Maternal nutrient restriction: Effects on offspring immune function

描述（由申请方提供）：妊娠期间母亲营养不良与新生儿死亡率和感染易感性增加以及慢性疾病（包括心血管疾病、儿童哮喘和糖尿病）发病率增加有关。许多这些并发症可能是由于常见的潜在免疫缺陷引起的子宫内缺乏适当的营养。为了解决MNR（母体营养限制）对非人灵长类动物（NHP）发育编程的影响，妊娠和新生儿研究中心开发了一组狒狒后代，其母亲接受的饮食限制为自由进食对照组所摄入热量的70%（R24 RR 0213667）。这种NHP MNR模型提供了一个独特的机会，以检查妊娠期间营养物质供应减少对年轻成年后代免疫力的影响。已经证明，这些MNR后代具有较低的出生体重并表现出生理变化，最显著的是持续到儿童期的胰岛素抵抗增加。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15-16岁的人类。这将使我们能够使用针对年轻成人进行优化的测定方法进行正在进行的老化研究（R 01 AG 030119）。我们假设MNR妊娠的后代将改变免疫发育编程，导致先天性和适应性免疫调节缺陷。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应答的功能能力（目的I）。将测量响应于初次（初始）和二次（记忆或加强）免疫的B细胞和T细胞免疫的参数。然后，在没有免疫激发的情况下，将功能能力与目标II中评估的免疫健康参数相关联。这些措施包括：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，以鉴定相对于对照，淋巴细胞中由MNR调节的基因。总之，使用这一有价值的NHP队列将提供一个独特的机会，在一个良好控制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。该项目具有创新性和及时性，因为它既包括免疫挑战（疫苗），以测试功能能力，又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。这些方法还可以揭示免疫健康的潜在候选生物标志物，其然后可以促进鉴定免疫学上“处于风险中”的儿童，从而导致可能具有更大功效的疫苗组合物/方案。

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.