Chronic alcoholism and hepatitis B virus (HBV) infection are associated with chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) in millions of people worldwide. Epidemiologic evidence shows a higher frequency of HBV markers among chronic alcoholics compared to the general population, and more severe liver disease among chronically infected alcoholics compared to patients suffering from chronic alcoholism or HBV infection alone. The applicant laboratory has recently developed an HBV transgenic mouse on a severe combined immunodeficient (SCID) host, which supports consistent levels of virus gene expression and replication. Since the SCID host is not tolerant to the virus, adoptive transfer of unprimed syngeneic splenocytes resulted in the development either acute or chronic hepatitis, with either complete or partial clearance of virus markers from serum and liver, respectively. Interestingly, the introduction of ethanol in a liquid Lieber-DiCarli diet strongly up-regulated HBV gene expression and replication in these mice, and that when ethanol fed mice were adoptively transferred with 5 x 10[7] splenocytes, which usually results in acute hepatitis, they develop chronic liver disease (CLD) instead. Since the pathogenesis of hepatitis B is immune mediated, and T cells play a central role in the clearance of virus infected hepatocytes, the objective of this work is to identify the changes in anti-viral T cell immunity that are responsible for the ethanol mediated changes in pathogenesis. This will be addressed by asking whether the shift from acute to chronic liver disease is associated with changes in the presence, frequency, and distribution of T cell responses to one or more virus antigens (aim 1). Experiments will also be conducted to ask whether chronic hepatitis could be converted back to acute, resolving hepatitis by (1) polarizing the immune response toward Th1, or (2) adoptively transferring primed splenocytes to one or more virus antigens (aim2). Together, these experiments will identify the T cell subsets and specificities associated with the ethanol mediated shift from acute to chronic hepatitis, and then therapeutically manipulate T cell immunity so as to prevent the development of CLD in ethanol fed, adoptively transferred mice.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Lucas, Diane
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Thomas Jefferson University
Schools of Medicine
United States
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Feitelson, Mark A; Clayton, Marcia M; Reis, Helena Mgpv et al. (2008) Pharmacotherapy of chronic viral hepatitis and hepatocellular carcinoma. Expert Opin Pharmacother 9:2233-45
Chichester, Jessica A; Feitelson, Mark A; Calkins, Catherine E (2006) Different response requirements for IFNgamma production in ELISPOT assays by CD4+ T cells from mice early and late after immunization. J Immunol Methods 309:99-107
Chichester, Jessica A; Feitelson, Mark A; Calkins, Catherine E (2006) Transient inhibition of Th1-type cytokine production by CD4 T cells in hepatitis B core antigen immunized mice is mediated by regulatory T cells. Immunology 118:438-48