Alcoholic liver disease remains a major worldwide health problem. This project will continue studies designed to investigate the hypothesis that metabolically derived aldehydes complex with liver cell proteins forming stable aldehyde adducts that may act as antigens to induce immune responses and play a role in alcohol related liver damage. Recent studies have shown that acetaldehyde and the lipid peroxidation-derived aldehyde, malondialdehyde, can react together with proteins in a synergistic manner to form distinct hybrid adducts which have been designated as MAA adducts. MAA adducts have been found in the livers of ethanol-fed rats and are immunogenic with the production of highly specific antibodies in the absence of adjuvants. Additionally, dependent upon the immunizing protein modified, the antibodies can be either to MAA or to the unmodified protein. Experimental models have demonstrated that antibodies to both self and non-self proteins can be generated following adduct modification. Therefore, it is suggested that proteins are modified with MAA as a result of chronic ethanol consumption and thereby induce an unique immune response to the MAA-epitope, as well as to nonmodified epitopes on soluble carrier proteins. The ability of MAA-modified soluble proteins to induce immune responses is dependent on the unique features of antigen processing andpresentation, and mechanisms of B- and T-cell immunoregulation. The mechanisms of MAA-induced protein immune responses will be addressed by the following specific aims: 1) Characterize the ability of soluble MAA-adducted non-self (HEL, OVA) and self (MSA) proteins to induce antibody responses in the absence of adjuvant to the MAA epitopes or to unmodified carrier protein epitopes; 2) Determine the T cell proliferative responses to MAA adducted non-self and self soluble proteins following immunization in the absence of adjuvants; 3) Determine the cell types that are involved in the uptake, processing, and presentation of MAA-adducted non-self and self proteins 4) Using an in vitro model of Class I antigen presentation, assess the ability of MAA adducted proteins to induce cytotoxic T cell responses to non-self and self-antigens 5) Identify self liver proteins modified with MAA; Determine the effects of chronic ethanol consumption on each of these processes. Using the assays defined above, assess the in vivo role of MAA in initiating these responses in the presence and absence of chronic ethanol consumption. Overall, these studies will begin to develop the mechanisms by which MAA-modified proteins in the presence or absence of alcohol may induce antibody and T cell responses in the absence of adjuvants. Additionally, they should develop the techniques necessary to assess how endogenous MAA-proteins influence the immune system.
Showing the most recent 10 out of 15 publications
