Modulation of immune responses by genetically engineered dendritic cells

• Main Author: Wang, Qi
• Other Authors: Ruedl Christiane
• Format: Theses and Dissertations
• Language: English
• Published: 2013
• Subjects: DRNTU::Science::Biological sciences
• Online Access: http://hdl.handle.net/10356/52424
• Institution: Nanyang Technological University

Dendritic cells (DCs) are the key players in initiating and guiding innate and adaptive immune responses. In vivo targeting DCs and silencing immune responses via tolerogenic DCs are one of the most promising approaches against a variety of immune-mediated diseases. However many regulatory functions of DCs are still elusive and better understanding of the DC biology would improve the efficacy of the existing and future treatments. One goal of this project was to generate tolerogenic DCs by genetically over-expressing immunosuppressive cytokines, IL-10, and the newly discovered IL-35. Here, we describe an inducible overexpression system of these two regulatory cytokines, which allowed us to investigate them in vivo function when secreted by DCs. IL-10, but not IL-35, maintained DCs in an immature state and blocked their maturation process when co-treated with a TLR agonist. However, both cytokines showed a comparable inhibitory effect on T cell activation as well as on antibody generation. In an experimental animal model of airway inflammation, the induction of both cytokines during the sensitization and challenge period suppressed strongly all tested allergic parameters, including eosinophilia, bronchial hyperresponsiveness to methacholine as well as IgE response. The obtained results indicate that both IL-10 and IL-35 have potential therapeutic application for the control of allergic reactions and other inflammatory disorders. The second goal of this project was to understand the function of different subsets of myeloid cells, such as DCs and macrophages, in the immune response during allergic reaction. To achieve this goal we exploited a worldwide unique set of transgenic mouse strains including CLEC9A-, Siglec-H- and CD11b-DTR mice, which were used to ablate specifically subsets of DCs and macrophages in vivo. Ablation of CLEC9A+ DCs or Siglec-H+ DCs during OVA sensitization/challenge phase or only during the challenge phase had no impact on eosinophilia and IgE response, suggesting that both CD103+ DCs and pDCs are not required for the induction of airway inflammation. On the contrary, ablation of CD11b+ myeloid cells in sensitized CD11b-DTR mice during i.n. challenge displayed significantly reduction in eosinophilia as well as peribronchial and perivascular inflammatory infiltrates. Collectively, our findings support a crucial role of CD11b+ myeloid cell, most likely CD11b+ DCs, in the development of allergic airway inflammation