Introduction: Multiple Sclerosis (MS) is an autoimmune disease affecting the central nervous system. Whilst different immunomodulatory treatments are available, a cure for MS doesn’t exist yet. Antigen-specific immunotherapies represent an approach to re-educate immunity toward homeostasis without general immunosuppression and could be curative. We developed an autologous monocyte-derived tolerogenic dendritic cell product (VitD3-TolDCs) which showed safety in a Phase I clinical trial in MS patients. In this study, we aim at profiling the influence of MS-intrinsic systemic inflammation on monocytes and VitD3-tolDCs derived from patients, in order to find pathways that could be modulated to increase the potency of the cell product.
Methods: Monocytes (18vs18) and VitD3-TolDCs (7vs7) from naïve active MS patients and HD were profiled via flow cytometry and methylation microarrays. Next, gene expression was evaluated through qPCR and bulk RNAseq. Finally, we evaluated the capability of MS VitD3-TolDCs to induce allogeneic PBMCs proliferation compared to HD.
Results: MS monocytes shift from classical to the intermediate subset and show increased expression of inflammation markers. Moreover, we identified gene expression and methylation changes and enrichment of specific transcription factors in MS monocytes. Finally, VitD3-tolDCs from MS patients, despite presenting less methylation changes, resulted less able to suppress allogenic proliferation.
Conclusions: MS monocytes present an inflammatory phenotype and generate less powerful tolDCs in comparison to HD. Given the involvement of specific TFs in the gene signature of MS patients´ monocytes, we are currently exploring if these proteins could be targeted to increase the potency of tolDCs derived from MS patients.
