Immune Tolerance and Inflammation in ABPA in Patients with Cystic Fibrosis

Children'S Hosp Pittsburgh/Upmc Hlth Sys, Pittsburgh PA

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Abstract

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