Abstract
The administration of autologous tolerogenic dendritic cells (tolDC) has become a promising alternative for the treatment of autoimmune diseases, such as multiple sclerosis (MS). Specifically, the use of vitamin D3 for the generation of tolDC (vitD3-tolDC) constitutes one of the most widely studied approaches, as it has evidenced significant immune regulatory properties, both in vitro and in vivo. In this article, we generated human vitD3-tolDC from monocytes from healthy donors and MS patients, characterized in both cases by a semi-mature phenotype, secretion of IL-10 and inhibition of allogeneic lymphocyte proliferation. Additionally, we studied their transcriptomic profile and selected a number of differentially expressed genes compared to control mature and immature dendritic cells for their analysis. Among them, qPCR results validated CYP24A1, MAP7 and MUCL1 genes as biomarkers of vitD3-tolDC in both healthy donors and MS patients. Furthermore, we constructed a network of protein interactions based on the literature, which manifested that MAP7 and MUCL1 genes are both closely connected between them and involved in immune-related functions. In conclusion, this study evidences that MAP7 and MUCL1 constitute robust and potentially functional biomarkers of the generation of vitD3-tolDC, opening the window for their use as quality controls in clinical trials for MS.
Highlights
The role of dendritic cells (DC) within the immune system is crucial, since they are in charge of orchestrating immune responses and maintaining the homeostasis between immunogenicity and tolerance
We have evidenced that CYP24A1, MAP7 and MUCL1 genes appear strongly induced in vitD3-tolerogenic DC (tolDC), both in healthy donors and multiple sclerosis (MS) patients
The study of the protein expression of MAP7 and MUCL1 further supported these results. The study of these genes in the context of the whole transcriptome of the vitD3-tolDC has elucidated that the role of MAP7 and MUCL1 —but not of CYP24A1— seems to be closely related with important and widely described immune- and nonimmune-related pathways, which correlates with many of the results that we have obtained at the phenotypical, functional and transcriptomic levels
Summary
The role of dendritic cells (DC) within the immune system is crucial, since they are in charge of orchestrating immune responses and maintaining the homeostasis between immunogenicity and tolerance. If the immune homeostasis is lost, and a breach of tolerance causes mDC to recognize and present specific self-antigens to T cells, different autoimmune pathologies may develop depending on which protein or tissue is targeted, such as multiple sclerosis (MS), rheumatoid arthritis or type 1 diabetes. These complex disorders involve many innate and adaptive mechanisms of the immune system, and their etiology still remains unknown. For this reason, a cure has not been found yet, and the currently available treatments consist in strong immunomodulatory or immunosuppressive drugs. Many initiatives are focused on assessing the actual efficacy of tolerogenic cell therapies
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