Engineered antigen-presenting cells and artificial lymph nodes

Objectives

Cellular immunity initiated by dendritic cells (DC) and mediated by T-lymphocytes contributes considerably to the efficient defence and control of viral or bacterial infections. This project aims to investigate the cellular airway immune response following intervention with lentiviral vector-based techniques in order to enhance or modulate DC function. Special emphasis will be given to mucosally acquired pathogens and the characterisation of DC populations involved in T-cell activation. Second, we aim to evaluate artificial scaffolds based on hydrogels mimicking extracellular matrix and specifically shaped 3-dimensional scaffolds generated by laser-based methods for DC generation and T-cell stimulation.

Research Focus

In collaboration with R. Gerardy-Schahn we investigated the function polysialic acid (PSA) expression and identified the CD8?+ dendritic cells (DCs) as the main subpopulation to carry PSA. We identified the polysialyltransferase ST8SiaIV to be required to adequate PSA expression on DCs and that DCs deficient of ST8SiaIV had an impaired CCL21-dependent migratory capacity to peripheral lymph nodes. Interestingly, PSA did not impact on the ability of the DCs to induce T-cell proliferation in vitro and in vivo and histological investigations revealed that toll-like receptor (TLR) induced migration of DCs within spleens was not affected. Our data suggest that at least in the spleen, disturbed CCL21-dependent migration due to absence of PSA, can by compensated by CCL19 directed migration. These studies reveal novel functions of PSA on specific DC subpopulations for migration and chemokine sensing. Using Down syndrome associated myeloid leukemia (DS-AMKL) as a model for acute myeloid leukemia with high mTOR activity, we sought to develop novel therapeutic options. Gene expression-based chemical genomics identified histone deacetylase (HDAC) inhibitors, such as valproic acid (VPA), as potent therapeutic agents against highly sensitive DS-AMKL blasts. 

In collaboration with the Klusmann group we demonstrated that HDAC inhibitor treatment of DS-AMKL cell lines and primary cells further repressed autophagy below a critical threshold leading to accumulation of mitochondria, production of reactive oxygen species, DNA-damage and apoptosis, which could be reverted upon autophagy activation. In conclusion, we identified autophagy inhibition as a novel mechanism of HDAC inhibitor-induced apoptosis that selectively targets leukemic cells with low basal level autophagy. 

In collaboration with the Stripecke group we will use a third-generation self-inactivating bicistronic lentiviral vector systems. This has shown that high-titer expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) efficiently achieved simultaneous and persistent co-delivery of the transgenes into DCs. GM-CSF regulates cellular proliferation, differentiation and upregulation of MHC and costimulatory molecules in myeloid cells through binding to its receptor and is required to generate cells with morphologic characteristics of DC from bone marrow cultures. IL-4 down-regulates CD14, which is a liopolysaccharide receptor, and blocks the development of macrophages. Alternatively, IFN-alpha instead of IL-4 will be used. Lentiviral vectors will be used to generate self-differentiating DCs, which will be phenotypically and functionally characterized both in vitro as well as in vivo. We will focus our study on the lung mucosa as this is a large mucosal site utilized by many pathogens to establish infection and explore immunity against model antigens and infectious antigens such as from CMV and HSV.

Collaborations

Teaching

  • Lectures and Tutorials for the Ph.D. programme ‘Molecular Medicine’, ‘Infection Biology’, and ‘Regenerative Sciences’, Lectures in Immunology and Internal Medicine for medical students

Equipment and Service Facilities

[Please find a list of all available equipment here]

Publications

[Please find the publications of this workgroup here]

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