TY - JOUR
T1 - Frequencies of HCV-specific effector CD4+ T cells by flow cytometry
T2 - Correlation with clinical disease stages
AU - Rosen, Hugo R.
AU - Miner, Camette
AU - Sasaki, Anna W.
AU - Lewinsohn, David M.
AU - Conrad, Andrew J.
AU - Bakke, Antony
AU - Bouwer, H. G.Archie
AU - Hinrichs, David J.
N1 - Funding Information:
Abbreviations: HCV, hepatitis C virus; APC, antigen-presenting cell; NS, nonstructural (antigen); Th, T helper; PBMC, peripheral blood mononuclear cell; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ; CMV, cytomegalovirus. From the 1Departments of Medicine, 2Molecular Microbiology, and Immunology, 3Gastroenterology/Hepatology and Liver Transplantation, Portland Veterans Affairs Medical Center/Oregon Health and Science University, Portland OR; 4National Genetics Institute, Los Angeles, CA; and 5Earle A. Chiles Research Institute, Providence Medical Center, Portland, OR. Received April 18, 2001; accepted October 18, 2001. Supported by the Research Enhancement Award Program (HCV REAP), Veterans Affairs, Washington, D.C. H.R.R. is supported by National Institutes of Health grants and a VA merit review grant. The Portland VA Medical Center has provided laboratory space. Address reprint requests to: Hugo R. Rosen, M.D., Medical Director, Liver Transplantation, Division of Gastroenterology/Hepatology and Liver Transplantation Program, Portland Veterans Affairs Medical Center, 3710 SW U.S. Veterans Hospital Rd., P3-GI Portland, OR 97207. E-mail: hugo.rosen@med.va.gov; fax: 503-220-3426. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3501-0026$35.00/0 doi:10.1053/jhep.2002.30293
PY - 2002
Y1 - 2002
N2 - Hepatitis C virus (HCV) is the leading cause of chronic hepatitis, affecting approximately 2% of the world's population. The immune mechanisms responsible for the highly variable natural history in a given individual are unknown. We used a multiparameter flow cytometric technique to functionally and phenotypically characterize HCV-specific effector T cells in the peripheral blood of 32 individuals with different stages of hepatitis C disease (resolved, mild chronic, advanced chronic) and normal controls. We found the highest frequencies of virus-specific effector cells with an activated memory phenotype (CD45RO+CD69+) in subjects who had resolved HCV infection, either spontaneously or with antiviral therapy. Effector cells from patients with resolved infection produced Th1 type cytokines following stimulation with nonstructural antigens (NS3 and NS4), whereas effector cells from chronically infected patients produced Th1 type cytokines predominantly following stimulation with the HCV core antigen. Stimulation with superantigen staphylococcal enterotoxin (SEB) induced the same levels of cytokine production in the different patient groups. Among the HCV-seropositive patients, viral load inversely correlated with the Th1 effector cell response to NS3. Interleukin (IL)-4 was produced only in response to the control antigens, but not in response to the HCV recombinant proteins. Taken together, these findings suggest that a vigorous HCV-specific CD4+ Th1 response, particularly against the nonstructural proteins of the virus, may be associated with viral clearance and protection from disease progression. Prospective studies using this new flow cytometric assay will be required to determine whether antiviral therapy modifies the frequency, specificity, and function of these virus-specific effector cells.
AB - Hepatitis C virus (HCV) is the leading cause of chronic hepatitis, affecting approximately 2% of the world's population. The immune mechanisms responsible for the highly variable natural history in a given individual are unknown. We used a multiparameter flow cytometric technique to functionally and phenotypically characterize HCV-specific effector T cells in the peripheral blood of 32 individuals with different stages of hepatitis C disease (resolved, mild chronic, advanced chronic) and normal controls. We found the highest frequencies of virus-specific effector cells with an activated memory phenotype (CD45RO+CD69+) in subjects who had resolved HCV infection, either spontaneously or with antiviral therapy. Effector cells from patients with resolved infection produced Th1 type cytokines following stimulation with nonstructural antigens (NS3 and NS4), whereas effector cells from chronically infected patients produced Th1 type cytokines predominantly following stimulation with the HCV core antigen. Stimulation with superantigen staphylococcal enterotoxin (SEB) induced the same levels of cytokine production in the different patient groups. Among the HCV-seropositive patients, viral load inversely correlated with the Th1 effector cell response to NS3. Interleukin (IL)-4 was produced only in response to the control antigens, but not in response to the HCV recombinant proteins. Taken together, these findings suggest that a vigorous HCV-specific CD4+ Th1 response, particularly against the nonstructural proteins of the virus, may be associated with viral clearance and protection from disease progression. Prospective studies using this new flow cytometric assay will be required to determine whether antiviral therapy modifies the frequency, specificity, and function of these virus-specific effector cells.
UR - http://www.scopus.com/inward/record.url?scp=0036139684&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036139684&partnerID=8YFLogxK
U2 - 10.1053/jhep.2002.30293
DO - 10.1053/jhep.2002.30293
M3 - Article
C2 - 11786976
AN - SCOPUS:0036139684
SN - 0270-9139
VL - 35
SP - 190
EP - 198
JO - Hepatology
JF - Hepatology
IS - 1
ER -