Oxidation of LDL (OxLDL) renders it immunogenic and both a humoral and cell-mediated response occurs. The overall goal of this unit is to explore the role of the immune response to OxLDL, with emphasis on the humoral immunity that occurs in human populations. We will measure the autoantibody titers to epitopes of oxidized LDL in plasma of human subjects already enrolled in a variety of well established epidemiologic studies containing both men and women of various ethnic backgrounds. We will determine the relationship of the titers to clinical and anatomical measures of atherosclerosis and to a variety of risk factors such as age, smoking hyperlipidemia, gender, diabetes and/or ethnic background. In particular, we will determine if the titer of these antibodies is predictive of future clinical events and whether interventions, such as hypolipidemic or antioxidant therapy in humans and animal models will alter autoantibody titers. We will determine if immune complexes with LDL are found in plasma in animals and humans, and if there relate to the extent of atherosclerosis. We will utilize sensitive immunological techniques to determine if epitopes of OxLDL found in atherosclerotic lesions are also present on circulating LDL and if the levels of these differ in various patient populations. We will clone and characterize naturally occurring monoclonal antibodies to epitopes of OxLDL derived from apo E- derived from apo E-deficient with extensive atherosclerosis. Because these mice have not been immunized exogenously, the monoclonal antibodies to OxLDL presumably define epitopes actually formed in vivo. These antibodies will be used to characterize in detail a spectrum of epitopes present in OxLDL and, in turn, these defined antigens will be used as immunogens in Unit 3 to determine if immunization of mice with these epitopes will augment the humoral immune response and ameliorate atherosclerosis, as was previously observed in WHHL rabbits immunized with autologous malondialdehyde-modified LDL. Finally, together with Unit 2, we will also utilize these antibodies to define the epitopes on OxLDL that bind to the various OxLDL receptors present on macrophages. Thus, these studies should provide both clinical and basic information that will help to better understand the role of the immune response to oxidation of LDL, and may provide useful diagnostic tools and outline new therapeutic options.
Showing the most recent 10 out of 120 publications
