Abstract

Alcoholic liver disease remains a major worldwide health problem. Although many varied pathogenic mechanisms have been implicated in the development of ethanol-induced hepatocellular damage, recent studies suggest that the immune system may play a key role in the initiation or maintenance of liver damage. This project will study the hypothesis that alcohol metabolized to acetaldehyde complexes with liver cell membrane proteins forming stable acetaldehyde adducts. These acetaldehyde-protein adducts may act as antigens, inducing an immune response characteristic of autoimmune phenomenon. Furthermore, acute or chronic ingestion of alcohol itself may alter the immune response to acetaldehyde-surface protein epitopes.
The specific aims are: 1) To develop a panel of polyclonal and monoclonal antibodies that recognize epitopes on acetaldehyde-modified liver cell membrane surfaces, including antibodies directed against acetaldehyde adducts on intact liver cell culture line. 2) Develop antibodies that uniquely recognize epitopes on acetaldehyde-modified proteins formed under reducing versus non-reducing conditions. 3) Demonstrate the presence of acetaldehyde-modified surface antigens on intact liver cells by direct binding of antibodies to liver cell culture line; by in situ binding of antibodies to murine liver cells modified by in vivo alcohol feeding; by detection of anti-acetal dehyde/liver surface membrane adducts by using a B lymphocyte in vitro culture system. The role of the T helper and T suppressor cells in regulating this immune response to acetal dehyde- surface membrane adducts by using a B lymphocyte in vitro culture system. The role of T helper and T suppressor cells in regulating this immune response will be defined. In addition, the effect of in vivo ethanol feeing on the immunoregulatory subpopulations will be studied. The immunoregulatory requirements of anti-acetal dehyde-membrane antibody production noted in vitro will be confirmed by in vivo depletion of selective lymphocyte subsets utilizing adult thymectomy and in vivo monoclonal antibody administration.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007818-02
Application #
3111738
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1989-04-01
Project End
1992-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
University of Nebraska Medical Center
Department
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198

  Publications

Thiele, Geoffrey M; Klassen, Lynell W; Tuma, Dean J (2008) Formation and immunological properties of aldehyde-derived protein adducts following alcohol consumption. Methods Mol Biol 447:235-57
Duryee, Michael J; Freeman, Thomas L; Willis, Monte S et al. (2005) Scavenger receptors on sinusoidal liver endothelial cells are involved in the uptake of aldehyde-modified proteins. Mol Pharmacol 68:1423-30
Duryee, Michael J; Klassen, Lynell W; Freeman, Thomas L et al. (2004) Lipopolysaccharide is a cofactor for malondialdehyde-acetaldehyde adduct-mediated cytokine/chemokine release by rat sinusoidal liver endothelial and Kupffer cells. Alcohol Clin Exp Res 28:1931-8
Duryee, Michael J; Willis, Monte S; Freeman, Thomas L et al. (2004) Mechanisms of alcohol liver damage: aldehydes, scavenger receptors, and autoimmunity. Front Biosci 9:3145-55
Willis, Monte S; Klassen, Lynell W; Carlson, Deborah L et al. (2004) Malondialdehyde-acetaldehyde haptenated protein binds macrophage scavenger receptor(s) and induces lysosomal damage. Int Immunopharmacol 4:885-99
Willis, Monte S; Thiele, Geoffrey M; Tuma, Dean J et al. (2003) T cell proliferative responses to malondialdehyde-acetaldehyde haptenated protein are scavenger receptor mediated. Int Immunopharmacol 3:1381-99
Duryee, Michael J; Klassen, Lynell W; Freeman, Thomas L et al. (2003) Chronic ethanol consumption impairs receptor-mediated endocytosis of MAA-modified albumin by liver endothelial cells. Biochem Pharmacol 66:1045-54
Thiele, Geoffrey M; Szabo, Gyongyi; Kovacs, Elizabeth J et al. (2002) Modulation of immunity and viral-host interactions by alcohol. Alcohol Clin Exp Res 26:1897-908
Willis, Monte S; Klassen, Lynell W; Tuma, Dean J et al. (2002) In vitro exposure to malondialdehyde-acetaldehyde adducted protein inhibits cell proliferation and viability. Alcohol Clin Exp Res 26:158-64
Willis, Monte S; Klassen, Lynell W; Tuma, Dean J et al. (2002) Adduction of soluble proteins with malondialdehyde-acetaldehyde (MAA) induces antibody production and enhances T-cell proliferation. Alcohol Clin Exp Res 26:94-106

Showing the most recent 10 out of 24 publications