Abstract
MS is a chronic auto-immune disorder of the central nervous system (CNS) and the leading cause of non-traumatic disabling disease in young adults. Although the exact cause of MS remains to be elucidated, it is currently accepted that both genetic and environmental factors affect complex immunological responses, both in the periphery and the CNS. To date, there is still no cure for MS, but several immune-modifying and/or -suppressive treatments, especially targeting the peripheral immune system, have been developed over time. However, these have varying efficacy, have limited long-term effectiveness, and sometimes life-threatening side effects, thereby underscoring the urgent need for novel therapeutic approaches to be developed and evaluated. Tolerogenic dendritic cells (tolDCs) are professional antigen-presenting cells with immunosuppressive properties, priming the immune system into a tolerogenic or unresponsive state against various (self)antigens. TolDCs are essential in maintenance of central and peripheral tolerance
through induction of T cell clonal deletion, T cell anergy, generation and activation of regulatory T-cells (Tregs), as well as the direct modulation of pro-inflammatory environments. For that reason, tolDCs show considerable promise as candidates for specific cellular therapy for treatment of allergic diseases, autoimmune diseases or transplant rejections. In this context, the Laboratory of
Experimental Hematology (LEH, Cools' team) recently recruited nine patients for a phase I clinical trial evaluating the potential safety and feasibility of tolDCs for the treatment of multiple sclerosis (MS) (NCT02618902). While no serious adverse events are observed in all treated patients, much remains to be understood about the exact molecular and cellular interactions these therapeutic cells
provoke in vivo. Accumulating evidence shows that extracellular vesicles (EVs) secreted by immune cells play a key
role in intercellular communication. In this project, we aim to determine the immune-regulatory mechanism by tolDCs, hypothesising that it would be mediated by EVs and their immunosuppressive cargo. To achieve this goal, we will apply an unbiased multi-omics approach, both in vitro and in vivo, to unravel the therapeutic potential of tolDC-derived EVs. We hereby anticipate that our findings will lead to ground-breaking insights on current understanding of EVs in immune-regulatory therapy and ultimately will lead to the development of a novel (non-cellular) off-the-shelf therapeutic compound to be evaluated in patients suffering from detrimental auto-immune disorders, including MS. This highly innovative application addresses the use of tolDC-derived EVs as disease-modifying treatment in MS and is expected to provide new insights into how immune tolerance is initiated following interaction of key immune-regulatory cargo of the EVs with peripheral and CNS immune cells.
With this project, we present a clinically relevant project relying on inventive fundamental research with a high translational value and valorization potential. The integrative multiomics analysis will give a better insight in the molecular pathways involved in the induction of tolerance and immunoregulation by tolDCs. Furthermore, this project could lead to the development of a cell-free therapy based on tolDC-EV for the treatment of MS, which can surpass drawbacks associated with cell therapy. In addition, the possibility of allogenic exosome therapy would result in a more positive cost-benefit ratio since an "off-the-shelf" product is less expensive than an individualized cell therapy. Hence, the study proposed here is merely the beginning of numerous possible new research questions as well as clinical translation.
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