Maternal nutrient restriction: Effects on offspring immune function

母体营养限制：对后代免疫功能的影响

• 批准号: 8433316
• 负责人: ELLEN KRAIG
• 金额: $ 21.28万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8433316
• 关键词: 16 year old; 6 year old; Activities of Daily Living; Address; Adult; Adult Children; Affect; Age; Aging; Animals; Antibodies; Antigens; Autoimmunity; B-Lymphocytes; Behavioral; Biological Assay; Biological Markers; Blood; Blood Cells; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Caloric Restriction; Cardiovascular Diseases; Cardiovascular system; Cells; Child; Childhood; Childhood Asthma; Chronic Disease; Communicable Diseases; Coupled; Cytotoxic T-Lymphocytes; Defect; Development; Diabetes Mellitus; Diet; Disease; Eating; Elderly; Endocrine; Equilibrium; Ethics; Excision; Exhibits; Fetal Growth; Food; Genes; Health; Helper-Inducer T-Lymphocyte; Heterogeneity; Human; Immune; Immune System and Related Disorders; Immune response; Immune system; Immunity; Immunization; Incidence; Individual; Infection; Inflammation; Inflammatory; Insulin Resistance; Lactation; Long-Term Effects; Low Birth Weight Infant; Lymphocyte; Lymphocyte Subset; Lymphoid; Macaca mulatta; Malnutrition; Measures; Memory; Modeling; Molecular Profiling; Monoclonal Antibody R24; Mothers; Myelogenous; Natural Immunity; Neonatal Mortality; Newborn Infant; Nutrient; Nutritional; Nutritional status; Outcome; Papio; Pathology; Physiological; Population; Predisposition; Pregnancy; Pregnant Women; Primates; Production; Proteins; Protocols documentation; Regulation; Relative (related person); Research; Risk; Serum; Specificity; Systems Development; T memory cell; T-Cell Receptor; T-Cell Receptor-Rearrangement Excision DNA Circles; T-Lymphocyte; Testing; Vaccine Antigen; Vaccines; Yersinia pestis; adaptive immunity; arm; base; cohort; cytokine; dietary restriction; feeding; immune function; immunoregulation; in utero; indexing; innovation; insight; maternal nutrient restriction; mother nutrition; nonhuman primate; novel; nutrition; offspring; pregnant; programs; response; young adult

DESCRIPTION (provided by applicant): Poor maternal nutrition during pregnancy has been associated with increased neonatal mortality and susceptibility to infection and a higher incidence of chronic diseases including cardiovascular disorders, childhood asthma and diabetes. Many of these complications could be due to common underlying immune deficits elicited in utero by the lack of appropriate nutrition. To address the effects of MNR (maternal nutrient restriction) on developmental programming in non-human primates (NHP), the Center for Pregnancy and Newborn Research has developed a cohort of baboon offspring whose mothers received a diet restricted to 70% of the caloric value eaten by the ad lib fed controls (R24 RR0213667). This NHP MNR model offers a unique opportunity to examine the consequences of decreased nutrient availability during pregnancy on immunity in young adult offspring. It has been demonstrated that these MNR offspring have lower birth weights and exhibit physiological changes, most notably increased insulin resistance that persist into childhood. The immune health of these NHP offspring will be tested when they are 5-6 years old, equivalent to post-pubertal 15-16 year old humans. This will allow us to use assays that have been optimized for young adults for an ongoing aging study (R01AG030119). We hypothesize that the offspring of MNR pregnancies will have altered immune developmental programming, resulting in defects in the regulation of innate and adaptive immunity. To address this hypothesis, the baboons will be challenged with a protein vaccine to assess the functional capability of their antigen-specific adaptive immune responses (Aim I). Parameters of both B cell and T cell immunity will be measured in response to primary (naive) and secondary (memory or boost) immunizations. The functional capacity will then be correlated with parameters of immune health to be assessed in Aim II in the absence of an immune challenge. These will include: serum cytokine levels, blood cell populations, T cell repertoire, thymic function, and cel population- specific expression profiling to identify genes regulated in lymphocytes by MNR relative to control. In summary, use of this valuable NHP cohort will provide a unique opportunity to dissect the effects of MNR during pregnancy and lactation on immune system development in a well-controlled primate model. The project is innovative and timely as it incorporates both an immune challenge (vaccine) to test functional capacity coupled with assessments of general immune health. Moreover, expression profiling of T and B cells will provide the first insights into specific mechanisms that effect long-term immune consequences of malnutrition during pregnancy. These approaches may also reveal potential candidate biomarkers of immune health that could then facilitate the identification of immunologically "at risk" children leading o vaccine compositions/protocols that are likely to have greater efficacy.

描述（由申请人提供）：怀孕期间母亲营养不良与新生儿死亡率增加、感染易感性增加以及心血管疾病、儿童哮喘和糖尿病等慢性疾病发病率增加有关。其中许多并发症可能是由于子宫内缺乏适当营养而引起的常见潜在免疫缺陷所致。为了解决 MNR（母体营养限制）对非人类灵长类动物 (NHP) 发育规划的影响，妊娠和新生儿研究中心培育了一组狒狒后代，其母亲的饮食限制为热量值的 70%被即兴喂养控制吃掉（R24 RR0213667）。这种 NHP MNR 模型提供了一个独特的机会来检查怀孕期间营养供应减少对年轻成年后代免疫力的影响。事实证明，这些 MNR 后代出生体重较低，并表现出生理变化，最显着的是胰岛素抵抗增加，并持续到童年。这些NHP后代的免疫健康状况将在他们5-6岁时接受测试，相当于青春期后的15-16岁人类。这将使我们能够使用针对年轻人优化的检测方法来进行正在进行的衰老研究 (R01AG030119)。我们假设 MNR 妊娠的后代将改变免疫发育程序，导致先天性和适应性免疫的调节缺陷。为了解决这一假设，狒狒将接受蛋白质疫苗的攻击，以评估其抗原特异性适应性免疫反应的功能能力（目标 I）。 B 细胞和 T 细胞免疫参数将根据初次（初始）和二次（记忆或加强）免疫进行测量。然后，功能能力将与在没有免疫挑战的情况下在目标 II 中评估的免疫健康参数相关联。这些包括：血清细胞因子水平、血细胞群、T 细胞库、胸腺功能和细胞群特异性表达谱，以识别淋巴细胞中相对于对照受 MNR 调节的基因。总之，使用这个有价值的 NHP 队列将为在控制良好的灵长类动物模型中剖析妊娠和哺乳期间 MNR 对免疫系统发育的影响提供独特的机会。该项目具有创新性和及时性，因为它结合了测试功能能力的免疫挑战（疫苗）和对一般免疫健康状况的评估。此外，T 细胞和 B 细胞的表达谱将提供关于 影响怀孕期间营养不良的长期免疫后果的具体机制。这些方法还可能揭示免疫健康的潜在候选生物标志物，从而有助于识别免疫学“处于危险中”的儿童，从而导致可能具有更大功效的疫苗组合物/方案。