The airway mucosal immune system is normally highly efficient in inducing antigen specific T regulatory cells (Tregs) that control the default Th2 response to innocuous allergens. However in some susceptible individuals, these regulatory mechanisms are inefficient resulting in Th2 sensitization and development of high IgE titres. Recent epidemiological findings suggest exposure to high allergen doses may counter-intuitively protect against sensitization. Our studies have shown that reduced allergen uptake in vivo, regulated at the level of the tissue micro-environment, is linked to induction of deficient Treg responses leading to development of sensitization.
Our aim is to provide mechanistic insights into how dendritic cell allergen load modulates development of tolerance versus sensitization. For this, we use an experimental animal model employing two rat strains that mimic the spectrum of atopic sensitization observed within humans, viz low (resistant) versus high (susceptible) IgE responders.
During repeated intra-nasal allergen exposures in naïve animals, allergen specific IgE was only observed in the high responder rats. Both strains initially displayed neutrophil infiltration in the lungs, which resolved in the low responders but progressed to eosinophil infiltration in the high responders after 21 exposures. Initial allergen uptake was higher in the low responders and interestingly, both de novo allergen uptake and lymph node delivery increased after 21 exposures in both strains although this remained lower in the high responding rats. Further analysis will reveal what dendritic subset carries the allergen in the two strains and how that contributes to Treg induction and the two immunological outcomes observed in this model. It will also reveal how allergen load impacts on dendritic cell uptake, trafficking and Treg induction in this model, which would provide mechanistic clues towards understanding how we may prevent allergic sensitization.