Maternal nutrient restriction: Effects on offspring immune function

描述（由申请人提供）：怀孕期间孕产妇营养不良与新生儿死亡率和感染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病发病率增加有关。这些并发症中的许多可能是由于缺乏适当的营养在子宫内引起的共同的潜在免疫缺陷。为了解决MNR（母体营养限制）对非人灵长类动物（NHP）发育计划的影响，怀孕和新生儿研究中心开发了一组狒狒后代，其母亲的饮食限制为自由喂养对照组（R24 RR0213667）所吃热量值的70%。这个NHP MNR模型提供了一个独特的机会来检查怀孕期间营养物质可用性降低对年轻成年后代免疫力的影响。研究表明，这些MNR后代的出生体重较低，并表现出生理变化，最明显的是持续到童年的胰岛素抵抗增加。这些NHP后代的免疫健康将在他们5-6岁时进行测试，相当于青春期后的15-16岁的人类。这将允许我们在一项正在进行的衰老研究中使用针对年轻人优化的检测方法（R01AG030119）。我们假设，MNR妊娠的后代将改变免疫发育程序，导致先天和适应性免疫调节缺陷。为了解决这一假设，将对狒狒进行蛋白质疫苗挑战，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细胞免疫的参数将在初次（初始）和二次（记忆或增强）免疫应答中被测量。然后将功能能力与免疫健康参数相关联，在没有免疫挑战的情况下，在Aim II中进行评估。这些将包括：血清细胞因子水平、血细胞群、T细胞库、胸腺功能和细胞群特异性表达谱，以确定相对于对照组，MNR在淋巴细胞中调节的基因。总之，使用这个有价值的NHP队列将提供一个独特的机会，在一个控制良好的灵长类动物模型中，剖析妊娠和哺乳期MNR对免疫系统发育的影响。该项目具有创新性和及时性，因为它既包括测试功能能力的免疫挑战（疫苗），也包括对一般免疫健康的评估。此外，T细胞和B细胞的表达谱将提供第一个见解

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.