Abstract
Allergic asthma is a chronic disease of the lungs associated with bronchoconstriction, increased type 2 (Th2) cytokines interleukin (IL-) 4, IL-5, IL-13, eosinophilia, and chronic inflammation in the airways. There has been a rapid increase in asthma prevalence in developed countries which was linked to decreased incidence of infectious diseases.|Since the recognition of distinct T helper cell subsets that differ in cytokine production and effector functions as it relates to asthma, challenging concepts have evolved to allow the use of therapeutic modalities that modulate the Thl/ Th2 balance in asthma without deleterious side effects. Primarily, these concepts have focused on modulation of antigen presentation to T cells and inhibition of antigen-specific Th2 responses and/or increasing the Thl response. Flt3-ligand (Flt3-L) is a growth factor for dendritic cells, and induces type 1 T cell responses. The receptor for Flt3L is a member of the type 111 tyrosine kinase receptor family. A series of experiments were designed to examine the ability of Flt3-L to reverse allergic airway inflammation in acute and chronic murine models of asthma. BALB/c mice were sensitized and challenged with ovalbumin (OVA) and airway hyperresponsiveness (AHR) to methacholine was established. The mice were then treated with FU3-L or Flt3-L plasmid. A comprehensive evaluation of the hallmarks of asthma was then performed, which included measurement of pulmonary functions and AHR to methacholine, bronchoalveolar lavage (BAL) eosinophilia, serum total and anti-OVA IgE, IgGl, and lgG2a, and serum and BAL cytokines. Treatment with Flt3-L and FU3-L plasmid in pre-sensitized mice significantly suppressed AFIR, BAL total cellularity and absolute eosinophil counts and inflammation in the lung tissue. FH3-L administration was observed to significantly decrease pro-inflammatory cytokines IL-4, and 1L-5 in BAL and serum. Furthermore, FU3-L prevented AHR in a murine model of chronic allergic airway inflammation. There was no significant effect of FU3-L treatment on serum total IgE levels. Flt3-L treatment also downregulated goblet cell hyperplasia, and basement membrane thickening.|These data suggest that Flt3-L and FU3-L plasmid treatment can reverse established experimental allergic airway inflammation and AHR, and might provide a novel approach for treating asthma.