Tumor Immunology Group (TIGr)
In 2015-2016 we continued our tumor immunology program on the role and effects of DC generated in the presence of exogenously added IL-15 and into their subsequent crosstalk with T cells and natural killer cells (Anguille et al, PlosOne 2015).
We also investigated how mRNA electroporation can be exploited to generate ‘designer’ DCs with increased immunostimulatory effects. In this respect, we showed that IFN-α mRNA electroporation of DCs significantly increased the stimulation of tumor antigen-specific cytotoxic T cell as well as anti-tumor NK cell effector functions in vitro through high levels of IFN-α secretion (Willemen et al, Cancer Immunol Immunother 2015).
Transfection of IL-15 and/or IL-15 receptor alpha mRNA into Mo-DC to enable IL-15 transpresentation also seems an interesting approach to boost antitumoral natural killer cell activity (Van den Bergh et al, Oncotarget 2015).
Also, we developed protocols to efficiently isolate, characterize and expand gd-T cells that can interact with other immune cells for increased anti-tumor immunity for adoptive immunotherapy purposes (Van Acker et al, OncoImmunology 2015 & J Hematol Oncol. 2016 ).
Immune Regulation and tolerogenic Immune Strategies group (IRIS)
For the multiple sclerosis research line, we demonstrated altered DC phenotype and function in the blood of MS patients, indicative of an inflammatory disease state and suggesting involvement of DC in MS.
Circulating DC of MS patients display a pro-inflammatory and migratory phenotype, evidenced by aberrant expression of maturation markers and upregulated expression of chemokine receptors CCR5 and CCR7. Since chemokine ligands have also been reported to be upregulated in parenchymal lesions and CSF of MS patients, this observation has prompted us to investigate the transmigration of these potentially pathogenic DC through the BBB (research funded by the Charcot research fund and DOCPRO-BOF).
MS is a complex multifactorial disease. Our data suggest that both certain genetic MS risk factors and treatment of MS are associated with changes in the DC compartment. Furthermore, lifestyle interventions can affect the number of circulating DC subsets by Flt3L- and MMP-9-dependent process (Deckx et al., Am J Phys Med Rehabil. 2015 & Mediators of Inflammation 2016 ).
Hence, dendritic cells may represent an interesting target for therapeutic intervention The clinical applicability of tolerogenic DC will depend on the capacity to preserve their tolerogenic phenotype upon in vivo injection. In this respect, it was recently demonstrated that in vitro generated monocyte-derived DC from MS patients are comparable to those from controls and that they thus may be suitable for tolerance-inducing immunotherapy. In addition, we demonstrated that IL-10 and vitamin D3 induce maturation-resistant DC, preventing the upregulation of costimulatory molecules and secretion of proinflammatory cytokines (Lee et al, J Immunol Res 2016).
In this perspective, the LEH plans a first-in-man pilot study in MS patients to address safety, feasibility and efficacy of tolerogenic DC vaccination for which an IWT-TBM project was granted. For the CNS cell grafting research line, we also continued our pre-clinical in vivo neuro-immune modulation research, focussing on in vivo delivery of the immune modulating cytokine interleukin 13 (IL13), either by implantation of genetically engineered mesenchymal stem cells (MSC) or by direct lentiviral vector injection.
With these studies, we have clearly demonstrated that local delivery of IL13, by both methods, is able to direct alternative activation programs in both brain-resident microglia and central nervous system (CNS) infiltrating macrophages. This intervention has additionally been shown to (i) reduce MSC allograft-specific immune responses (Hoornaert et al. Stem Cells 2016), (ii) to prevent demyelination in the cuprizone mouse model (Guglielmettie et al. Glia 2016 & Le Blon et al. Journal of NeuroInflammation 2016), and (iii) to improve functional recovery following spinal cord injury (Dooley et al. Stem Cell Reports 2016).
Given the exceptional capability of IL-13 to modulate deleterious immune responses in pre-clinical animal models of peripheral and CNS inflammation, we are currently initiating novels studies to: (i) further understand the working mechanism of IL-13 mediated immune suppression in vivo, and (ii) to evaluate the immune-modulating potential of IL-13 in various mouse and human preclinical settings applying induced pluripotent stem cell (iPSC) technology and 3D brain organoid cell culture models.