Integrative omics approach to identify the mechanism of tolerance induction by tolerogenic dendritic cell­ derived extracellular vesicles in multiple sclerosis.

While first generation tolDC-based therapies have shown considerable clinical promise, a better understanding of tolDC immunobiology will open many possibilities for enhancing or redirecting their therapeutic activities. In this project, we aim to investigate mechanisms linking metabolic activity of tolDC to their functional polarization. We hypothesize that tolDC-derived EV have the potential to regulate tolerance-inducing molecular pathways. We aim to identify metabolites involved in the mode-of-action of tolDC immunoregulation. For this, the following objectives have been set forth: (1) To purify tolDC-derived EV from MS patients and healthy controls and to assess their immunoregulatory function using in vitro systems (2) To identify key metabolomic and lipidomic biomarkers in patients and healthy control tolDC-derived EV using omics analysis (3) To engineer and validate the key factors in tolerance induction and therapeutic repair in tolDC-derived EV (4) To investigate the therapeutic effectiveness of immunometabolite-containing EV in vivo In summary, this research project will contribute to a better understanding of the mode-of-action of vitD3-treated tolDC, focusing on EV and metabolite/bioactive lipid components. We envisage that our results will provide proof of the immunoregulatory capacities of EV and provide new insights in the use of EV or modified form for the treatment of MS.

Keywords:EXTRACELLULAR VESICLES, MULTIPLE SCLEROSIS, DENDRITIC CELLS

Disciplines:Cellular therapy, Autoimmunity, Inflammation, Regulation of metabolism