Oxidation, immune modulation and atherogenesis in vivo

体内氧化、免疫调节和动脉粥样硬化形成

• 批准号: 6577277
• 负责人: WULF PALINSKI
• 金额: $ 25.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6577277
• 关键词: active immunization; antioxidants; apolipoprotein E; atherosclerotic plaque; cellular immunity; developmental immunology; dietary lipid; heat shock proteins; humoral immunity; hypercholesterolemia; immunocytochemistry; immunopathology; laboratory mouse; low density lipoprotein; low density lipoprotein receptor; microarray technology; molecular pathology; mother /embryo /fetus nutrition; nutrition related tag; oxidative stress; oxidized lipid; peroxisome proliferator activated receptor; pregnancy immunology; receptor expression; tocopherols

DESCRIPTION (provided by the applicant): Substantial evidence indicates that immune mechanisms may both enhance and inhibit atherogenesis. We previously showed that oxidation of LDL triggers extensive humoral and cellular immune responses and that active immunization with oxidized LDL (OxLDL) reduces lesion progression. Hypercholesterolemia and concomitant increased oxidative stress may also influence the recruitment of immune-competent cells by modulating arterial gene expression through interference with oxidation-sensitive signaling pathways, including NFkB, PPARgamma, and apoptotic pathways. Unit 4 will test the following hypotheses in vivo: 1) that both humoral and cellular immune responses contribute to the beneficial effect of immunization by several mechanisms, including the removal of OxLDL from the circulation and shifts from Thl cells secreting pro-atherogenic IFNgamma to Th2 cells secreting antiatherogenic cytokines; 2) that vitamin E and ligand-induced PPARgamma activation reduce the intimal recruitment of T cells by interfering with oxidation-sensitive regulation of gene expression in the arterial wall, and 3) that enhanced lesion and antigen-formation during fetal development influences humoral and cellular immune responses later in life. The effects of humoral immune responses on atherosclerosis and the underlying mechanisms will be determined by passively immunizing normal and antibody-deficient (mu knockout) LDL receptor-deficient (LDLR-/-) mice with antibodies to oxidation-specific epitopes. To determine the occurrence of T cell shifts and their impact on atherogenesis, we will compare the effects of immunization with OxLDL (which reduces atherosclerosis) to those of immunization with heat shock protein 65 (which enhances it). The contribution of T cell-mediated immunity will be established by transferring T cells or T cell subsets from immunized mice into naive recipients. The effects of antioxidants, naturally decreased LDL oxidation (lipoxygenase deficiency), and PPARgamma activation on arterial gene expression and T cell recruitment into lesions of different stages will be established by microarrays, real-time PCR, immunocytochemistry, and PCR-based tracking of T cells in LDLR-/- mice and 12/15 lipoxygenase deficient LDLR-/- mice. To determine the consequences of increased antigen formation during fetal development on postnatal immune responses, fetal lesion formation will be enhanced in mice by maternal exposure to hypercholesterolemia. These experiments will provide a better understanding of the mechanisms by which immune responses to OxLDL modulate atherogenesis and potentially lead to new preventive approaches.

描述（由申请人提供）：