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: 8118860
• 负责人: JAY K KOLLS
• 金额: $ 51.6万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8118860
• 关键词: Affect; Allergic; Allergic Bronchopulmonary Aspergillosis; Allergic Disease; Antibodies; Antigen-Presenting Cells; Antigens; 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; Fibrosis; Flow Cytometry; Foxes; Generations; Glucans; High Prevalence; Hypersensitivity; IL2RA gene; IgE; Immune Tolerance; 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; Phenotype; Play; Population; Production; Regulatory T-Lymphocyte; Role; Sputum; Stimulus; Surface; Swelling; T cell response; T-Lymphocyte; Testing; Time; Universities; Voriconazole; Wheezing; Work; adaptive immunity; 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; 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变应性疾病。