It has been shown that long term alcohol ingestion can lead to the development of chemical changes to proteins. It is believed that metabolism of alcohol by alcohol dehydrogenase to acetaldehyde (AA) and lipid peroxidation of polyunsaturated fats to malondialdehyde (MDA) results in the adduction of proteins with both of these aldehyde species. In fact, AA and MDA have been shown to react in a synergistic manner to form a distinct adduct (MAA) that has been found in in vitro as well as in vivo experimentally. This MAA adduct has been shown to induce a strong antibody response to both the MAA epitope(s) and to the carrier protein without the use of adjuvants. We hypothesize that following chronic ethanol consumption MAA-modified proteins induce and 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 and immune response is dependent on unique features of antigen processing antigen presentation, and mechanisms of T-cell immunoregulatory circuits. The principal objective of this research project is to define and characterize the humoral and cellular immune responses to MAA-adducted proteins. To determine the cell types primarily involved in the uptake, processing and presentation of proteins modified by MAA and assess whether these immune mechanisms play a role in the development and/or progression of alcohol liver disease. We propose to address the effects of chronic ethanol consumption on these problems using the following specific aims: 1) Characterize the ability if MAA adducted proteins to induce and antibody (humoral immune) response without adjuvant to the MAA epitopes on soluble proteins; 2)Characterize the T cell response to MAA adducted soluble proteins following immunization; 3) Determine the cell types that are involved in the uptake, processing, and presentation of MAA-adducted proteins.
