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，婴儿在初次免疫后疫苗诱导的免疫力减弱，需要多种增强剂来建立免疫记忆。与配方奶相比，母乳喂养的婴儿疫苗反应持续时间更长，幅度更大，但母乳喂养增强免疫启动的机制尚不清楚。母乳喂养对接种疫苗的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区系来增强天然免疫力。这项拟议的研究验证了这样一种假设，即母乳喂养通过调节婴儿肠道的微生物定植，在2个月和4个月大的婴儿接种后，加速了B细胞的启动和免疫球蛋白的多样性。研究将集中在针对流感嗜血杆菌(Hib)和肺炎链球菌的结合疫苗的反应[Prevnar 13(R)]。这项应用的一个主要目标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，从出生到一岁的婴儿的免疫反应和胃肠道微生物定植情况将在出生后至少四个月内完全母乳喂养的婴儿中进行检查，而不是那些完全接受配方奶喂养的婴儿。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度突变的频率，并将研究结果与既定的疫苗反应措施联系起来，包括针对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吞噬细胞活性。2)通过检测新生儿T、B细胞成熟程度、B细胞类型转换重组程度、促炎细胞因子水平、巨噬细胞活化程度、新生儿单核/巨噬细胞产生BAFF的能力以及通过Toll样受体激活后新生儿单核/巨噬细胞产生BAFF和APRIL的能力，评价新生儿先天免疫反应与免疫球蛋白多样性的关系。3)探讨母乳喂养和配方奶喂养婴儿对疫苗的体液免疫应答与肠道微生物区系的关系。这项拟议的研究采用了创新的策略，以解决我们对人类免疫发展的理解上的一个重大差距。结果将为婴儿喂养在发展对疫苗的免疫力方面的作用提供新的措施，并为母亲就其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.