Abstract
Background & Aims T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). Methods We enrolled 200 adults with CHB who participated in the National Institutes of Health-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. Results Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3+CD127- regulatory T cells and CD4+ T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg)+ than HBeAg- patients (percent responders: 3% vs 23%; P =.00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg+ than HBeAg- patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. Conclusions HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell-based immune signatures for clinical phenotypes. These findings suggest additional T-cell-independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.
Original language | English (US) |
---|---|
Pages (from-to) | 684-695.e5 |
Journal | Gastroenterology |
Volume | 150 |
Issue number | 3 |
DOIs | |
State | Published - Mar 1 2016 |
Keywords
- HBRN
- IFN
- IL10
- LPS
ASJC Scopus subject areas
- Hepatology
- Gastroenterology
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In: Gastroenterology, Vol. 150, No. 3, 01.03.2016, p. 684-695.e5.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Hepatitis B Virus-Specific and Global T-Cell Dysfunction in Chronic Hepatitis B
AU - Park, Jang June
AU - Wong, David K.
AU - Wahed, Abdus S.
AU - Lee, William M.
AU - Feld, Jordan J.
AU - Terrault, Norah
AU - Khalili, Mandana
AU - Sterling, Richard K.
AU - Kowdley, Kris V.
AU - Bzowej, Natalie
AU - Lau, Daryl T.
AU - Kim, W. Ray
AU - Smith, Coleman
AU - Carithers, Robert L.
AU - Torrey, Keith W.
AU - Keith, James W.
AU - Levine, Danielle L.
AU - Traum, Daniel
AU - Ho, Suzanne
AU - Valiga, Mary E.
AU - Johnson, Geoffrey S.
AU - Doo, Edward
AU - Lok, Anna S F
AU - Chang, Kyong Mi
N1 - Funding Information: We gratefully acknowledge our collaborators in Hepatitis B Research Network including: The HBRN: Harvard Consortium: Raymond T. Chung, MD (Massachusetts General Hospital, Boston, MA). Minnesota Alliance for Research in Chronic Hepatitis B Consortium Lewis R. Roberts, MB, ChB, PhD (Mayo Clinic Rochester, Rochester, MN). Saint Louis Midwest Hep B Consortium: Adrian M. Di Bisceglie, MD (Saint Louis University School of Medicine, St Louis, MO), Mauricio Lisker-Melman, MD (Washington University, St. Louis, MO). University of Toronto Consortium: Harry L. A. Janssen, MD, PhD (Toronto Western & General Hospitals, Toronto, Ontario), Joshua Juan, MD (Toronto Western & General Hospitals, Toronto, Ontario), Colina Yim (Toronto Western & General Hospitals, Toronto, Ontario), Jenny Heathcote, MD (Toronto Western & General Hospitals, Toronto, Ontario). HBV CRN North Texas Consortium: Robert Perrillo, MD (Baylor University Medical Center, Dallas, TX), Son Do, MD (University of Texas Southwestern, Dallas, TX). Los Angeles Hepatitis B Consortium: Steven-Huy B. Han, MD (David Geffen School of Medicine, UCLA, Los Angeles, CA), Tram T. Tran, MD (Cedars Sinai Medical Center, Los Angeles, CA). San Francisco Hepatitis B Research Group Consortium: Stewart L. Cooper, MD (California Pacific Medical Center, Research Institute & Sutter Pacific Medical Foundation, Division of Hepatology, San Francisco, CA). Michigan Hawaii Consortium: Robert J. Fontana, MD (University of Michigan, Ann Arbor, MI), Naoky Tsai, MD (The Queen''s Medical Center, Honolulu, HI). Chapel Hill, NC Consortium: Michael W. Fried, MD, (University of North Carolina at Chapel Hill, Chapel Hill, NC), Keyur Patel, MD (Duke University Medical Center, Durham, NC), Donna Evon, PhD (University of North Carolina at Chapel Hill, Chapel Hill, NC). PNW/Alaska Clinical Center Consortium: Margaret Shuhart, MD (Harborview Medical Center, Seattle, WA), Chia C. Wang, MD (Harborview Medical Center, Seattle, WA). Liver Diseases Branch, NIDDK: Marc G. Ghany, MD, MHsc (National Institutes of Health, Bethesda, MD), T. Jake Liang, MD (National Institutes of Health, Bethesda, MD). Data Coordinating Center: Steven Belle, PhD, MScHyg (Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA), Yona Cloonan, PhD (Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA), Central Pathology: David Kleiner, MD, PhD (Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD). In addition to the authors and the research participants, the HBRN would like to acknowledge the contributions of the following: Harvard Consortium: Nezam Afdhal, MD, Asad Javaid, MBBS, Jianghe Niu, Johanna Han, Imad Nasser, MD (Beth Israel Deaconess Medical Center, Boston, MA). Minnesota Alliance for Research in Chronic Hepatitis B: Alisha C. Stahler, Linda Stadheim, RN (Mayo Clinic Rochester, Rochester, MN), Mohamed Hassan, MD (University of Minnesota, Minneapolis, MN). Saint Louis Midwest Hep B Consortium: Debra L. King, RN, Rosemary A. Nagy, MBA, RD, LD, Jacki Cerkoski, RN, MSN (Saint Louis University School of Medicine, St Louis, MO). University of Toronto Consortium: Victor Lo, MASc (Toronto Western & General Hospitals, Toronto, Ontario), Danie La, RN (Toronto Western & General Hospitals, Toronto, Ontario), Lucie Liu (Toronto Western & General Hospitals, Toronto, Ontario). HBV CRN North Texas Consortium: Stacey Minshall, RN, BSN (Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas), Sheila Bass (University of Texas Southwestern, Dallas, TX). Los Angeles Hepatitis B Consortium: Samuel French, MD, Velma Peacock, RN (David Geffen School of Med, UCLA, Los Angeles, CA), San Francisco Hepatitis B Research Group Consortium: Ashley Ungermann, MS, Claudia Ayala, MS, Emma Olson, BS, Ivy Lau, BS (University of California-San Francisco), Veronika Podolskaya, BS, NCPT, Nata DeVole, RN (California Pacific Medical Center, Research Institute), Michigan Hawaii Consortium: Barbara McKenna, MD, Kelly Oberhelman, PAC, Sravanthi Kaza, Bpharm, Cassandra Rodd, BS (University of Michigan, Ann Arbor, MI), Leslie Huddleston, NP, Peter Poerzgen, PhD (The Queen''s Medical Center, Honolulu, HI), Chapel Hill, NC Consortium: Jama M. Darling, MD, A. Sidney Barritt, MD, Tiffany Marsh, BA, Vikki Metheny, ANP, Danielle Cardona, PA-C (University of North Carolina at Chapel Hill, Chapel Hill, NC), Virginia Commonwealth University Medical Center: Velimir A. Luketic, MD, Paula G Smith, RN, BSN, Charlotte Hofmann, RN (Virginia Commonwealth University Health System, Richmond, VA), PNW/Alaska Clinical Center Consortium: Terri Mathisen, RN, BSN, Susan Strom, MPH (University of Washington Medical Center, Seattle WA), Jody Mooney, Lupita Cardona-Gonzalez (Virginia Mason Medical Center, Seattle WA), Liver Diseases Branch, NIDDK, NIH: Jay H. Hoofnagle, MD, Averell H. Sherker, MD, Rebecca J. Torrance, RN, MS, Sherry R, Hall, MS, Nancy Fryzek, RN, BSN, Elenita Rivera, BSN, Nevitt Morris, Vanessa Haynes-Williams, Immunology Center: Philadelphia Corporal Michael J. Crescenz VA Medical Center Medical Research, Keith Torrey, BS, Michael Betts, PhD (University of Pennsylvania, Philadelphia, PA), Luis J. Montaner, DVM, DPhil (Wistar Institute, Philadelphia, PA), Data Coordinating Center: Michelle Danielson, PhD, Tamara Haller, Geoffrey Johnson, MS, Stephanie Kelley, MS, Sharon Lawlor, MBA, Joan M. MacGregor, MS, Andrew Pelesko, BS, Donna Stoliker, Ella Zadorozny, MS (Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA). The HBRN was funded by a U01 grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to the following investigators Lewis R. Roberts, MB, ChB, PhD (DK 082843), Anna Suk-Fong Lok, MD (DK082863), Steven H. Belle, PhD, MScHyg (DK082864), Kyong-Mi Chang, MD (DK082866), Michael W. Fried, MD (DK082867), Adrian M. Di Bisceglie, MD (DK082871), William M. Lee, MD (U01 DK082872), Harry L. A. Janssen, MD, PhD (DK082874), Daryl T.-Y. Lau, MD, MPH (DK082919), Richard K. Sterling, MD, MSc (DK082923), Steven-Huy B. Han, MD (DK082927), Robert C. Carithers, MD (DK082943), Norah A. Terrault, MD, MPH (U01 DK082944), an interagency agreement with NIDDK: Lilia M. Ganova-Raeva, PhD (A-DK-3002-001) and support from the intramural program, NIDDK, National Institutes of Health (NIH): Marc G. Ghany, MD. Additional funding to support this study was provided to Kyong-Mi Chang, MD, the Immunology Center (NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases P30DK50306, NIH Public Health Service Research Grant M01-RR00040, VA Merit Review BX000649), Richard K. Sterling, MD, MSc (UL1TR000058, NCATS (National Center for Advancing Translational Sciences, NIH), Norah A. Terrault, MD, MPH (CTSA grant number UL1TR000004), Michael W. Fried, MD (Clinical and Translational Science Award [CTSA] grant number UL1TR001111), and Anna Suk-Fong Lok (CTSA grant number UL1RR024986). Additional support was provided by Gilead Sciences, Inc. and Roche Molecular Systems via a cooperative research and development agreement through the NIDDK. This study was supported by NIH grants UO-1DK082866 and R01-AI-47519; the Philadelphia VA Medical Research; NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases P30DK50306 and its Molecular Biology and Cell Culture Core Facilities; the NIH Public Health Service Research Grant M01-RR00040. This material is based on work supported in part by the Office of Research and Development, Department of Veterans Affairs and with the resources and the use of facilities at the Philadelphia Corporal Michael J. Crescenz VA Medical Center. The contents of this work do not represent the views of the Department of Veterans Affairs or the United States Government. Funding Information: Funding The HBRN was funded by a U01 grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to the following investigators Lewis R. Roberts, MB, ChB, PhD (DK 082843), Anna Suk-Fong Lok, MD (DK082863), Steven H. Belle, PhD, MScHyg (DK082864), Kyong-Mi Chang, MD (DK082866), Michael W. Fried, MD (DK082867), Adrian M. Di Bisceglie, MD (DK082871), William M. Lee, MD (U01 DK082872), Harry L. A. Janssen, MD, PhD (DK082874), Daryl T.-Y. Lau, MD, MPH (DK082919), Richard K. Sterling, MD, MSc (DK082923), Steven-Huy B. Han, MD (DK082927), Robert C. Carithers, MD (DK082943), Norah A. Terrault, MD, MPH (U01 DK082944), an interagency agreement with NIDDK: Lilia M. Ganova-Raeva, PhD (A-DK-3002-001) and support from the intramural program, NIDDK, National Institutes of Health (NIH): Marc G. Ghany, MD. Additional funding to support this study was provided to Kyong-Mi Chang, MD, the Immunology Center (NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases P30DK50306, NIH Public Health Service Research Grant M01-RR00040, VA Merit Review BX000649), Richard K. Sterling, MD, MSc (UL1TR000058, NCATS (National Center for Advancing Translational Sciences, NIH), Norah A. Terrault, MD, MPH (CTSA grant number UL1TR000004), Michael W. Fried, MD (Clinical and Translational Science Award [CTSA] grant number UL1TR001111), and Anna Suk-Fong Lok (CTSA grant number UL1RR024986). Additional support was provided by Gilead Sciences, Inc. and Roche Molecular Systems via a cooperative research and development agreement through the NIDDK. This study was supported by NIH grants UO-1DK082866 and R01-AI-47519; the Philadelphia VA Medical Research; NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases P30DK50306 and its Molecular Biology and Cell Culture Core Facilities; the NIH Public Health Service Research Grant M01-RR00040. This material is based on work supported in part by the Office of Research and Development, Department of Veterans Affairs and with the resources and the use of facilities at the Philadelphia Corporal Michael J. Crescenz VA Medical Center. The contents of this work do not represent the views of the Department of Veterans Affairs or the United States Government.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - Background & Aims T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). Methods We enrolled 200 adults with CHB who participated in the National Institutes of Health-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. Results Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3+CD127- regulatory T cells and CD4+ T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg)+ than HBeAg- patients (percent responders: 3% vs 23%; P =.00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg+ than HBeAg- patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. Conclusions HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell-based immune signatures for clinical phenotypes. These findings suggest additional T-cell-independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.
AB - Background & Aims T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). Methods We enrolled 200 adults with CHB who participated in the National Institutes of Health-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. Results Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3+CD127- regulatory T cells and CD4+ T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg)+ than HBeAg- patients (percent responders: 3% vs 23%; P =.00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg+ than HBeAg- patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. Conclusions HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell-based immune signatures for clinical phenotypes. These findings suggest additional T-cell-independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.
KW - HBRN
KW - IFN
KW - IL10
KW - LPS
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UR - http://www.scopus.com/inward/citedby.url?scp=84959336489&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2015.11.050
DO - 10.1053/j.gastro.2015.11.050
M3 - Article
C2 - 26684441
AN - SCOPUS:84959336489
SN - 0016-5085
VL - 150
SP - 684-695.e5
JO - Gastroenterology
JF - Gastroenterology
IS - 3
ER -