The role of CCR5/CXCR3 expressing CD8+ cells in liver damage and viral control during persistent hepatitis C virus infection.
OBJECTIVE
CXCR3 and CCR5 play a major role in recruiting cytotoxic T cells (Tc) and secreting secondary type 1 cytokines (Tc1) in the liver. HCV could impair their expression as a survival mechanism. The role of these chemokine receptors on CD8+ cells in chronic hepatitis C is analysed.


METHODS
Serum, chemokines, peripheral blood and intrahepatic lymphocytes from chronic hepatitis C patients were studied. CXCR3/CCR5 expressing CD8+ cells were quantified by flow-cytometry. Serum chemokines concentration (CXCL10/CCL3) was measured by ELISA. Basal data were correlated with liver inflammation. Longitudinal data were obtained during treatment and correlated with virologic response.


RESULTS
CCR5/CXCR3 expressing CD8+ cells were enriched in the liver and correlated with inflammation. Chronic HCV patients presented the same frequency of CCR5(high)/CXCR3(high) expressing CD8+ cells in peripheral blood as in healthy controls but higher serum concentration of CXCL10/CCL3. Treatment with PEG-interferon alpha-2b plus ribavirin increased CCR5(high)/CXCR3(high) expressing CD8+ cells frequency in peripheral blood and decreased CXCL10/CCL3 serum concentration. Increase in CXCR3(high) expressing CD8+ cells after 24 weeks of treatment was correlated with SVR.


CONCLUSIONS
In chronic hepatitis C, anti-viral treatment induces an increase in CD8+ cells expressing chemokine receptors associated with Tc1 response and a reduction in their ligands. Achievement of viral control is associated with an increase in CXCR3(high) expressing CD8+ cells during treatment.
Larrubia
Juan-Ramón
JR
Liver Research Unit, Hospital Universitario Guadalajara, University of Alcalá, Spain. jlarrubiam@meditex.es
Calvino
Miryam
M
Benito
Selma
S
Sanz-de-Villalobos
Eduardo
E
Perna
Cristian
C
Pérez-Hornedo
Jaime
J
González-Mateos
Fernando
F
García-Garzón
Silvia
S
Bienvenido
Antonio
A
Parra
Trinidad
T
D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D054405:Chemokine CCL3 / Q000097:blood / Q000276:immunology; D054357:Chemokine CXCL10 / Q000097:blood / Q000276:immunology; D002908:Chronic Disease / Q000628:therapy; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000188:drug therapy / Q000276:immunology* / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use; D008099:Liver / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D019713:Receptors, CCR5 / Q000097:blood / Q000276:immunology*; D054367:Receptors, CXCR3 / Q000097:blood / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
C515429:CCL3 protein, human; C114753:CXCL10 protein, human; C515187:CXCR3 protein, human; D054405:Chemokine CCL3; D054357:Chemokine CXCL10; D016207:Cytokines; D016898:Interferon-alpha; D019713:Receptors, CCR5; D054367:Receptors, CXCR3