Effect of breast feeding on immunologic priming in young infants.

描述（申请人提供）：与年龄较大的儿童不同，婴儿的疫苗诱导免疫力在初次免疫后减弱，需要多次加强以建立免疫记忆。与配方奶喂养相比，母乳喂养的婴儿疫苗应答的持续时间和程度有所改善，但母乳喂养增强免疫启动的机制尚不清楚。母乳喂养增强对疫苗接种的免疫反应的范围从对免疫发育的直接影响到通过改变肠道微生物群来增强先天免疫。拟议的研究测试了这样的假设：母乳喂养通过调节婴儿肠道的微生物定植来加速2个月和4个月大免疫后的B细胞启动和免疫球蛋白多样性。研究将重点关注对流感嗜血杆菌（HIb）和肺炎链球菌结合疫苗的反应[Prevnar 13（R）]。本申请的主要目的是确定母乳喂养影响新生儿B细胞发育和抗体亲和力成熟的机制。为了验证我们的假设，我们将在出生后至少前四个月完全母乳喂养的婴儿与完全配方奶粉喂养的婴儿之间检查从出生到一岁的免疫反应和胃肠道微生物定植。该项目有三个具体目标：1）通过深度测序检查免疫球蛋白多样性的发展和体细胞高突变的频率，并将结果与疫苗应答的既定措施相关联，包括Prevnar 13（R）疫苗中包含的流感嗜血杆菌和肺炎球菌多糖血清型的免疫后滴度和调理吞噬活性。2)通过检查T和B细胞成熟程度、B细胞类别转换重组程度、促炎细胞因子水平、巨噬细胞活化程度和新生儿单核细胞/巨噬细胞经Toll样受体活化后产生BAFF和APRIL的能力，评价婴儿先天免疫应答与免疫球蛋白多样性之间的关系。3)评估母乳喂养和配方奶粉喂养婴儿对疫苗接种的体液免疫应答与肠道微生物群之间的关系。拟议的研究采用创新策略来解决我们对人类免疫发育理解的重大差距。研究结果将为婴儿喂养在疫苗免疫力发展中的作用提供新的衡量标准，并为母亲就婴儿的营养选择做出知情选择提供证据。

DESCRIPTION (provided by applicant): Unlike older children, vaccine-induced immunity among infants wanes after initial immunization and multiple boosters are necessary to establish immunologic memory. Compared to formula feeding, infants who are breast fed have improved duration and magnitude of vaccine responses but the mechanisms by which breast feeding enhances immunologic priming are unknown. Breast feeding's enhancement of immune responses to vaccination range from direct effects on immune development to augmentation of innate immunity by altering commensal gut microbiota. The proposed research tests the hypothesis that breast feeding accelerates B cell priming and immunoglobulin diversity following immunizations at 2 and 4 months of age by modulating the microbial colonization of the infant gut. Studies will focus on the response to the conjugated vaccines against Haemophilus influenza (HIb) and Streptococcus pneumonia [Prevnar 13(R)]. A major goal of this application is to determine mechanisms by which breast feeding impacts neonatal B cell development and antibody affinity maturation. To test our hypothesis, immune responses and gastrointestinal microbe colonization from birth to one year of age will be examined among infants who are exclusively breast fed for at least the first four months of life versus those who are exclusively formula fed. The project has three specific aims: 1) To examine the development of immunoglobulin diversity and frequency of somatic hypermutation by deep sequencing and relating the findings to established measures of vaccine response, including post immunization titers against Haemophilus influenza and pneumococcal polysaccharide serotypes contained in the Prevnar 13(R) vaccine and opsonophagocytic activity. 2) To evaluate the relationship between the infant innate immune response and immunoglobulin diversity by examining the extent of T and B cell maturation, the extent of B cell class switch recombination, levels of pro-inflammatory cytokines, extent of macrophage activation, and capacity of neonatal monocytes/macrophages to produce BAFF and APRIL following activation via Toll-like receptors. 3) To assess the relationship between humoral immune responses to vaccination and gut microbiota between breast fed and formula fed infants. The proposed research applies innovative strategies to address a significant gap in our understanding of human immune development. Results will provide novel measures for the role of infant feeding in development of immunity to vaccines and evidence for informed choices by mothers about the nutritional options for their infants.