Chronic hepatitis C (HCV) infection is a major cause of liver disease, cirrhosis, and hepatocellular carcinoma (HCC) in alcoholics. Although it has been established that chronic alcoholics have a high incidence of CV infection, the reasons for these high rates are unknown but may partially relate to the effects of ethanol on the humoral and cellular immune responses to viral structural and non-structural proteins. Past studies revealed that chronic ethanol feeding in a murine model has a profound inhibitory effect on the generation of viral-specific CD4+ and CD8+ T-cell activity to HCV core and NS5 proteins used as the immunogens. More important, this inhibitory effect of ethanol was completely reversed by co-immunization with an IL2 or GM- CSF expression plasmids following genetic immunization suggesting that dendritic cells (DCs) could be involved in these abnormal immune responses and thus, there may not be intrinsic abnormalities in CD4+ and CD8+ cells per se. We have established an experimental model system to study the effects of chronic ethanol consumption on DC function generated in vivo under controlled conditions. This approach allowed us to characterize ethanol's effect on DCs with respect to cell surface markers, cytokine profiles, antigen presentation ability, and endocytosis capacity. Furthermore, we evaluated the subsequent role of DC dysfunction in the generation of cytotoxic T-lymphocytes (CTL) immune responses following genetic immunization with a plasmid expressing NS5 protein by using adoptive transfer of syngeneic DCs. In vivo generation of DCs combined with syngeneic DC transfer and DMA-based immunization revealed that ethanol induced dysfunction of DCs is the major factor responsible for the reduce cellular immune response to HCV. This finding may have relevance to persistent HCV infection in alcoholics and identifies a critical cell type that is at risk for ethanol effects. The central hypothesis in this proposal is that altered DC function is one of the major immunologic changes produced by ethanol and there may be differential effects of chronic ethanol on DC subpopulations which subsequently impairs the cellular immune response necessary for viral clearance. Therefore, we would like to develop and implement strategies that increase the ability of the ethanol consuming host to generate better anti-viral responses. We plan to do the following:
Specific Aim 1 : Evaluate the role of DCs on immune responses to HCV in chronic ethanol-fed mice.
Specific Aim 2 : Explore two new approaches of specific viral antigen targeting to activate DCs in vivo during chronic ethanol exposure.
Specific Aim 3. Characterize the possible genetic mechanisms responsible for DC dysfunction produced by ethanol. These investigations open new avenues to enhance antiviral immune response in the setting of chronic ethanol consumption by improving DC function.
|Ortiz, Vivian; Wands, Jack R (2014) Chronic ethanol diet increases regulatory T-cell activity and inhibits hepatitis C virus core-specific cellular immune responses in mice. Hepatol Res 44:788-97|
|Derdak, Zoltan; Villegas, Kristine A; Harb, Ragheb et al. (2013) Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease. J Hepatol 58:785-91|
|de la Monte, Suzanne; Derdak, Zoltan; Wands, Jack R (2012) Alcohol, insulin resistance and the liver-brain axis. J Gastroenterol Hepatol 27 Suppl 2:33-41|
|Qin, Yanli; Tang, Xiaoli; Garcia, Tamako et al. (2011) Hepatitis B virus genotype C isolates with wild-type core promoter sequence replicate less efficiently than genotype B isolates but possess higher virion secretion capacity. J Virol 85:10167-77|
|de la Monte, Suzanne M; Pang, Maoyin; Chaudhry, Rajeev et al. (2011) Peroxisome proliferator-activated receptor agonist treatment of alcohol-induced hepatic insulin resistance. Hepatol Res 41:386-98|
|Derdak, Zoltan; Lang, Charles H; Villegas, Kristine A et al. (2011) Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease. J Hepatol 54:164-72|
|Feng, Dechun; Eken, Ahmet; Ortiz, Vivian et al. (2011) Chronic alcohol-induced liver disease inhibits dendritic cell function. Liver Int 31:950-63|
|Eken, Ahmet; Ortiz, Vivian; Wands, Jack R (2011) Ethanol inhibits antigen presentation by dendritic cells. Clin Vaccine Immunol 18:1157-66|
|Qin, Yanli; Zhang, Jiming; Garcia, Tamako et al. (2011) Improved method for rapid and efficient determination of genome replication and protein expression of clinical hepatitis B virus isolates. J Clin Microbiol 49:1226-33|
|He, Jiman; de la Monte, Suzanne; Wands, Jack R (2010) The p85beta regulatory subunit of PI3K serves as a substrate for PTEN protein phosphatase activity during insulin mediated signaling. Biochem Biophys Res Commun 397:513-9|
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