Identifizierung der Mechanismen und Charakterisierung der allergologischen, immunologischen und klinischen Relevanz der Induktion von Toleranz gegenüber Kontaktallergenen
Final Report Abstract
The aims of our project were to identify and characterize the mechanisms of low zone tolerance (LZT) to type IV allergens and to explore whether type I allergic responses can also prevented by LZT. While we did not find evidence for low zone tolerance to type I allergens, we managed to how exactly LZT works in type IV allergies: We demonstrated that it is tumor necrosis factor (TNF) released by tolerogenic CD11+CD8+ dendritic cells (DCs) located in skin-draining lymph nodes that drives tolerance development to contact allergens. Dendritic cell-derived TNF protects from contact allergy by inducing apoptosis in allergen-specific effector CD8+ T cells via TNF receptor 2 but does not contribute to the generation and function of regulatory T cells of LZT. Activation of tolerogenic DCs by LZT effector CD8+ T cells and enhanced TNF receptor 2 expression by contact allergy effector CD8+ T cells are required for LZT. These findings explain how tolerance protects from allergic diseases, which will allow for new strategies of allergy prevention. The experiments performed in the context of this project also led to observations and subsequent projects and publications on the role of endothelin A in type I allergic responses and the role of mast cells, key effector cells of type I allergic responses in limiting inflammation.
Publications
- Evidence that the endothelin A receptor can enhance IgE-dependent anaphylaxis in mice. J. Allergy Clin. Immunol. 2011: 128; 424-426
Metz, M., Schäfer, B., Tsai, M., Maurer, M., and Galli, S. J.
- T cell killing by tolerogenic dendritic cells protects from allergy in mice. J. Clin. Invest. 2011: 121; 3860-3871
Luckey, U., Maurer, M., Schmidt, T., Lorenz, N., Seebach, B., Metz, M., and Steinbrink, K.
