Analyses of interactions between innate and adaptive immunity during contact allergen-specific immune responses

• Applicant: Professorin Dr. Kerstin Steinbrink
• Subject Area: Dermatology
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 236648302

The allergic contact dermatitis is one of the most frequent occupational dermatological diseases and forces a restricted quality of life in affected patients and high socio-economic costs. In the last decades the well-established murine model of contact hypersensitivity has allowed for analysis of the underlying immune mechanisms of the allergic skin reaction. However, effective strategies for preventive and long-lasting therapeutic strategies of the allergic contact dermatitis are still lacking. In our work, we have focused on the induction of specific immune tolerance. One goal is the analysis of the murine model of low zone tolerance (LZT) to contact allergens which resembles the physiologic epicutaneous exposure to low sub-immunogenic amounts of allergens in everyday live of humans. We found that during the induction phase of LZT regulatory CD4+CD25+Foxp3+ T cells induce tolerogenic CD11c+ dendritic cells DC which are required for the generation hapten-specific LZT regulatory CD8+ T cells. Thereafter, these regulatory T cells induce an increased TNF production of CD11c+CD8+ DC. Apoptosis of effector CD8+ T cells of the CHS is driven by this cytokine resulting in prevention of the allergic skin immune response. Recently, it was demonstrated that contact allergens/haptens directley or indirectly activated processes of the innate immunity (e.g. by activation of pattern recognition receptors [PRR]) that were critical for the allergic immune response. In contrast, mechanisms of the innate immunity (cell-related: neutrophils, macrophages, etc. or PRR-related) have not yet been explored in tolerance reactions to contact allergens. Therefore, we envisage to analyze the function of the innate immunity in contact allergen-/hapten-specific immune tolerance reactions (epicutaneous and oral LZT) and their interaction with mechanisms of the adaptive immunity. We intend to focus on the activation of regulatory T cells and their interaction with tolerogenic DC resulting in induction of hapten-specific tolerance reactions. Analyses of processes of the innate immunity will encompass the function of immune cells (neutrophils, myeloid-derived cells) and PRR-related mechanisms (with focus on TLR2) to evaluate their functions in hapten-specifc tolerance. The results of the applied project may identify novel targets for the modulation and prevention of allergic immune responses.

• DFG Programme: Research Grants