Alcoholic liver disease remains a major worldwide health problem for which no specific pathophysiology has been defined. This project will continue studies designed to investigate the hypothesis that metabolically derived acetaldehyde complexes with liver cell proteins forming stable acetaldehyde adducts. These acetaldehyde-protein adducts may then act as antigens, inducing an immune response which may contribute to alcohol related liver damage. The initial studies of this ongoing project developed a series of unique monoclonal and purified polyclonal antibodies that reacted with a variety of specific acetaldehyde adduct species formed in vitro. Specific acetaldehyde adduct species detected included: 1) N-ethyl lysine adducts; 2) reduced non-N-ethyl lysine adducts; 3) non-reduced adducts; and 4) non-reduced adducts """"""""stabilized"""""""" under in vitro conditions. Adducts formed in vitro under non-reducing conditions can be modified by antigen processing cells in vivo to express completely different antigenic structures. Thus, some anti-acetaldehyde antibodies seen in the serum of humans or animals exposed to alcohol might represent antigen processing changes from APC engulfment of non-reduced protein adducts. In addition, it appears that both the humoral and cellular immune response to acetaldehyde adducts made under physiologic conditions is under genetic control. While chemically different adducts can be detected using specific antibodies, it is still unclear which of these adducts may be involved in the biochemical and/or immunologic alterations seen following chronic alcohol ingestion.
The specific aims of the ongoing project are: 1) Determine the biological relevance of specific acetaldehyde adducts. This will be done by defining specific chemical adduct species using immunologic means and probing liver specimens from animals exposed to alcohol with these defined antibodies. 2) Determine the nature of the in vivo conversion of non-reduced acetaldehyde adduct epitopes to reduced adduct epitopes. The role of MHC proteins in the antigen processing; the intracellular mechanisms utilized; and the specific tissue source of APC's will be studied. 3) Evaluate the T cell response to the biologically significant acetaldehyde adduct epitope defined above. Specific T cell lines that respond to the biologically relevant epitope will be developed and used to investigate activation following chronic alcohol exposure.
|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|
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|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|
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