitis B

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http://www.gastrojournal.org/article/PIIS0016508509017478/abstract?rss=yes

JOURNAL OF GASTROENTEROLOGY

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

Antiviral Intrahepatic T-Cell Responses Can Be Restored by Blocking Programmed

Death-1 Pathway in Chronic Hepatitis B

Paola Fisicaro, Caterina Valdatta, Marco Massari‡, betta Loggi§,

betta Biasini, Luca Sacchelli, Cristina Cavallo, Enrico M. Silini∥,

Pietro Andreone§, e Missale, Carlo Ferrari

Received 6 March 2009; accepted 17 September 2009. published online 05 October

2009.

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.

Laboratory of Viral Immunopathology, Unit of Infectious Diseases and

Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

‡ Unit of Infectious Diseases, Azienda Ospedaliera S.M.N. di Reggio Emilia;

Reggio Emilia, Italy

§ Department of Clinical Medicine, Laboratory of Cellular Immunology,

University of Bologna, Bologna, Italy

∥ Anatomia e Istologia Patologica, Dipartimento di Patologia e Medicina di

Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

Reprint requests Address requests for reprints to: Carlo Ferrari, MD, Professor,

Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology,

Azienda Ospedaliero-Universitaria di Parma, Via Gramsci, 14, 43100 Parma, Italy.

fax: (39) 0521-703 857

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.

PII: S0016-5085(09)01747-8

doi:10.1053/j.gastro.2009.09.052

© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

[Guest guest]

http://www.gastrojournal.org/article/PIIS0016508509017478/abstract?rss=yes

JOURNAL OF GASTROENTEROLOGY

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

Antiviral Intrahepatic T-Cell Responses Can Be Restored by Blocking Programmed

Death-1 Pathway in Chronic Hepatitis B

Paola Fisicaro, Caterina Valdatta, Marco Massari‡, betta Loggi§,

betta Biasini, Luca Sacchelli, Cristina Cavallo, Enrico M. Silini∥,

Pietro Andreone§, e Missale, Carlo Ferrari

Received 6 March 2009; accepted 17 September 2009. published online 05 October

2009.

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.

Laboratory of Viral Immunopathology, Unit of Infectious Diseases and

Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

‡ Unit of Infectious Diseases, Azienda Ospedaliera S.M.N. di Reggio Emilia;

Reggio Emilia, Italy

§ Department of Clinical Medicine, Laboratory of Cellular Immunology,

University of Bologna, Bologna, Italy

∥ Anatomia e Istologia Patologica, Dipartimento di Patologia e Medicina di

Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

Reprint requests Address requests for reprints to: Carlo Ferrari, MD, Professor,

Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology,

Azienda Ospedaliero-Universitaria di Parma, Via Gramsci, 14, 43100 Parma, Italy.

fax: (39) 0521-703 857

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.

PII: S0016-5085(09)01747-8

doi:10.1053/j.gastro.2009.09.052

© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.