Developmental immune programming and postnatal atherosclerosis

发育免疫编程和产后动脉粥样硬化

• 批准号: 7810732
• 负责人: WULF PALINSKI
• 金额: $ 47.74万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7810732
• 关键词: Active Immunization; Adult; Adult Children; Affect; Agonist; Animal Model; Animals; Antiatherogenic; Antibodies; Antigens; Antioxidants; Aorta; Arterial Fatty Streak; Arteries; Atherosclerosis; B-Lymphocytes; Blood Circulation; CD8B1 gene; Cardiovascular Diseases; Childhood; Cholesterol; Complex; Development; Diabetes Mellitus; Diagnostic; Disease; Environment; Epidemiology; Epitopes; Experimental Models; Female; Gene Proteins; Goals; Human; Hybridomas; Hypertension; Immune; Immune response; Immunization; Immunoglobulin M; Immunoglobulins; Immunohistochemistry; Inflammation; Insulin Resistance; LDL glycosylated lipoproteins; Lasers; Lead; Lesion; Leukocytes; Life; Link; Lipid Peroxidation; Lymphocyte; Maternal antibody; Metabolic; Metabolic syndrome; Microscopy; Modeling; Monoclonal Antibodies; Mothers; Mus; Nuclear; Obesity; Oryctolagus cuniculus; Oxidative Stress; PPAR Pathway; Partner in relationship; Predisposition; Pregnancy; Prevalence; Prevention; Probability; Publications; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; T cell differentiation; T-Lymphocyte; Testing; Text; Therapeutic; adaptive immunity; atherogenesis; atheroprotective; cytokine; diabetic; fetal; hypercholesterolemia; immunoregulation; in utero; in vivo; insulin sensitivity; male; novel; novel strategies; offspring; oxidation; oxidized low density lipoprotein; postnatal; programs; protective effect; protein expression; public health relevance; research study; tool

DESCRIPTION (provided by applicant): The in utero environment is an important determinant of cardiovascular disease. The increasing prevalence of maternal obesity, hypercholesterolemia, insulin resistance and diabetes during pregnancy is therefore expected to lead to a wave of cardiovascular disease in offspring, but little is known about the mechanisms of in utero programming. Although metabolic changes associated with diabetic conditions are complex, pathogenic mechanisms and therapeutical targets for three key factors, hypercholesterolemia, insulin resistance, and inflammation, can now be determined in experimental models. Maternal hypercholesterolemia and the ensuing increased oxidative stress lead to increased fatty streak formation in fetal aortas and increased susceptibility to atherosclerosis later in life. Recent evidence indicated that selective B and T cell- dependent postnatal immune responses are also programmed in utero by mechanisms independent of transplacental passage of immunoglobulins, and that this can be influenced by maternal adaptive immunity prior to pregnancy. Maternal immunization with OxLDL, an antigen prevalent in atherosclerotic lesions, enhanced specific IgM immune responses and markedly reduced atherosclerosis in adult offspring. Given the importance of immune mechanisms and inflammation in both maternal conditions and offspring athero-genesis, we propose to further investigate the mechanisms of in utero immune programming and the protective effects of maternal immunomodulation. Specifically, we will: 1) establish that in utero programming of postnatal immune responses is not unique to OxLDL, by demonstrating that maternal immunization with other antigens, in particular diabetes-related ones, has similar consequences on immune programming and atherosclerosis; 2) establish the role of maternal antibodies in developmental programming by determining whether passive maternal immunization protects offspring; 3) determine whether prior immunization protects mothers against insulin resistance, and whether it protects offspring by increasing their insulin sensitivity, affecting splenic and arterial cytokine expression and T cell differentiation, and reducing atherogenesis under conditions of postnatal hypercholesterolemia, obesity, or insulin resistance; 4) use immune-deficient models lacking B or T cells to establish whether the antiatherogenic effect of maternal OxLDL immunization in offspring is due to humoral or cellular mechanisms; and 5) use a novel strategy to generate monoclonal antibodies and antigen-independent B cells that are differentially expressed in offspring of immunized mothers, and establish their antiatherogenic effect. PUBLIC HEALTH RELEVANCE: These studies will elucidate essential mechanisms of developmental immune programming and may define new therapeutical strategies and tools to reduce cardiovascular disease in offspring of mothers with gestational insulin resistance and diabetes. They may also reduce the susceptibility of offspring to other immune-modulated disease, and lead to new immunoprevention of insulin resistance, in general.

描述（由申请人提供）：子宫内环境是心血管疾病的重要决定因素。因此，怀孕期间孕产妇肥胖、高胆固醇血症、胰岛素抵抗和糖尿病的日益流行预计将导致后代心血管疾病的浪潮，但对子宫内编程的机制知之甚少。虽然与糖尿病相关的代谢变化很复杂，但现在可以通过实验模型确定高胆固醇血症、胰岛素抵抗和炎症这三个关键因素的致病机制和治疗靶点。母亲高胆固醇血症和随之而来的氧化应激增加导致胎儿主动脉脂肪条纹的形成增加，并增加了以后生活中动脉粥样硬化的易感性。最近的证据表明，选择性B细胞和T细胞依赖性的出生后免疫反应也在子宫内通过独立于免疫球蛋白经胎盘传递的机制进行编程，并且这可能受到怀孕前母体适应性免疫的影响。母亲免疫OxLDL（一种普遍存在于动脉粥样硬化病变中的抗原）可增强特异性IgM免疫反应，并显著减少成年后代的动脉粥样硬化。鉴于免疫机制和炎症在母体条件和后代动脉粥样硬化发生中的重要性，我们建议进一步研究子宫内免疫编程的机制和母体免疫调节的保护作用。具体来说，我们将：1)通过证明母体免疫其他抗原，特别是与糖尿病相关的抗原，对免疫编程和动脉粥样硬化有类似的影响，确定出生后免疫反应的子宫编程不是OxLDL所独有的；2)通过确定母体被动免疫对后代的保护作用，确立母体抗体在发育规划中的作用；3)确定事先免疫是否可以保护母亲免受胰岛素抵抗，以及是否通过增加后代的胰岛素敏感性、影响脾和动脉细胞因子表达和T细胞分化、减少出生后高胆固醇血症、肥胖或胰岛素抵抗条件下的动脉粥样硬化来保护后代；4)利用缺乏B细胞或T细胞的免疫缺陷模型，确定母体OxLDL免疫对后代的抗动脉粥样硬化作用是由于体液机制还是细胞机制；5)利用新策略产生单克隆抗体和抗原非依赖性B细胞，在免疫母代后代中差异表达，并确定其抗动脉粥样硬化作用。公共卫生相关性：这些研究将阐明发育免疫编程的基本机制，并可能确定新的治疗策略和工具，以减少妊娠期胰岛素抵抗和糖尿病母亲后代的心血管疾病。它们还可能降低后代对其他免疫调节疾病的易感性，并在一般情况下导致新的胰岛素抵抗免疫预防。