Immune Tolerance and Inflammation in ABPA in Patients with Cystic Fibrosis

囊性纤维化患者 ABPA 的免疫耐受和炎症

• 批准号: 7524104
• 负责人: JAY K KOLLS
• 金额: $ 52.51万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 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/7524104
• 关键词: Affect; Allergic; Allergic Bronchopulmonary Aspergillosis; Antibodies; Antigen-Presenting Cells; Antigens; Aspergillosis; Aspergillus; Aspergillus fumigatus; Asthma; Azoles; Binding; Biological Assay; Blood; Bronchiectasis; CD4 Positive T Lymphocytes; Caspofungin; Cell Culture System; Cells; Coculture Techniques; Cystic Fibrosis; Data; Dendritic Cells; Development; Diagnosis; Disease; Fibrosis; Flow Cytometry; Foxes; Generations; Glucans; High Prevalence; Hypersensitivity; IL2RA gene; IgE; Immune Tolerance; Immunity; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-13; Interleukin-4; Interleukin-5; Knowledge; Laboratories; Ligands; Ligase; Lung; Lung diseases; Mediating; Microscopy; Modeling; Mus; Organism; Patients; Personal Satisfaction; Phenotype; Play; Polymerase Chain Reaction; Population; Production; Research Personnel; Role; Sputum; Stimulus; Surface; Swelling; T-Lymphocyte; Testing; Time; Universities; Voriconazole; Wheezing; Work; atopy; base; beta-1,3-glucan; beta-Glucans; beta-glucan receptor; cystic fibrosis patients; cytokine; dectin 1; human subject; inhibitor/antagonist; macrophage; monocyte; neutralizing antibody; neutrophil; peripheral blood; programs; receptor; response

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic disease characterized clinically by wheezing, pulmonary infiltrates, bronchiectasis, and fibrosis that affects patients with asthma and cystic fibrosis (CF). In patients with ABPA, immunological responses to a variety of Aspergillus fumigatus (Af) antigens result in a heightened Th2 response and an elevated immunoglobulin E (IgE) level. At our CF Center ABPA affects 7% of the CF population however over 30% are colonized with Af. Preliminary data in our laboratory demonstrates that Dectin-1, a beta-glucan receptor expressed in dendritic cells and macrophages is required for recognition of swollen conidia; a form of Af that precedes hyphal development. Preliminary data suggest that Dectin-1 is also required for Th2 response in CF patients with ABPA. Additionally patients with Af colonization without ABPA have elevated antigen specific IL-10 responses which we propose is due the development of regulatory T-cell response in these patients. Based on these data, we hypothesize that CF patients with ABPA require monocyte/dendritic cell expression of dectin-1 for the presentation of specific Aspergillus antigens (namely swollen conidia) as well as for Th2 cytokine elaboration. Moreover, we hypothesize that a decreased in Treg cells is required for development of APBPA compared to CF patients colonized with Aspergillus but no evidence of ABPA. To test these hypotheses, we propose the following specific aims: Specific Aim 1: To test the hypothesis that CF patients with ABPA require Dectin-1 expression on peripheral blood monocytes/dendritic cells and that binding of A. fumigatus to Dectin-1 will produce a heightened inflammatory response in patients with ABPA compared to non-ABPA patients. Specific Aim 2: To test the hypothesis that T cells from CF patients with ABPA will have decreased adaptive Treg function. Specific Aim 3. To test the hypothesis that anti-fungals targeted against glucan synthetase block both proinflammatory and Th2 cytokine induction in peripheral blood of patients with CF with ABPA. Understanding these responses in ABPA will increase our knowledge regarding mechanisms of allergy vs. tolerance in human subjects.

过敏性支气管肺曲霉病（ABPA）是一种以喘息为临床特征的过敏性疾病， 肺浸润、支气管扩张和影响哮喘和囊性纤维化（CF）患者的纤维化。在 在ABPA患者中，对多种烟曲霉（Af）抗原的免疫应答导致 Th 2应答增强和免疫球蛋白E（IgE）水平升高。在我们的CF中心，ABPA影响7% 然而，超过30%的CF种群被AF定殖。 表明Dectin-1，一种在树突状细胞和巨噬细胞中表达的β-葡聚糖受体， 用于识别肿胀的分生孢子;菌丝发育前的一种Af。初步数据表明 Dectin-1也是ABPA CF患者Th 2应答所必需的。此外，Af患者 没有ABPA的定植有升高的抗原特异性IL-10应答，我们认为这是由于 这些患者中调节性T细胞反应的发展。基于这些数据，我们假设CF ABPA患者需要单核细胞/树突状细胞表达dectin-1，以呈递特异性 曲霉属抗原（即肿胀的分生孢子）以及Th 2细胞因子的加工。而且我们 假设与CF患者相比，APBPA的发生需要Treg细胞减少 曲霉菌定植，但没有ABPA的证据。为了验证这些假设，我们提出以下建议： 具体目的：具体目的1：检验患有ABPA的CF患者需要Dectin-1表达的假设 对外周血单核细胞/树突状细胞的作用以及A.对Dectin-1的作用将产生一种 与非ABPA患者相比，ABPA患者的炎症反应增强。具体目标二： 为了检验来自患有ABPA的CF患者的T细胞将具有降低的适应性Treg功能的假设。 具体目标3。为了验证针对葡聚糖合成酶的抗真菌药物阻断促炎性细胞因子和抗真菌药物的假设， ABPA对CF患者外周血Th 2细胞因子的诱导作用。理解 ABPA中的这些反应将增加我们对过敏与耐受机制的了解， 人类实验对象