Understanding allergen-specific immunotherapy’s mechanisms

Allergies are an overreaction of the immune system to innocuous environmental and food substances called allergens. Allergic diseases are major public health problems in industrialized countries because of their increasing prevalence and potentially life-threatening consequences, affecting about 30% of the population. Type I allergy is mediated by immunoglobulin E antibodies (IgE), which, together with the allergen, activate effector cells, such as mast cells and T cells, resulting in the release of substances which cause allergic symptoms such as rhinitis, conjunctivitis, asthma, allergic dermatitis and in the worst-case systemic anaphylaxis. Allergen-specific immunotherapy (AIT) is the only curative treatment for IgE-mediated allergy. It has the potential to induce long-term clinical tolerance but is not effective in all patients. Various in vitro tests have been developed to understand the immune mechanisms underlying successful AIT; however, in vivo models to test and study the human antibody- and T cell-induced responses are lacking. We have previously engrafted non-obese diabetic severe-combined-immunodeficient c-/- (NSG) mice with allergen-specific T cell lines (TCL) derived from birch pollen-allergic donors and found evidence that the CD4+ T cell phenotype was maintained in vivo. This project aims to establish two novels in vivo models using human immune cell engrafted NSG mice. The first model will allow us to analyze changes in tissue-resident effector CD4+ T cells during AIT. To achieve this, mice will be engrafted with TCL from donors with birch pollen-related food allergies and subsequently subjected to immunotherapy. The human CD4+ T cells will then be isolated from the murine lungs and analyzed. In the second model, mice will be engrafted with human stem cells that develop into functional human mast cells. This will enable us to study the effect of the allergen-specific IgE blocking antibodies taken from patients that underwent AIT on IgE-mediated mast cell activation and degranulation. Once established, our murine models will also allow us to study how external factors influence mast cell and T cell responses. Ultimately, the results obtained in this project will help to unravel the molecular and cellular immune mechanisms underlying successful allergy treatment.