Effect of breast feeding on immunologic priming in young infants.

描述（由申请人提供）：与年龄较大的儿童不同，婴儿在初次免疫后疫苗诱导的免疫力会减弱，需要多种增强剂来建立免疫记忆。与配方奶喂养相比，母乳喂养的婴儿疫苗反应的持续时间和程度都有所改善，但母乳喂养增强免疫启动的机制尚不清楚。母乳喂养对疫苗免疫反应的增强范围从对免疫发育的直接影响到通过改变共生肠道微生物群来增强先天免疫。该研究验证了母乳喂养通过调节婴儿肠道微生物定植加速2和4月龄免疫后B细胞启动和免疫球蛋白多样性的假设。研究将集中于对流感嗜血杆菌（HIb）和肺炎链球菌结合疫苗的反应[Prevnar 13(R)]。该应用程序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，免疫反应和胃肠道微生物定植将在出生到一岁之间进行检查，这些婴儿至少在出生后的头四个月被完全母乳喂养，而那些完全配方奶粉喂养。该项目有三个具体目标：1)通过深度测序来研究免疫球蛋白多样性的发展和体细胞超突变的频率，并将这些发现与疫苗反应的既定指标联系起来，包括对流感嗜血杆菌和肺炎球菌多糖血清型的免疫后滴度，以及Prevnar 13(R)疫苗和抗噬细胞活性。2)通过检测T细胞和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、巨噬细胞激活程度以及新生儿单核/巨噬细胞通过toll样受体激活后产生BAFF和APRIL的能力，评估婴儿先天免疫应答与免疫球蛋白多样性的关系。3)评价母乳喂养和配方奶粉喂养婴儿接种疫苗后体液免疫应答与肠道菌群的关系。拟议的研究应用创新策略来解决我们对人类免疫发育的理解中的重大差距。研究结果将为婴儿喂养在疫苗免疫发展中的作用提供新的衡量标准，并为母亲在知情的情况下为婴儿选择营养方案提供证据。

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.