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

[Guest guest]

Gastroenterology. 2009 Sep 30. [Epub ahead of print]

Anti-Viral Intrahepatic T-Cell Responses can be Restored by Blocking Programmed

Death-1 Pathway in Chronic Hepatitis B.

Fisicaro P, Valdatta C, Massari M, Loggi E, Biasini E, Sacchelli L, Cavallo MC,

Silini EM, Andreone P, Missale G, Ferrari C.

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

Azienda Ospedaliero-Universitaria di Parma, Italy.

BACKGROUND & AIMS:: The anti-viral 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)-gamma 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-gamma and IL2 production by circulating and 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 anti-viral

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.

PMID: 19800335 [PubMed - as supplied by publisher]

[Guest guest]

Gastroenterology. 2009 Sep 30. [Epub ahead of print]

Anti-Viral Intrahepatic T-Cell Responses can be Restored by Blocking Programmed

Death-1 Pathway in Chronic Hepatitis B.

Fisicaro P, Valdatta C, Massari M, Loggi E, Biasini E, Sacchelli L, Cavallo MC,

Silini EM, Andreone P, Missale G, Ferrari C.

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

Azienda Ospedaliero-Universitaria di Parma, Italy.

BACKGROUND & AIMS:: The anti-viral 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)-gamma 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-gamma and IL2 production by circulating and 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 anti-viral

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.

PMID: 19800335 [PubMed - as supplied by publisher]

[Guest guest]

Gastroenterology. 2009 Sep 30. [Epub ahead of print]

Anti-Viral Intrahepatic T-Cell Responses can be Restored by Blocking Programmed

Death-1 Pathway in Chronic Hepatitis B.

Fisicaro P, Valdatta C, Massari M, Loggi E, Biasini E, Sacchelli L, Cavallo MC,

Silini EM, Andreone P, Missale G, Ferrari C.

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

Azienda Ospedaliero-Universitaria di Parma, Italy.

BACKGROUND & AIMS:: The anti-viral 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)-gamma 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-gamma and IL2 production by circulating and 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 anti-viral

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.

PMID: 19800335 [PubMed - as supplied by publisher]

[Guest guest]

Gastroenterology. 2009 Sep 30. [Epub ahead of print]

Anti-Viral Intrahepatic T-Cell Responses can be Restored by Blocking Programmed

Death-1 Pathway in Chronic Hepatitis B.

Fisicaro P, Valdatta C, Massari M, Loggi E, Biasini E, Sacchelli L, Cavallo MC,

Silini EM, Andreone P, Missale G, Ferrari C.

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

Azienda Ospedaliero-Universitaria di Parma, Italy.

BACKGROUND & AIMS:: The anti-viral 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)-gamma 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-gamma and IL2 production by circulating and 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 anti-viral

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.

PMID: 19800335 [PubMed - as supplied by publisher]