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.
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