associated with elevated serum IgE levels in response to inhaled allergens, amongst which house dust mite (HDM) is the most common. Specific immunotherapy (SIT) is the only treatment available today that holds the promise of restoring normal immunity to allergens. The proposed project aims to elucidate the mode of action of HDM SIT. We will investigate the immunoregulatory changes at the local tissue level and ex vivo in the peripheral blood of patients with uncontrolled severe persistent allergic rhinitis undergoing HDM SIT. This will include monitoring of HDM-specific Igs and skin prick tests, and analyzing T and B cell phenotype, proliferation and cytokine production. Furthermore we want to study in vivo whether SIT causes any changes in the potential of the peripheral blood mononuclear cells (PBMC) of patients to cause features of AAI. For this purpose, we will make use of the HDM AAI mouse model in which SCID mice will be reconstituted with PBMC from patients before and during SIT. We will first analyze immunoregulatory effects of SIT and, based on these results, we will further dissect the cellular (by depletion of Breg or Treg cells) and the humoral (by blocking IL-10 or TGF-β1) mechanisms of SIT. This project could point towards the key players in the mechanism of SIT, which could contribute to the development of more effective and safer forms of immunotherapy for allergic airway diseases.