Understanding the Role of Autoantibodies Targeting ApoA-I Year 2

The mechanisms that lead to atherosclerosis based on decreased levels of apolipoproteinA-I (ApoAI) are not well understood and efforts to clarify these details have thus far been unsuccessful. Autoantibodies targeting ApoA-I have been identified in patients with chronic inflammation as a result of other underlying disorders or due to a major cardiac events, but their role in disease progression is unclear. Few studies have focused on modulating the autoantibody response toward ApoA-I, but efforts in this area would provide new targets to treat patients and a platform for new therapeutic discovery to build healthier lives free of cardiovascular disease. We hypothesize that the role of anti-ApoA-I antibodies shifts during disease progression from protective, prior to atherosclerosis onset, to pathogenic as chronic inflammation during CVD persists. We have devised an immunomodulation strategy to more precisely evaluate the role of autoantibodies targeting ApoA-I through epitope specific activation of B cells using an immunostimulatory formulation or epitope specific B cell depletion using an immunosuppressive formulation. Our innovative approach is based on evidence that antibody responses target ApoA-I, and are induced toward post-translationally modified residues within the sequence. By implementing modified or unmodified peptide epitopes into liposomal formulations that activate or inhibit an epitope specific response we will be able to investigate the role of antibodies targeting ApoA-I in a precise manner. The data generated from these proposed studies will provide evidence of the nuanced autoimmune response targeting ApoA-I to better understand one potential mechanism of ApoA-I induced atherosclerosis. These data will also offer a new paradigm to the treatment of atherosclerosis and cardiovascular disease. To investigate this hypothesis we propose to measure the antibody titers toward modified and unmodified peptide epitopes by ELISA using serum from atherosclerotic mice, monkeys and human patients. We will then study the induction and depletion of epitope specific antibodies in vivo using liposomal formulations containing the modified and unmodified peptides and correlate antibody titers to disease progression.