IMMUNE RESPONSE TO ACETALDEHYDE ADDUCTS ON LIVER CELLS

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.