Immune responses to OxLDL and atherosclerosis

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DESCRIPTION (provided by the applicant): Oxidation of LDL renders it immunogenic and both humoral and cellular immune responses occur. Considerable evidence suggests that adaptive immune response to OxLDL are important: For example, OxLDL-specific T cells are present within lesions, and immunization of animal models with homologous OxLDL decreases the rate of progression of atherosclerosis. This Unit will test the following hypotheses: That certain adaptive immune response to epitopes of OxLDL can be beneficial; That there are human oxidation-specific autoantibodies that have similar properties to those cloned from apoE-deficient mice (i.e. the ability to affect macrophage uptake of OxLDL); That the presence of oxidized moieties on apoptotic cells render these cells immunogenic and proinflammatory; That the oxidation-specific antibodies can be used to detect rates of oxidation of LDL in vivo; and that various oxidation-specific markers in plasma are of clinical utility in identifying patients at increased risk for cardiovascular disease. We will test these hypotheses by determining the mechanisms by which immunization of hypercholesterolemic mice with MDA-LDL, as a model epitope of OxLDL, ameliorates atherosclerosis and specifically test the hypothesis that immunization causes a switch from a proatherogenic Th1 phenotype to an antiatherogenic Th2 phenotype. We will characterize T cell responses to the immunization with MDA-LDL and perform adoptive transfer experiments of T cell populations from immunized mice into naive mice and determine the effects on atherogenesis. We will also determine the components of MDA-LDL responsible for the protective effect. We will clone human oxidation- specific autoantibodies from an immunoglobulin phage display library and determine their biological properties. We will determine the epitopes on OxLDL and apoptotic cells recognized by antibodies that block uptake by macrophages, which in turn should bind to specific scavenger receptors. We will immunize mice with syngenic apoptotic cells and determine if they are immunogenic and if these cells induce monocyte binding to endothelial cells because of oxidized phospholipids on their surface. We will use immunological techniques to determine the in vivo rates of oxidation of LDL in vivo in animals and humans. Finally, we will examine general and high-risk populations to determine if various immunological markers of OxLDL are of clinical value in identifying individuals at increased risk for cardiovascular disease. In summary, these data should contribute to an improved understanding of the consequences of the immunogenicity of OxLDL.