RELM Peptides Alter Lung Defense

描述（由申请人提供）：RFA（粘膜免疫防御机制）要求开展探索性/开发性研究项目，旨在研究呼吸道粘膜表面的免疫机制，以获得新的见解，促进疫苗开发，保护粘膜表面免受感染和炎症。抗体产生和记忆B细胞和T细胞在肺中分布，表明有形成适应性免疫应答的能力，但呼吸道粘膜疫苗的开发一直很困难。成功的粘膜疫苗需要提供记忆、随后的识别和病原体的清除。尽管持续暴露于吸入的微生物，下肺粘膜通常保持无菌。肺粘膜保护可归因于先天性和适应性免疫系统、细胞和分子，其增强微生物清除。对导致微生物清除率降低的粘膜特性知之甚少。我们已经确定了粘膜表面的一个属性，减少微生物的清除，这可能会损害粘膜疫苗的有效性。抵抗素样分子（RELM肽）在粘膜表面由炎症刺激诱导。使用转基因小鼠模型诱导RELM-？在肺上皮中产生，我们已经确定了RELM-？的一种新特性，这将导致体内肺部细菌清除率降低。这些数据表明，抗原攻击可能诱导RELM肽，导致微生物清除率降低。本申请的目的是通过测试RELM肽通过抑制先天清除机制来防止病原体的有效消除的中心假设来获得这种矛盾免疫应答的知识。为了验证这一假设，我们将使用RELM-？作为一个模型和（1）确定是否RELM-？影响清除病原体的粘膜疫苗的目标（目的1）;（2）确定是否RELM-？影响前哨细胞，并降低已知的先天分子（目标2）的水平;（3）确定是否水平的RELM-？还是RELM-？可以使用临床上可应用的药理学抑制剂来降低信号传导（Aim 3）。长期目标是了解导致清除率降低的粘膜特性，这最终可能会损害疫苗的有效性。 相关性：患有潜在慢性肺或心血管疾病的个体吸入病原体逃逸肺保护机制导致肺部感染的风险增加，这些个体群体可以从针对可能的肺部病原体的粘膜疫苗的开发中受益。宿主和病原体之间相互作用的结果取决于增强微生物杀灭和抑制清除机制之间的平衡。我们正在寻求获得关于肺RELM分子如何减少微生物清除的知识。

DESCRIPTION (provided by applicant): The RFA, Immune Defense Mechanisms at the Mucosa, requests exploratory/developmental research projects that propose to study immune mechanisms at respiratory mucosal surfaces to gain new insights that will facilitate vaccine development to protect mucosal surfaces from infection and inflammation. Antibody producing and memory B cells and T cells populate the lung indicating a capacity to form adaptive immune responses, yet development of respiratory mucosal vaccines has been difficult. A successful mucosal vaccine needs to provide for memory, subsequent recognition, and clearance of pathogens. The lower pulmonary mucosa generally remains sterile in spite of continuous exposure to inhaled microbes. Lung mucosal protection is attributable to the innate and adaptive immune system, cells and molecules, which enhance microbial clearance. There is little knowledge of mucosal properties that lead to reduced microbial clearance. We have identified a property of the mucosal surface that reduces microbial clearance, which could compromise the effectiveness of mucosal vaccines. Resistin-like molecules (RELM peptides) are induced at the mucosal surface by inflammatory stimuli. Using a transgenic mouse model of inducible RELM-? produced in the pulmonary epithelium, we have identified a novel property of RELM-?, which is to cause reduced bacterial clearance from the lung in vivo. These data suggest that antigen challenges may induce RELM peptides leading to reduced microbial clearance. The purpose of this application is gain knowledge of this paradoxical immune response by testing the central hypothesis that RELM peptides prevent efficient elimination of pathogens by inhibiting innate clearance mechanisms. To test this hypothesis we will use RELM-? as a model and (1) determine whether RELM-? affects clearance of pathogens which are targets of mucosal vaccines (Aim 1); (2) determine if RELM-? affects sentinel cells and reduces levels of known innate molecules (Aim 2); (3) determine if levels of RELM-? or RELM-? signaling can be reduced using clinically applicable pharmacological inhibitors (Aim 3). The long-term goal is to gain knowledge of mucosal properties that cause reduced clearance, which ultimately may compromise effectiveness of vaccines. RELEVANCE: Individuals with underlying chronic lung or cardiovascular diseases have increased risk of inhaled pathogens escaping lung protective mechanisms causing lung infections and these groups of individuals could benefit from the development of mucosal vaccines against likely lung pathogens. The outcome of the interaction between host and pathogen depends on the balance between mechanisms that enhance microbial killing and those that inhibit clearance. We are seeking to gain knowledge regarding how lung RELM molecules reduce microbial clearance.