? ? This program entitled """"""""Host Factors in Fungal Asthma and Fibrosis"""""""" has its goal to translate our basic knowledge in antigen recognition, mechanisms of allergy and tolerance, and high throughput genomics and proteomics to 1) improve our understanding of allergjc and fibrotic lung diseases and 2) use this knowledge to design interventions to prevent or ameliorate these pathogenic processes. Towards this end, this SCCOR application proposes two closely linked clinical and basic science projects. One clinical and basic science project will investigate the role of beta-glucan and the beta-glucan receptor Dectin-1 in the development of allergy or tolerance to the ubiquitous fungus Aspergillus fumigatus. These studies will be conducted in the context of a cohort of patients with Cystic Fibrosis that have defined Aspergillus colonization with and without Allergic Bronchopulmonary Aspergillosis (ABPA) and a basic science project that uses a novel rodent model of immune tolerance or allergy to define the role of the local pulmonary immune system and surfactant proteins in the development of allergy versus tolerance. Another clinical and basic science project will be focused on pulmonary fibrosis. The clinical project will use gene expression and protein expression profiling to better define subgroups of patients with idiopathic pulmonary fibrosis (IPF) as well as further define abnormalities in adaptive T -cell biology that occurs in these patients. A closely linked basic project will investigate the role of KGF and the ligands for CXCR3 (CXCL9, CXCL10, and CXCL11) in regulating the fibrotic response to bleomycin lung injury in rodents. The overall theme of this SCCOR is to define molecular pathways that regulate adaptive immunity to antigens and to improve our understanding of interactions between immune cells and parenchymal cells in the development of fibrosis or in the setting of allergy (or tolerance). These themes are in concert with the goals of the RFA to: characterize innate and adaptive immune responses, develop genomic and proteomic signatures of pulmonary pathways and conduct studies in humans that have direct diagnostic and potentially therapeutic application. The long-term objective of the SCCOR is to use the knowledge of the molecular pathways to improve diagnosis and treatment of patients suffering form chronic lung diseases particularly allergic and fibrotic lung diseases. End of Abstract) ? ? INDIVIDUAL PROJECTS AND CORE UNITS ? ? PROJECT 1. Immune Tolerance and Inflammation in ABPA in Patients with Cystic Fibrosis ? (Kolls, Jay K.) ? ? DESCRIPTION (provided by applicant): ? ? 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. (End of Abstract) ? ? ?
Showing the most recent 10 out of 54 publications
