Developmental immune programming and postnatal atherosclerosis

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，妊娠期间母亲肥胖、高胆固醇血症、胰岛素抵抗和糖尿病的日益普遍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是复杂的，但现在可以在实验模型中确定高胆固醇血症、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。母体高胆固醇血症和随之而来的氧化应激增加导致胎儿胎盘中脂肪条纹形成增加，并增加日后对动脉粥样硬化的易感性。最近的证据表明，选择性B和T细胞依赖性出生后免疫应答也通过独立于免疫球蛋白经胎盘通过的机制在子宫内编程，并且这可以受到怀孕前母体适应性免疫的影响。母体免疫与氧化低密度脂蛋白，一种抗原普遍存在于动脉粥样硬化病变，增强特异性IgM免疫反应，并显着减少动脉粥样硬化在成年后代。鉴于免疫机制和炎症在母体条件和后代动脉粥样硬化形成中的重要性，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。具体而言，我们将：1）通过证明用其他抗原，特别是糖尿病相关抗原的母体免疫对免疫编程和动脉粥样硬化具有类似的后果，确定出生后免疫应答的子宫内编程不是OxLDL独有的; 2）通过确定被动母体免疫是否保护后代，确定母体抗体在发育编程中的作用; 3）确定先前的免疫是否保护母亲免受胰岛素抵抗，以及它是否通过增加其胰岛素敏感性、影响脾和动脉细胞因子表达和T细胞分化以及减少在出生后高胆固醇血症、肥胖或胰岛素抵抗的条件下的动脉粥样硬化形成来保护后代; 4）使用缺乏B或T细胞的免疫缺陷模型来确定母体OxLDL免疫在后代中的抗动脉粥样硬化作用是由于体液机制还是细胞机制;和5）使用新的策略来产生单克隆抗体和抗原非依赖性B细胞，其在免疫母亲的后代中差异表达，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，并可能定义新的治疗策略和工具，以减少患有妊娠期胰岛素抵抗和糖尿病的母亲的后代的心血管疾病。它们还可能降低后代对其他免疫调节疾病的易感性，并导致新的胰岛素抵抗免疫预防。

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.