Pulmonary Immunity To Pathogens In Neonates

抽象的。新生儿容易感染各种传染病，导致严重的发病和死亡。每年有400多万6个月以下的婴儿死于传染病。 虽然针对许多这些疾病的疫苗，如流感，是可用的，其中许多要么不工作，在婴儿或需要多次加强，以获得最佳的保护。此外，很明显，新生儿中的某些类型的免疫反应可以编程免疫系统，使其在以后的生活中变得更抵抗或更容易发生特应性反应，如过敏或哮喘。新生儿免疫结果差（或改变）的潜在机制被认为包括炎症反应的改变， 对微生物产物的反应、树突状细胞（DC）的延迟成熟以及未成熟的B和T细胞区室可能具有与成人显著不同的库和功能。此外，淋巴器官如淋巴结、鼻相关类淋巴组织（NALT）和支气管相关类淋巴组织（BALT）在新生儿中在结构上是不成熟的，并且缺乏适当的结构元件， 对于有效地引发T细胞、支持生殖中心和产生高亲和力抗体应答是必需的。然而，目前尚不清楚这些差异如何导致新生儿免疫功能的改变。因此，我们必须首先确定新生儿免疫系统在流感感染的背景下如何发挥作用，然后设计疫苗以引起新生儿的长期保护性免疫应答。本提案中的实验将首先确定新生儿对流感免疫应答不良的机制，特别是关于不成熟的淋巴组织和结构。此外，这些实验将测试表达参与淋巴器官成熟的细胞因子和趋化因子的重组流感疫苗在新生儿中引发稳健和长期免疫应答的能力。最后，本提案中的实验将确定负责 新生儿肺部炎症或感染后免疫应答的持续改变。 总之，这些实验将定义新生儿免疫的独特功能，并将确定如何克服一些免疫缺陷负责过度发病率和死亡率的这一人口在肺部感染。

Abstract. Neonates are susceptible to a variety of infectious diseases that cause significant morbidity and mortality. Over four million infants less than 6 months of age succumb to infectious disease every year. Although vaccines against many of these diseases, such as influenza, are available, many of them either do not work in infants or require multiple boosts to obtain optimal protection. In addition, it is clear that some types of immune responses in neonates can program the immune system to become either more resistant or more susceptible to developing atopic responses, such as allergies or asthma, later in life. The mechanisms underlying poor (or altered) immune outcomes in neonates are thought to include altered inflammatory responses to microbial products, delayed maturation of dendritic cells (DCs) and immature B and T cell compartments that may have repertoires and functions that differ dramatically from those in adults. Moreover, lymphoid organs such as lymph nodes, Nasal Associated Lymphoid Tissue (NALT) and Bronchus Associated Lymphoid Tissue (BALT) are structurally immature in neonates and lack the proper architectural elements that are necessary for efficiently priming T cells, supporting germinal centers and generating high-affinity antibody responses. However, it is not known how each of these differences contributes to altered immune function in neonates. Therefore, it is essential that we first determine how the neonatal immune system functions in the context of influenza infection and then design vaccines to elicit long-lived protective immune responses in neonates. The experiments in this proposal will first determine the mechanisms responsible for poor immune responses to influenza in neonates, particularly regarding immature lymphoid tissues and architecture. In addition, these experiments will test the ability of recombinant influenza vaccines expressing cytokines and chemokines involved in lymphoid organ maturation to elicit robust and long-lived immune responses in neonates. Finally, the experiments in this proposal will determine the mechanisms responsible for the sustained alterations in immune responses following pulmonary inflammation or infection in neonates. Together, these experiments will define the unique features of neonatal immunity and will determine how to overcome some of the immune defects responsible for excessive morbidity and mortality of this population in response to pulmonary infections.