RELM Peptides Alter Lung Defense

描述（由申请人提供）：RFA，粘膜免疫防御机制，要求探索性/发展性研究项目，建议研究呼吸道粘膜表面的免疫机制，以获得新的见解，从而促进疫苗开发，保护粘膜表面免受感染和炎症。产生抗体和记忆的B细胞和T细胞填充肺部，表明有能力形成适应性免疫反应，但呼吸道粘膜疫苗的开发一直很困难。一个成功的粘膜疫苗需要提供记忆，随后的识别和清除病原体。尽管持续暴露于吸入的微生物中，肺下粘膜通常仍保持无菌。肺粘膜保护是由于先天和适应性免疫系统，细胞和分子，增强微生物清除。我们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减少微生物清除的特性，这可能会损害粘膜疫苗的有效性。抵抗素样分子（RELM肽）在粘膜表面被炎症刺激诱导。利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-？这是为了减少体内肺部的细菌清除率。这些数据表明抗原刺激可能诱导RELM肽导致微生物清除率降低。本应用的目的是通过测试RELM肽通过抑制先天清除机制阻止病原体有效消除的中心假设来获得这种矛盾的免疫反应的知识。为了验证这一假设，我们将使用RELM-？(1)确定RELM-？影响作为粘膜疫苗目标的病原体的清除（目的1）；(2)确定RELM-？影响前哨细胞并降低已知先天分子的水平（目的2）；(3)确定RELM-？或RELM - ?使用临床适用的药物抑制剂可以减少信号传导（目的3）。长期目标是获得导致清除率降低的粘膜特性的知识，这最终可能会损害疫苗的有效性。

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.