Chronic ethanol consumption impairs cellular immune responses against HCV NS5 protein due to dendritic cell dysfunction.
OBJECTIVE
Alcoholic patients with and without chronic liver disease have a high incidence of infection with hepatitis C virus (HCV). Long-term ethanol consumption in mice has been associated with a strikingly reduced CD8(+) cytotoxic T-lymphocyte (CTL) response to HCV nonstructural proteins following DNA-based immunization. This study evaluated the effect of ethanol on dendritic cells (DCs) as a mechanism(s) for reduced CTL activity.


METHODS
Mice were fed an ethanol-containing or isocaloric pair-fed control diet for 8 weeks, followed by DC isolation from the spleen. DCs were evaluated with respect to endocytosis properties, cell surface markers, allostimulatory activity, and cytokine production following stimulation. Immune responses to HCV NS5 protein were generated by genetic immunization. Syngeneic transfer was used to determine if DC dysfunction contributed to abnormal cellular immune responses.


RESULTS
Long-term ethanol exposure resulted in a reduced number of splenic DCs but did not alter endocytosis capacity. There was an increase in the myeloid and a reduction in the lymphoid DC population. Ethanol reduced expression of CD40 and CD86 costimulatory molecules on resting DCs, which was corrected following stimulation with lipopolysaccharide or poly I:C. There was impaired allostimulatory activity. Cytokine profiles of DCs isolated from ethanol-fed mice were characterized by enhanced interleukin (IL)-1beta and IL-10 and decreased tumor necrosis factor alpha, IL-12, interferon gamma, and IL-6 secretion. Impaired CTL responses to NS5 were corrected by syngeneic transfer of control DCs.


CONCLUSIONS
Altered DC function is one of the major changes induced by long-term ethanol consumption, which subsequently impairs the cellular immune response necessary for viral clearance.
Aloman
Costica
C
Liver Research Center, Rhode Island Hospital and Brown Medical School, Providence, Rhode Island 02903, USA.
Gehring
Stephan
S
Wintermeyer
Philip
P
Kuzushita
Noriyoshi
N
Wands
Jack R
JR
D000437:Alcoholism / Q000276:immunology* / Q000503:physiopathology; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D004705:Endocytosis / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects; D007111:Immunity, Cellular / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D011070:Poly I-C / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014185:Transplantation, Isogeneic; D017361:Viral Nonstructural Proteins / Q000276:immunology*; D012324:RNA-Dependent RNA Polymerase
D015703:Antigens, CD; D002492:Central Nervous System Depressants; D016207:Cytokines; D000431:Ethanol; D008070:Lipopolysaccharides; D011070:Poly I-C; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase