The objective of this research proposal is to examine the role of plasmacytoid dendritic cells (pDC) in the generation of immune tolerance within the gastrointestinal system. The biology of pDC during viral infection has been well studied, and it is clear that these cells possess cellular machinery that facilitates rapid and robust production of proinflammatory type I interferons in response to viral nucleic acids. However, in models of cancer, transplant, and allergy, pDC can induce tolerance and inhibit an immune response. Furthermore, previous studies have suggested that gut associated pDC may suppress the generation of inflammatory responses to antigens delivered through the diet. To further elucidate the tolerogenic function of these cells, we propose to investigate how pDC impact a model of food allergy. Using the BDCA2-DTR transgenic mice which can be specifically depleted of pDC for extended periods of time, we will 1) examine how pDC influence the CD4 T cell response to dietary antigens during steady state and during abrogation of oral tolerance through coadministration of adjuvant, and 2) evaluate the role of pDC within the sensitization and effector phases of a preclinical model of food allergy and anaphylaxis. From our previous studies in a model of allergic contact hypersensitivity, we have discovered that pDC depletion exacerbates pathology by altering the innate and adaptive phases of the immune response to allergen. Thus, we hypothesize that pDC will limit pathology in a model of food allergy by influencing the mucosal immune response to allergen and/or by inhibiting the differentiation of effector Th2 cells. The proposed research will provide better insight into the pathogenesis of gastrointestinal allergy and may lead to improved preventative or therapeutic options for the growing population affected by this disease.
Food allergy is a disease that currently affects at least 4% of children and appears to be increasing in incidence and severity. The immune response that leads to an inflammatory reaction to ingested antigens is complex, involving innate inflammatory mediators, activation of antigen presenting cells, and eventually expansion of antigen-specific T cells and generation of IgE. Although plasmacytoid dendritic cells are implicated in the inhibition of allergic responses at other mucosal sites and are known to contribute to the generation of oral tolerance, the impact of pDC on food allergy has never been investigated. We propose to assess how pDC affect gastrointestinal allergic responses, with the goal of revealing new targets for therapeutic interventions in food allergy.
| Swiecki, M; Miller, H L; Sesti-Costa, R et al. (2017) Microbiota induces tonic CCL2 systemic levels that control pDC trafficking in steady state. Mucosal Immunol 10:936-945 |
