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Transfection of Vitamin D3-Induced Tolerogenic Dendritic Cells for the Silencing of Potential Tolerogenic Genes. Identification of CSF1R-CSF1 Signaling as a Glycolytic Regulator.

ABSTRACT: The use of autologous tolerogenic dendritic cells (tolDC) has become a promising strategy to re-establish immune tolerance in autoimmune diseases. Among the different strategies available, the use of vitamin D3 for the generation of tolDC (VitD3-tolDC) has been widely tested because of their immune regulatory properties. To identify molecules and pathways involved in the generation of VitD3-tolDC, we established an easy and fast gene silencing method based on the use of Viromer blue to introduce siRNA into monocytes on day 1 of culture differentiation. The analysis of the effect of CD209 (DC-SIGN) and CD115 (CSF1R) down-modulation on the phenotype and functionality of transfected VitD3-tolDC revealed a partial role of CD115 in their tolerogenicity. Further investigations showed that CSF1R-CSF1 signaling is involved in the induction of cell metabolic reprogramming, triggering glycolysis to produce high amounts of lactate, a novel suppressive mechanism of T cell proliferation, recently found in autologous tolerogenic dendritic cells (ATDCs).

SUBMITTER: Mansilla MJ

PROVIDER: S-EPMC8305050 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Comparative transcriptomic profile of tolerogenic dendritic cells differentiated with vitamin D3, dexamethasone and rapamycin.

Project description:Tolerogenic dendritic cell (tolDC)-based therapies have become a promising approach for the treatment of autoimmune diseases by their potential ability to restore immune tolerance in an antigen-specific manner. However, the broad variety of protocols used to generate tolDC in vitro and their functional and phenotypical heterogeneity are evidencing the need to find robust biomarkers as a key point towards their translation into the clinic, as well as better understanding the mechanisms involved in the induction of immune tolerance. With that aim, in this study we have compared the transcriptomic profile of tolDC induced with either vitamin D3 (vitD3-tolDC), dexamethasone (dexa-tolDC) or rapamycin (rapa-tolDC) through a microarray analysis in 5 healthy donors. The results evidenced that common differentially expressed genes could not be found for the three different tolDC protocols. However, individually, CYP24A1, MUCL1 and MAP7 for vitD3-tolDC; CD163, CCL18, C1QB and C1QC for dexa-tolDC; and CNGA1 and CYP7B1 for rapa-tolDC, constituted good candidate biomarkers for each respective cellular product. In addition, a further gene set enrichment analysis of the data revealed that dexa-tolDC and vitD3-tolDC share several immune regulatory and anti-inflammatory pathways, while rapa-tolDC seem to be playing a totally different role towards tolerance induction through a strong immunosuppression of their cellular processes.

| S-EPMC6175832 | biostudies-literature

Dimethyl Fumarate Restores Functional Vitamin-D3 Tolerogenic Dendritic Cells differentiated from Multiple Sclerosis Patients

Project description:Multiple Sclerosis (MS) is a chronic disease characterised by dysregulated self-reactive immune responses damaging neurons’ myelin sheath, causing disability. The primary therapeutic option, immunosuppressants, inhibit pathogenic anti-myelin responses but depresses the entire immune system. Antigen-specific autologous tolerogenic dendritic cell (tolDC) therapies offer an approach to restore tolerance to auto-antigens without causing generalised immunosuppression. However, immune dysregulation in MS could impact the phenotype and functionality of the starting material for cell therapy. In this study, we defined the immune signature of CD14+ monocytes, mature dendritic cells (mDCs) and Vitamin D3 tolDCs (VitD3-tolDCs) isolated from MS patients and healthy donors (HD). By using a multi-omic approach, we identified a shift in these cell types toward a proinflammatory profile dominated by alterations in the AhR pathway and increased NFkB signalling. Moreover, tolDCs isolated from MS patients showed reduced tolerogenic properties compared to those from HD, which were fully restored through AhR agonism and NFkB downregulation through in vivo or in vitro supplementation with Dimethyl Fumarate (DMF). Remarkably, a combined therapy of DMF and VitD3-tolDC was more efficient to reduce the clinical score of experimental autoimmune encephalomyelitis mice than monotherapies. In summary, we demonstrate that DMF restores the functionality of VitD3-tolDCs derived from MS patients. Moreover, a combined therapy with DMF and VitD3-tolDCs could offer enhanced therapeutic potential in treating MS.

2024-12-13 | GSE267576 | GEO

Combined Therapy of Vitamin D3-Tolerogenic Dendritic Cells and Interferon-β in a Preclinical Model of Multiple Sclerosis.

Project description:Autologous antigen-specific therapies based on tolerogenic dendritic cells (tolDC) offer the possibility to treat autoimmune diseases by restoring homeostasis and targeting specifically autoreactive responses. Here, we explore the hypothesis that systemic inflammation occurring in autoimmune diseases, such as multiple sclerosis (MS), can generate a disease-specific environment able to alter the functionality of tolDC. In this context in fact, a combined therapy of tolDC with an immunomodulatory treatment could potentiate the beneficial effect of this antigen-specific cell therapy. For this purpose, we analyzed the efficacy of a combined therapy based on the use of vitamin D3 (VitD3)-tolDC plus interferon beta (IFN-beta) in MS. VitD3-tolDC were generated from healthy donors and MS patients and co-cultured with allogeneic peripheral blood mononuclear cells, in the presence or absence of IFN-beta. In vitro, VitD3-tolDC treatment reduced the percentage of activated T cells and allogeneic proliferation, whereas VitD3-tolDC+IFN-beta treatment enhanced the suppressive ability of VitD3-tolDC and, additionally, induced a shift towards a Th2 profile. To determine the clinical benefit of the combined therapy, C57BL/6-experimental autoimmune encephalomyelitis (EAE)-induced mice were treated with antigen-specific VitD3-tolDC and/or IFN-beta. Treatment of EAE mice with combined therapy ameliorated the disease course compared to each monotherapy. These results suggest that a combined therapy based on antigen-specific VitD3-tolDC and IFN-beta may represent a promising strategy for MS patients.

| S-EPMC8698295 | biostudies-literature

Dimethyl Fumarate Restores Functional Vitamin-D3 Tolerogenic Dendritic Cells differentiated from Multiple Sclerosis Patients [Methylation_array]

2024-12-13 | GSE267660 | GEO

Vitamin D3-Induced Tolerogenic Dendritic Cells Modulate the Transcriptomic Profile of T CD4+ Cells Towards a Functional Hyporesponsiveness.

Project description:The use of autologous tolerogenic dendritic cells (tolDC) has become a promising alternative for the treatment of autoimmune diseases. Among the different strategies available, the use of vitamin D3 for the generation of tolDC (vitD3-tolDC) constitutes one of the most robust approaches due to their immune regulatory properties, which are currently being tested in clinical trials. However, the mechanisms that vitD3-tolDC trigger for the induction of tolerance remain elusive. For this reason, we performed a full phenotypical, functional, and transcriptomic characterization of T cells upon their interaction with autologous, antigen-specific vitD3-tolDC. We observed a strong antigen-specific reduction of T cell proliferation, combined with a decrease in the relative prevalence of TH1 subpopulations and IFN-? production. The analysis of the transcriptomic profile of T CD4+ cells evidenced a significant down-modulation of genes involved in cell cycle and cell response to mainly pro-inflammatory immune-related stimuli, highlighting the role of JUNB gene as a potential biomarker of these processes. Consequently, our results show the induction of a strong antigen-specific hyporesponsiveness combined with a reduction on the TH1 immune profile of T cells upon their interaction with vitD3-tolDC, which manifests the regulatory properties of these cells and, therefore, their therapeutic potential in the clinic.

| S-EPMC7856150 | biostudies-literature

MAP7 and MUCL1 Are Biomarkers of Vitamin D3-Induced Tolerogenic Dendritic Cells in Multiple Sclerosis Patients.

Project description: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.

| S-EPMC6598738 | biostudies-literature

Microarray of tolerogenic dendritic cells differentiated in the presence of vitamin D3, dexamethasone or rapamycin

Project description:The comparative analysis of the transcriptome of tolerogenic dendritic cells (tolDC) differentiated using different stimulus (either vitamin D3, dexamethasone or rapamycin) would allow to evidence potential common genes and pathways that could explain their potency as tolerance-inducing cells.

2018-07-31 | E-MTAB-6937 | biostudies-arrayexpress

Vitamin D3 induces IDO+ tolerogenic DCs and enhances Treg, reducing the severity of EAE.

Project description:BackgroundA growing body of evidence supports the hypothesis that vitamin D is an important environmental factor in the etiology of T-cell-mediated autoimmune diseases such as multiple sclerosis (MS).AimThe purpose of this study was exploring the mechanisms underlying the beneficial effect of vitamin D3 in encephalomyelitis (EAE).MethodsWe treated monophasic experimental autoimmune EAE, induced in Lewis rat, with vitamin D3 and adoptively transfer tolerogenic bone marrow-derived DCs generated in the presence of vitamin D3.ResultsThis study provides evidence that the in vivo administration of vitamin D3, as well as the adoptive transfer of vitamin D3 -induced IDO(+) immature/tolerogenic dendritic cells, leads to a significant increase in the percentage of CD4(+) CD25(+) Foxp3(+) regulatory T cells in the lymph nodes in a rat model of MS, experimental autoimmune EAE. Concomitant with the increase in this cell population, there is a significant decrease in the number of autoreactive T cells in the central nervous system. Bone marrow-derived DCs cultivated in the presence of vitamin D3 present a tolerogenic profile with high IL-10, TNF?, and IDO expression and decreased MHC-II and CD80 expression. The adoptive transfer of IDO (+) DCs induces a significant increase in the percentage of CD4(+) CD25(+) Foxp3(+) T cells in the lymph nodes, comparable with vitamin D3 treatment.ConclusionThese mechanisms contribute actively to the generation of a microenvironment in the lymph nodes that suppresses the activation of encephalitogenic T cells, resulting in the downregulation of the inflammatory response in the central nervous system.

| S-EPMC6493393 | biostudies-literature

1,25-dihydroxyvitamin D3 induces stable and reproducible therapeutic tolerogenic dendritic cells with specific epigenetic modifications.

Project description:Autologous, antigen-specific, tolerogenic dendritic cells (tolDCs) are presently assessed to reverse and possibly cure autoimmune diseases such as type 1 diabetes (T1D). Good Manufacturing Practice production and clinical implementation of such cell therapies critically depend on their stability and reproducible production from healthy donors and, more importantly, patient-derived monocytes. Here the authors demonstrate that tolDCs (modulated using 1,25-dihydroxyvitamin D3 and dexamethasone) displayed similar features, including protein, transcriptome and epigenome profiles, between two international clinical centers and between T1D and healthy donors, validating reproducible production. In addition, neither phenotype nor function of tolDCs was affected by repeated stimulation with inflammatory stimuli, underscoring their stability as semi-mature DCs. Furthermore, tolDCs exhibited differential DNA methylation profiles compared with inflammatory mature DCs (mDCs), and this was already largely established prior to maturation, indicating that tolDCs are locked into an immature state. Finally, approximately 80% of differentially expressed known T1D risk genes displayed a corresponding differential DNA methylome in tolDCs versus mDCs and metabolic and immune pathway genes were also differentially methylated and expressed. In summary, tolDCs are reproducible and stable clinical cell products unaffected by the T1D status of donors. The observed stable, semi-mature phenotype and function of tolDCs are exemplified by epigenetic modifications representative of immature-stage cells. Together, the authors' data provide a strong basis for the production and clinical implementation of tolDCs in the treatment of autoimmune diseases such as T1D.

| S-EPMC8715888 | biostudies-literature

Association between CSF1 and CSF1R Polymorphisms and Parkinson's Disease in Taiwan.

Project description:BACKGROUND:CSF1/CSF1R neuroinflammatory signaling is emerging as an important pathway involved in the pathogenesis of Parkinson's disease (PD). However, the genetic associations between CSF1/CSF1R and PD have not yet been explored. METHODS:We investigated the effects of two functional genetic variants, including CSF1 rs1058885 and CSF1R rs10079250 in a cohort including 502 Taiwanese patients with PD and 511 age- and gender-matched healthy controls. RESULTS:The CSF1 rs1058885 TT genotype was less frequent in PD patients compared with control subjects (odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.43-0.92, p = 0.015). The PD patients also had a lower frequency of the CSF1 rs1058885 T allele compared with the control subjects (OR = 0.80, 95% CI: 0.67-0.96, p = 0.014). No statistically significant differences in allelic and genotypic frequencies of CSF1R rs10079250 between the PD and control subjects were found, even after stratification by age at onset and gender. CONCLUSION:This study reports a genetic association between CSF1 and PD for the first time.

| S-EPMC6832167 | biostudies-literature

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