The Third Signal Cytokine Interleukin 12 Rather Than Immune Checkpoint Inhibitors Contributes to the Functional Restoration of Hepatitis D Virus-Specific T Cells
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The Third Signal Cytokine Interleukin 12 Rather Than Immune Checkpoint Inhibitors Contributes to the Functional Restoration of Hepatitis D Virus-Specific T Cells. / Schirdewahn, Thomas; Grabowski, Jan; Owusu Sekyere, Solomon; Bremer, Birgit; Wranke, Anika; Lunemann, Sebastian; Schlaphoff, Verena; Kirschner, Janina; Hardtke, Svenja; Manns, Michael Peter; Cornberg, Markus; Wedemeyer, Heiner; Suneetha, Pothakamuri Venkata.
In: J INFECT DIS, Vol. 215, No. 1, 01.01.2017, p. 139-149.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The Third Signal Cytokine Interleukin 12 Rather Than Immune Checkpoint Inhibitors Contributes to the Functional Restoration of Hepatitis D Virus-Specific T Cells
AU - Schirdewahn, Thomas
AU - Grabowski, Jan
AU - Owusu Sekyere, Solomon
AU - Bremer, Birgit
AU - Wranke, Anika
AU - Lunemann, Sebastian
AU - Schlaphoff, Verena
AU - Kirschner, Janina
AU - Hardtke, Svenja
AU - Manns, Michael Peter
AU - Cornberg, Markus
AU - Wedemeyer, Heiner
AU - Suneetha, Pothakamuri Venkata
N1 - © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - BACKGROUND: Hepatitis D virus (HDV) infection affects 15-20 million individuals worldwide and causes severely progressive hepatitis. It is unknown to what extent cellular immune responses contribute to liver disease and control of viral replication in HDV infection.METHODS: Immune cell frequencies and phenotypes were determined in 49 HDV-infected patients, 25 individuals with hepatitis B virus monoinfection and 18 healthy controls. T-cell proliferative and cytokine-producing capacities were analyzed by stimulation with overlapping peptides spanning the large HDV antigen. To restore T-cell responses, blocking antibodies (anti-cytotoxic T-lymphocyte antigen 4, anti-programmed death ligand 1) or proinflammatory cytokines (interleukin [IL] 12) were used.RESULTS: Immune cell frequencies and phenotypes did not vary between the groups. Exclusively, the senescence marker CD57 was significantly up-regulated in CD8+ T cells from patients with hepatitis delta. HDV-specific T-cell proliferation and cytokine production were weak and could only partly be rescued by blockade of the programmed death 1 pathway. However, a more robust and consistent increase in HDV-specific CD4+ and CD8+ T-cell responses was evident when the third signal cytokine IL-12 was added, which also affected cytomegalovirus- and Epstein-Barr virus-specific T cells.CONCLUSIONS: This investigation of virus-specific T-cell immunity in patients with HDV infection, the largest to date, revealed premature aging of immune cells and impaired T-cell functionality. This could be restored by blocking inhibitory pathways and, in particular, by supplementing with IL-12.
AB - BACKGROUND: Hepatitis D virus (HDV) infection affects 15-20 million individuals worldwide and causes severely progressive hepatitis. It is unknown to what extent cellular immune responses contribute to liver disease and control of viral replication in HDV infection.METHODS: Immune cell frequencies and phenotypes were determined in 49 HDV-infected patients, 25 individuals with hepatitis B virus monoinfection and 18 healthy controls. T-cell proliferative and cytokine-producing capacities were analyzed by stimulation with overlapping peptides spanning the large HDV antigen. To restore T-cell responses, blocking antibodies (anti-cytotoxic T-lymphocyte antigen 4, anti-programmed death ligand 1) or proinflammatory cytokines (interleukin [IL] 12) were used.RESULTS: Immune cell frequencies and phenotypes did not vary between the groups. Exclusively, the senescence marker CD57 was significantly up-regulated in CD8+ T cells from patients with hepatitis delta. HDV-specific T-cell proliferation and cytokine production were weak and could only partly be rescued by blockade of the programmed death 1 pathway. However, a more robust and consistent increase in HDV-specific CD4+ and CD8+ T-cell responses was evident when the third signal cytokine IL-12 was added, which also affected cytomegalovirus- and Epstein-Barr virus-specific T cells.CONCLUSIONS: This investigation of virus-specific T-cell immunity in patients with HDV infection, the largest to date, revealed premature aging of immune cells and impaired T-cell functionality. This could be restored by blocking inhibitory pathways and, in particular, by supplementing with IL-12.
KW - Adult
KW - Aged
KW - CD4-Positive T-Lymphocytes/immunology
KW - CD57 Antigens/immunology
KW - CD8-Positive T-Lymphocytes/immunology
KW - CTLA-4 Antigen/immunology
KW - Cytokines/biosynthesis
KW - Cytomegalovirus/immunology
KW - Female
KW - Hepatitis D, Chronic/immunology
KW - Hepatitis Delta Virus/chemistry
KW - Herpesvirus 4, Human/immunology
KW - Humans
KW - Interleukin-12/administration & dosage
KW - Lymphocyte Activation
KW - Male
KW - Middle Aged
KW - Programmed Cell Death 1 Receptor/immunology
KW - T-Box Domain Proteins/metabolism
KW - Virus Replication
U2 - 10.1093/infdis/jiw514
DO - 10.1093/infdis/jiw514
M3 - SCORING: Journal article
C2 - 27803174
VL - 215
SP - 139
EP - 149
JO - J INFECT DIS
JF - J INFECT DIS
SN - 0022-1899
IS - 1
ER -
