Developmental immune programming and postnatal atherosclerosis

描述(由申请人提供)：宫内环境是心血管疾病的重要决定因素。因此，孕期母亲肥胖、高胆固醇血症、胰岛素抵抗和糖尿病的患病率越来越高，预计会导致后代患心血管疾病的浪潮，但对宫内编程的机制知之甚少。尽管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。母亲的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中脂肪条纹的形成，并在以后的生活中增加对动脉粥样硬化的易感性。最近的证据表明，依赖于B和T细胞的选择性出生后免疫反应在子宫内也是通过独立于免疫球蛋白通过胎盘的机制编程的，这可以受到孕前母体适应性免疫的影响。OxLDL是动脉粥样硬化病变中普遍存在的一种抗原，母体免疫增强了成年后代的特异性IgM免疫反应，显著减少了成年后代的动脉粥样硬化。鉴于免疫机制和炎症在母体疾病和子代动脉粥样硬化形成中的重要性，我们建议进一步研究宫内免疫编程的机制和母体免疫调节的保护作用。具体地说，我们将：1)通过证明其他抗原，特别是与糖尿病相关的抗原免疫，对免疫编程和动脉粥样硬化具有类似的后果，确定出生后免疫反应的宫内编程不是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规划中的作用；3)确定以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后代的胰岛素敏感性，影响脾和动脉细胞因子的表达和T细胞分化，以及在出生后高胆固醇血症、肥胖或胰岛素抵抗的情况下减少动脉粥样硬化来保护后代；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；以及5)使用一种新的策略来产生在免疫母亲的后代中差异表达的单抗和抗原非依赖性B细胞，并建立它们的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，并导致对胰岛素抵抗的新的免疫预防。

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.