Maternal nutrient restriction: Effects on offspring immune function

描述(申请人提供)：孕期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而在子宫中引起的共同的潜在免疫缺陷。为了解决母体营养限制(MNR)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开发了一组狒狒后代，其母亲的饮食被限制在临时喂养对照组摄取的卡路里的70%(R24 RR0213667)。这一NHP MNR模型提供了一个独特的机会来研究怀孕期间营养供应减少对年轻成年后代免疫力的影响。已经证明，这些MNR后代出生时体重较低，并表现出生理变化，最显著的是胰岛素抵抗增加，并持续到儿童时期。这些NHP后代的免疫健康状况将在他们5-6岁时进行测试，相当于青春期后15-16岁的人类。这将使我们能够使用为年轻人优化的分析方法进行正在进行的衰老研究(R01AG030119)。我们推测，MNR妊娠的后代将改变免疫发育编程，导致先天免疫和获得性免疫调节的缺陷。为了解决这一假设，将用一种蛋白质疫苗挑战狒狒，以评估它们的抗原特异性适应性免疫反应(Aim I)的功能能力。B细胞和T细胞免疫的参数将在一次(幼稚)和二次(记忆或增强)免疫后进行测量。然后，在没有免疫挑战的情况下，功能能力将与免疫健康参数相关，在AIM II中进行评估。这些将包括：血清细胞因子水平、血细胞数量、T细胞谱、胸腺功能和细胞群体特异性表达谱，以确定MNR相对对照调节的淋巴细胞中的基因。总之，使用这一有价值的NHP队列将提供一个独特的机会，在受控良好的灵长类动物模型中剖析怀孕和哺乳期MNR对免疫系统发育的影响。该项目是创新和及时的，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和B细胞的表达谱将提供对 影响孕期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记物，然后可能有助于识别免疫“高危”儿童，从而导致可能具有更大疗效的疫苗组合物/方案。 公共卫生相关性：孕期产妇营养不良与低出生体重、新生儿死亡率、易患传染病和其他长期并发症有关；其中许多影响可能是由于在这一免疫发育的关键窗口期间缺乏重要营养物质造成的共同潜在免疫缺陷。我们有一个独特的机会来测量一群幼崽的免疫功能，这些幼崽的母亲在怀孕和哺乳期间被给予适度限制的饮食。这些研究将与人类直接相关，并应为潜在健康并发症的管理提供新的见解，如感染和炎症性疾病，这些并发症可能会随着这些高危后代成熟到成年，然后再到年龄而出现。

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.