Mechanisms of tolerance induction in allergen specific immunotherapy (SIT)
Final Report Abstract
Allergen specific immunotherapy (SIT) is the only causal treatment for IgE-mediated allergies such as allergic asthma and rhinitis. SIT acts by reprogramming the immune response, resulting in allergen tolerance and lasting improvement of disease activity. According to existing concepts, SIT leads to the generation of regulatory T cells that counterbalance the allergic response mainly via the production of inhibitory cytokines such as IL-10. The central role of IL-10 is suggested by mouse models of allergen immunotherapy in which blocking IL-10 abrogates the beneficial effect of SIT. Using mice in which T cells are incapable of producing IL-10, we have challenged this concept and demonstrated that allergen-specific tolerance can efficiently be induced even in the absence of T cell derived IL- 10. This clearly implies a role for T cell-independent IL-10 in tolerance induction. The funded project analyzed A) the critical cellular source, localization and kinetics of IL-10 production during SIT in vivo using novel IL-10 reporter mice, B) the functional contribution of IL-10 from different sources in cell type specific IL-10 deficient mutants, and C) the cellular targets of IL- 10 mediated effects in cell type specific IL-10 receptor deficient mice. From our results we conclude, that during immunotherapy a variety of different cells are stimulated to express IL-10. This effect was prominent in T cells, but also in B cells and dendritic cells. However, functionally no single cell type turned out to be the crucial IL-10 producer alone because tolerance induction was effective in all tested mice with a cell type specific IL-10 deficiency (T cell, B cell, T + B cell, dendritic cell, macrophage/granulocyte, mast cell). This suggests a high redundancy of the cellular sources of IL-10 in the context of immunotherapy and tolerance induction. In contrast to existing concepts that highlight T cell derived IL-10 as a key regulator we were able to show that in case of a failure of T cells in IL- 10 production other cell populations can stand in, while in case of an IL-10 deficiency in all hematopoetic cells tolerance induction failed. Looking at the cellular targets of IL-10 during immunotherapy we were able to show that direct effects of IL-10 on T cells or B cells are not critical for tolerance induction. Preliminary results in mice with a specific deletion of the IL-10 receptor in dendritic cells however indicate that IL-10 signaling in those cells may contribute at least partially to the induction of tolerance. The funded project extended our understanding of the mechanisms of immunotherapy and the role of IL-10 in tolerance induction. Our results suggest that functionally the immune regulatory role of IL-10 is safe guarded by a high redundancy, so that in case of loss of IL-10 production in one cell population the beneficial effects of IL-10 during tolerance induction is not affected.
Publications
- T cell derived interleukin 10 is dispensable for tolerance induction in a murine model of specific immunotherapy. Eur J Immunol 46(8), 2018-2027
Kunz S, Dolch A, Dorn B, Bewersdorff M, Alessandrini F, Surianarayanan S, Behrendt R, Karp CL, Mueller W, Martin SF, Roers A, Jakob T
(See online at https://doi.org/10.1002/eji.201646319|) - IL-10 signalling in dendritic cells is required for tolerance induction in a murine model of allergic airway inflammation. Eur J Immunol 49(2) 302–312;
Dolch A, Kunz S, Dorn B, Alessandrini F, Muller W, Jack RS, Martin SF, Roers A, Jakob T
(See online at https://doi.org/10.1002/eji.201847883)
