Host Factors Regulating Allergic Responses to Aspergillus

调节曲霉菌过敏反应的宿主因素

基本信息

批准号：
7524105
负责人：
Anuradha Ray
金额：
$ 43.87万
依托单位：
CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7524105
关键词：
Address Adjuvant Allergens Allergic Allergic Bronchopulmonary Aspergillosis Alveolar Macrophages Antigens Area Aspergillosis Aspergillus Aspergillus fumigatus Asthma Autoimmune Process Binding Biochemical Blocking Antibodies CD4 Positive T Lymphocytes Candida albicans Cell surface Cells Characteristics Chimeric Proteins Class Coculture Techniques Collectins Communicable Diseases Condition Cystic Fibrosis Data Defense Mechanisms Dendritic Cells Dependence Dermatophagoides pteronyssinus antigen p 1 Development Disease Drug Interactions Epitopes Exposure to Felis catus Histology Host Defense Host Defense Mechanism Hyphae IgE Immune Immune response Immune system Immunity Immunization Immunodominant Antigens Immunodominant Epitopes In Vitro Individual Infection Inflammation Inflammatory Integration Host Factors Invaded Investigation Lead Lung Manuscripts Measures Mediating Membrane Met-rANTES Mixed Lymphocyte Culture Test Modeling Molecular Mus Natural Immunity Pathology Peptides Pharmaceutical Preparations Physiologic pulse Play Pneumocystis carinii Population Prevention Production Proteins Pulmonary Surfactant-Associated Protein D Pulse taking Pyroglyphidae RANTES Reagent Reporting Research Personnel Respiratory System Rest Role Specificity Surface Swelling System T-Cell Activation T-Lymphocyte TLR2 gene Testing Therapeutic Transgenic Mice Vaccines base beta-Glucans beta-glucan receptor calreticulin cell type chemokine cystic fibrosis patients cytokine dectin 1 disorder risk fungus human SYK protein immunogenic improved in vivo interleukin-12 subunit p40 macrophage neutrophil notch protein novel outcome forecast pathogen prevent response surfactant transcription factor

项目摘要

Aspergillus fumigatus is a ubiquitous fungus that can cause allergic bronchopulmonary aspergillosis (ABPA) in susceptible individuals. The populations at high risk for this disease include patients with cystic fibrosis (CF) and severe asthma. Together, alveolar macrophages, neutrophils and dendritic cells serve to promote both inflammatory and protective responses against Aspergillus. Our preliminary data on mechanisms that trigger Aspergillus-induced pathology suggest important roles for specific cell surface and secreted molecules that together modulate the immune response to Aspergillus. These include cell surface molecules such as dectint on macrophages and DCs, lung expressed surfactant proteins (collectins) and specific cytokines/chemokines (RANTES and IL-12p40) secreted by Aspergillus-stimulated DCs. Also, an early pathogen-expressed molecule, Aspfl, was a poor allergen in vivo even in the context of strong Th2-skewing adjuvants. Interestingly, peptides derived from Aspfl were reported to be tolerogenic in mice. Collectively, these observations lead us to hypothesize that a) interactions between different cell types involving beta glucan on Aspergillus and dectint on host cells and immune defense molecules such as surfactants play an important role in inducing imrhunomodulatory cytokines and chemokines that induce the characteristic eosinophilic inflammation in ABPA and b) tolerance induction to Aspergillus can be achieved using specific pathogen Ags that together with innate defense mechanisms is an important mechanism that prevents unwarranted immune responses against the pathogen. To test these hypotheses we will: Aim I. Characterize the effect of A. fumigatus on the adaptive immune response and its dependence on specific cell surface components on cells of the immune system (dectin-1 and TLR2). Aim II. Determine the effect of surfactant D on Aspergillus-induced immune responses. Aim III. Determine whether repeated exposure to immunodominant peptides derived from Aspfl can induce tolerance to the whole pathogen. Thus, using a variety of molecular, biochemical and immunological approaches and genetically altered mice, our studies will focus on interactions between the pathogen, A. fumigatus, and the host in the induction and prevention of allergic responses to Aspergillus.

烟曲霉是一种普遍存在的真菌，可引起过敏性支气管肺曲霉病 (ABPA) 在易感人群中。这种疾病的高危人群包括囊性纤维化患者 (CF) 和严重哮喘。肺泡巨噬细胞、中性粒细胞和树突状细胞共同促进针对曲霉菌的炎症和保护性反应。我们关于机制的初步数据触发曲霉诱导的病理学表明特定细胞表面和分泌的重要作用共同调节对曲霉菌的免疫反应的分子。这些包括细胞表面分子例如巨噬细胞和 DC 上的 Dectint、肺表达的表面活性蛋白（集合素）和特定的由曲霉刺激的 DC 分泌的细胞因子/趋化因子（RANTES 和 IL-12p40）。另外，早病原体表达的分子 Aspfl 在体内是一种较差的过敏原，即使在强烈 Th2 倾向的情况下也是如此佐剂。有趣的是，据报道源自 Aspfl 的肽在小鼠中具有耐受性。总的来说，这些观察结果使我们推测：a) 涉及 β 的不同细胞类型之间的相互作用曲霉上的葡聚糖和宿主细胞上的葡聚糖以及表面活性剂等免疫防御分子发挥着重要作用在诱导免疫调节细胞因子和趋化因子中发挥重要作用，从而诱导特征 ABPA 中的嗜酸性粒细胞炎症和 b) 对曲霉的耐受诱导可以使用特定的方法来实现病原体抗原与先天防御机制一起是预防的重要机制针对病原体的不必要的免疫反应。为了检验这些假设，我们将：目的 I. 表征烟曲霉对适应性免疫反应的影响及其对免疫系统细胞上的特定细胞表面成分（dectin-1 和 TLR2）。目标二。确定表面活性剂 D 对曲霉菌诱导的免疫反应的影响。目标三。确定重复暴露于 Aspfl 衍生的免疫显性肽是否会诱导对整个病原体的耐受性。因此，使用各种分子、生化和免疫学方法以及基因改造的小鼠，我们的研究将重点关注病原体烟曲霉和宿主在诱导和传播过程中的相互作用。预防曲霉菌过敏反应。