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: 8284123
• 负责人: ELLEN KRAIG
• 金额: $ 18.64万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284123
• 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. PUBLIC HEALTH RELEVANCE: Poor maternal nutrition during pregnancy has been associated with low birth weight, neonatal mortality, susceptibility to infectious diseases and other long-term complications; many of these effects could be due to common underlying immune deficits that result from the lack of vital nutrients during this critical window of immune development. We have the unique opportunity to measure immune function in a cohort of young baboons whose mothers were given a moderately restricted diet during pregnancy and lactation. These studies will have direct relevance to humans and should provide novel insights into the management of potential health complications, like infection and inflammatory disorders, which might arise as these at-risk offspring mature into adulthood and then age.

描述（由申请人提供）：怀孕期间的孕产妇营养不良与新生儿死亡率和对感染的易感性增加以及包括心血管疾病，儿童哮喘和糖尿病在内的慢性疾病发生率更高。这些并发症中的许多并发症可能是由于缺乏适当的营养而在子宫内引起的常见免疫缺陷。为了解决MNR（产妇营养限制）对非人类灵长类动物（NHP）发育节目的影响，怀孕和新生儿研究中心已经开发了一系列狒狒后代，其母亲的饮食限制在AD LIB FED CONTROLS（R24 RR021366667）的饮食中，限制在饮食中的70％。该NHP MNR模型提供了一个独特的机会，可以检查妊娠期间养分减少对年轻成人后代免疫力的后果。已经证明，这些MNR后代的出生体重较低，并且表现出生理变化，最著名的是增加了胰岛素耐药性，这些胰岛素耐药性持续到童年。这些NHP后代的免疫健康将在5-6岁时进行测试，相当于青年后15-16岁的人类。这将使我们能够使用已对年轻人进行优化的测定法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节目，从而导致先天和适应性免疫的调节缺陷。为了解决这一假设，狒狒将受到蛋白质疫苗的挑战，以评估其抗原特异性适应性免疫反应的功能能力（AIM I）。 B细胞和T细胞免疫的参数将响应于原发性（幼稚）和次级（记忆或增强）免疫接种。然后，在没有免疫挑战的情况下，功能能力将与AIM II评估的免疫健康参数相关。这些将包括：血清细胞因子水平，血细胞群，T细胞库，胸腺功能和特定于群体的表达分析，以鉴定MNR相对于对照的MNR在淋巴细胞中调节的基因。总而言之，使用这种有价值的NHP队列将提供一个独特的机会，以在良好控制的灵长类动物模型中剖析怀孕期间MNR和哺乳对免疫系统发育的影响。该项目具有创新性和及时，因为它既包含了免疫挑战（疫苗），以测试功能能力以及评估一般免疫健康的评估。此外，T和B细胞的表达分析将提供第一个见解 在怀孕期间影响营养不良的长期免疫后果的特定机制。这些方法还可能揭示了免疫健康的潜在候选生物标志物，然后可以促进识别带有O疫苗成分/方案的免疫“风险”儿童，这些儿童可能具有更大的功效。 公共卫生相关性：怀孕期间的孕产妇营养不足与低出生体重，新生儿死亡率，对传染病的易感性和其他长期并发症有关；这些影响中的许多可能是由于在免疫发育的关键窗口中缺乏重要营养物质导致的常见潜在免疫缺陷。我们有独特的机会在一群年轻的狒狒中衡量免疫功能，在怀孕和哺乳期间，母亲的母亲受到适度限制的饮食。这些研究将与人类有直接的相关性，并应提供对潜在健康并发症的管理（例如感染和炎症性疾病）的新见解，这可能会随着这些高危后代成熟到成年和年龄而产生的。