RELM Peptides Alter Lung Defense

描述(申请人提供)：RFA，黏膜免疫防御机制，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，将促进疫苗的开发，以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细胞分布在肺中，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。一种成功的粘膜疫苗需要提供记忆、随后的识别和清除病原体。尽管持续暴露在吸入微生物中，下肺粘膜通常仍保持无菌状态。肺粘膜保护归因于先天和适应性免疫系统、细胞和分子，它们增强了微生物的清除。目前对导致微生物清除量降低的粘膜特性知之甚少。我们已经确定了粘膜表面的一种属性，它可以减少微生物的清除，这可能会损害黏膜疫苗的有效性。抵抗素样分子(RELM肽)是在炎性刺激下在粘膜表面诱导的。使用可诱导的RELm-？转基因小鼠模型？产生于肺上皮，我们已经确定了RELM-？的一个新特性，它可以在体内导致细菌从肺中的清除减少。这些数据表明，抗原挑战可能会诱导RELM多肽，导致微生物清除量减少。这一应用的目的是通过检验中心假设，即RELM多肽通过抑制天然清除机制防止病原体的有效消除，从而获得关于这种矛盾免疫反应的知识。为了验证这一假设，我们将使用RELm-？作为模型和(1)确定RELm-？影响作为粘膜疫苗目标的病原体的清除(目标1)；(2)确定RELM-？影响哨兵细胞并降低已知先天分子的水平(目标2)；(3)确定RELm-？或者RELM-？使用临床适用的药理抑制剂可以减少信号转导(目标3)。长期目标是了解导致清除量减少的粘膜属性，这最终可能会危及疫苗的有效性。 相关性：患有潜在慢性肺病或心血管疾病的人会增加吸入病原体逃离肺保护机制导致肺部感染的风险，这些群体可以从针对可能的肺部病原体的黏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促进微生物杀灭和抑制清除的机制之间的平衡。我们正在寻求关于肺RELM分子如何减少微生物清除量的知识。

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.