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Background Allergic rhinitis is characterized by rhinorrhea, nasal congestion, sneezing and nasal pruritus. Group 2 innate lymphoid cells (ILC2s), CD4+ T cells and eosinophils in nasal mucosa are increased significantly after nasal allergen challenge (NAC). Effects of intranasal corticosteroids (INCS) on ILC2s remain to be investigated. Methods Subjects (n = 10) with allergic rhinitis and mild asthma were enrolled in a single‐blind, placebo‐controlled, sequential treatment study and treated twice daily with intranasal triamcinolone acetonide (220 µg) or placebo for 14 days, separated by a 7‐day washout period. Following treatment, subjects underwent NAC and upper airway function was assessed. Cells from the nasal mucosa and blood, sampled 24 h post‐NAC, underwent flow cytometric enumeration for ILC2s, CD4+ T and eosinophil progenitor (EoPs) levels. Cell differentials and cytokine levels were assessed in nasal lavage. Results Treatment with INCS significantly attenuated ILC2s, IL‐5+/IL‐13+ILC2s, HLA‐DR+ILC2s and CD4+ T cells in the nasal mucosa, 24 h post‐NAC. EoP in nasal mucosa was significantly increased, while mature eosinophils were significantly decreased, 24 h post‐NAC in INCS versus placebo treatment arm. Following INCS treatment, IL‐2, IL‐4, IL‐5 and IL‐13 were significantly attenuated 24 h post‐NAC accompanied by significant improvement in upper airway function. Conclusion Pre‐treatment with INCS attenuates allergen‐induced increases in ILC2s, CD4+ T cells and terminal differentiation of EoPs in the nasal mucosa of allergic rhinitis patients with mild asthma, with little systemic effect. Attenuation of HLA‐DR expression by ILC2s may be an additional mechanism by which steroids modulate adaptive immune responses in the upper airways.

Eosinophilic asthma is the most prevalent phenotype of asthma. Although most asthmatics are adequately controlled by corticosteroid therapy, a subset (5–10%) remain uncontrolled with significant therapy-related side effects. This indicates the need for a consideration of alternative treatment strategies that target airway eosinophilia with corticosteroid-sparing benefits. A growing body of evidence shows that a balance between systemic differentiation and local tissue eosinophilopoietic processes driven by traffic and lung homing of bone marrow-derived hemopoietic progenitor cells (HPCs) are important components for the development of airway eosinophilia in asthma. Interleukin (IL)-5 is considered a critical and selective driver of terminal differentiation of eosinophils. Studies targeting IL-5 or IL-5R show that although mature and immature eosinophils are decreased within the airways, there is incomplete ablation, particularly within the bronchial tissue. Eotaxin is a chemoattractant for mature eosinophils and eosinophil-lineage committed progenitor cells (EoP), yet anti-CCR3 studies did not yield meaningful clinical outcomes. Recent studies highlight the role of epithelial cell-derived alarmin cytokines, IL-33 and TSLP, (Thymic stromal lymphopoietin) in progenitor cell traffic and local differentiative processes. This review provides an overview of the role of EoP in asthma and discusses findings from clinical trials with various therapeutic targets. We will show that targeting single mediators downstream of the inflammatory cascade may not fully attenuate tissue eosinophilia due to the multiplicity of factors that can promote tissue eosinophilia. Blocking lung homing and local eosinophilopoiesis through mediators upstream of this cascade may yield greater improvement in clinical outcomes.

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RATIONALE: Dysregulated cell proliferation in the lung is one of the key hallmarks in idiopathic pulmonary fibrosis (IPF). Proliferation of type II alveolar epithelial cells (AECs) and fibroblasts is a particularly important event in IPF development. However, it is not understood how such proliferation leads to an advanced stage of fibrosis. Therefore, it is very important to characterize the proliferation of type II AECs in IPF lungs with different histological appearances. METHODS: Lung samples were removed from the whole lung explants of patients with IPF and patients with pulmonary arterial hypertension (PAH, control subjects) undergoing lung transplantation at Tampa General Hospital (IRB protocol Pro00032158). Paraffin-embedded lung sections were immunohistochemically labeled for Ki67 (proliferation marker) and pro-SPC (a lineage marker for type II AEC). RESULTS: In normal looking alveoli of PAH and IPF lungs, Ki67 signals were sparsely colocalized with pro-SPC. In mildly affected alveoli with thickened interstitium in IPF lungs, Ki67 signals are noted with higher density than normal alveoli of PAH and IPF. Intriguingly, most of them are either weakly positive or negative for pro-SPC. In severely fibrotic regions in IPF lungs, most of the Ki67 positive cells are negative for pro-SPC. CONCLUSIONS: The results indicate that type II AEC proliferation is a key event in IPF. The results also suggest that type II AEC proliferation gradually shifts to proliferation of different cell types as the lung becomes more fibrotic. These cells are presumably dedifferentiated type II AECs that have lost pro-SPC expression or other progenitor cell types.

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