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

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.

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

Frontiers in Immunology ◽

10.3389/fimmu.2019.01251 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 1

Author(s):

Juan Navarro-Barriuso ◽

María José Mansilla ◽

Bibiana Quirant-Sánchez ◽

Alicia Ardiaca-Martínez ◽

Aina Teniente-Serra ◽

...

Keyword(s):

Multiple Sclerosis ◽

Dendritic Cells ◽

Vitamin D3 ◽

Tolerogenic Dendritic Cells ◽

Multiple Sclerosis Patients

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Cryopreserved vitamin D3-tolerogenic dendritic cells pulsed with autoantigens as a potential therapy for multiple sclerosis patients

Journal of Neuroinflammation ◽

10.1186/s12974-016-0584-9 ◽

2016 ◽

Vol 13 (1) ◽

Cited By ~ 18

Author(s):

María José Mansilla ◽

Raian Contreras-Cardone ◽

Juan Navarro-Barriuso ◽

Nathalie Cools ◽

Zwi Berneman ◽

...

Keyword(s):

Multiple Sclerosis ◽

Dendritic Cells ◽

Vitamin D3 ◽

Tolerogenic Dendritic Cells ◽

Multiple Sclerosis Patients

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Made to Measure: Patient-Tailored Treatment of Multiple Sclerosis Using Cell-Based Therapies

International Journal of Molecular Sciences ◽

10.3390/ijms22147536 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7536

Author(s):

Inez Wens ◽

Ibo Janssens ◽

Judith Derdelinckx ◽

Megha Meena ◽

Barbara Willekens ◽

...

Keyword(s):

Multiple Sclerosis ◽

Autoimmune Diseases ◽

Stromal Cells ◽

Mononuclear Cells ◽

Treatment Options ◽

Cell Types ◽

Peripheral Blood Mononuclear ◽

Tailored Treatment ◽

Key Issues ◽

The Central Nervous System

Currently, there is still no cure for multiple sclerosis (MS), which is an autoimmune and neurodegenerative disease of the central nervous system. Treatment options predominantly consist of drugs that affect adaptive immunity and lead to a reduction of the inflammatory disease activity. A broad range of possible cell-based therapeutic options are being explored in the treatment of autoimmune diseases, including MS. This review aims to provide an overview of recent and future advances in the development of cell-based treatment options for the induction of tolerance in MS. Here, we will focus on haematopoietic stem cells, mesenchymal stromal cells, regulatory T cells and dendritic cells. We will also focus on less familiar cell types that are used in cell therapy, including B cells, natural killer cells and peripheral blood mononuclear cells. We will address key issues regarding the depicted therapies and highlight the major challenges that lie ahead to successfully reverse autoimmune diseases, such as MS, while minimising the side effects. Although cell-based therapies are well known and used in the treatment of several cancers, cell-based treatment options hold promise for the future treatment of autoimmune diseases in general, and MS in particular.

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Stable antigen-specific T-cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients

European Journal of Immunology ◽

10.1002/eji.201141835 ◽

2012 ◽

Vol 42 (3) ◽

pp. 771-782 ◽

Cited By ~ 69

Author(s):

Dàlia Raϊch-Regué ◽

Laia Grau-López ◽

Mar Naranjo-Gómez ◽

Cristina Ramo-Tello ◽

Ricardo Pujol-Borrell ◽

...

Keyword(s):

Multiple Sclerosis ◽

Dendritic Cells ◽

T Cell ◽

Tolerogenic Dendritic Cells ◽

Multiple Sclerosis Patients

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Current Paradigms of Tolerogenic Dendritic Cells and Clinical Implications for Systemic Lupus Erythematosus

Cells ◽

10.3390/cells8101291 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1291 ◽

Cited By ~ 2

Author(s):

Ritprajak ◽

Kaewraemruaen ◽

Hirankarn

Keyword(s):

Systemic Lupus Erythematosus ◽

Dendritic Cells ◽

Autoimmune Diseases ◽

Lupus Erythematosus ◽

Ex Vivo ◽

Immunosuppressive Drugs ◽

Clinical Implications ◽

Systemic Lupus ◽

Tolerogenic Dendritic Cells

Tolerogenic dendritic cells (tolDCs) are central players in the initiation and maintenance of immune tolerance and subsequent prevention of autoimmunity. Recent advances in treatment of autoimmune diseases including systemic lupus erythematosus (SLE) have focused on inducing specific tolerance to avoid long-term use of immunosuppressive drugs. Therefore, DC-targeted therapies to either suppress DC immunogenicity or to promote DC tolerogenicity are of high interest. This review describes details of the typical characteristics of in vivo and ex vivo tolDC, which will help to select a protocol that can generate tolDC with high functional quality for clinical treatment of autoimmune disease in individual patients. In addition, we discuss the recent studies uncovering metabolic pathways and their interrelation intertwined with DC tolerogenicity. This review also highlights the clinical implications of tolDC-based therapy for SLE treatment, examines the current clinical therapeutics in patients with SLE, which can generate tolDC in vivo, and further discusses on possibility and limitation on each strategy. This synthesis provides new perspectives on development of novel therapeutic approaches for SLE and other autoimmune diseases.

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Dendritic cells derived from patients with multiple sclerosis show high CD1a and low CD86 expression

Multiple Sclerosis Journal ◽

10.1177/135245850100700204 ◽

2001 ◽

Vol 7 (2) ◽

pp. 95-99 ◽

Cited By ~ 27

Author(s):

Yu-Min Huang ◽

Mathilde Kouwenhoven ◽

Ya-Ping Jin ◽

Rayomand Press ◽

Wen-Xin Huang ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Dendritic Cells ◽

Mononuclear Cells ◽

Neurological Diseases ◽

Interleukin 4 ◽

Gm Csf ◽

The Central Nervous System ◽

Macrophage Colony ◽

Antigen Presenting

Dendritic cells (DC) are important antigen presenting cells (APC) and play a major role in initiating and orchestrating immune responses by priming T cells. Little is known about involvement of DC in multiple sclerosis (MS), where auto-aggressive T cells against myelin autoantigens are considered to contribute to inflammation and demyelination in the central nervous system. In this study, we compared phenotype and cytokine secretion of DC from patients with MS, other neurological diseases (OND) and healthy subjects. DC were generated from blood adherent mononuclear cells (MNC) by culture for 7 days with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). The yield and morphology of DC were similar in MS patients and controls. In both, the DC phenotype was that of immature myeloid lineage, comprising CD1a+ and CD11c+. The proportion of CD1a+ DC, being important for presentation of lipid antigens to T cells, was higher in MS patients compared to controls. The proportion of CD86+ DC, a co-stimulatory molecule that is assumed to promote Th2 differentiation, was low in MS. Low proportions of CD86+ DC were only observed in untreated MS patients but not in patients treated with IFN-b. Production of IL-10 and IL-12 p40 by DC did not differ in MS patients and controls. These findings indicate that alterations of functionally important surface molecules on DC are associated with MS.

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Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting allograft rejection and autoimmune diseases

Kidney International ◽

10.1111/j.1523-1755.2004.05401.x ◽

2004 ◽

Vol 65 (5) ◽

pp. 1538 ◽

Cited By ~ 4

Author(s):

Luciano Adorini

Keyword(s):

Vitamin D ◽

T Cells ◽

Dendritic Cells ◽

Regulatory T Cells ◽

Autoimmune Diseases ◽

Vitamin D Receptor ◽

Allograft Rejection ◽

Receptor Ligands ◽

Tolerogenic Dendritic Cells

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Cord blood stem-cell-derived dendritic cells generate potent antigen-specific immune responses and anti-tumour effects

Clinical Science ◽

10.1042/cs20110272 ◽

2012 ◽

Vol 123 (6) ◽

pp. 347-360 ◽

Cited By ~ 9

Author(s):

Ming-Cheng Chang ◽

Chien-Nan Lee ◽

Yu-Li Chen ◽

Ying-Cheng Chiang ◽

Wei-Zen Sun ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Cord Blood ◽

Antigen Presentation ◽

Mononuclear Cells ◽

Ex Vivo ◽

Cytotoxic T Cell ◽

Cell Mediated Immunity ◽

Specific Cell ◽

Surface Markers

The aim of the present study was to investigate whether CBSCs [(umbilical) cord blood stem cells] can be a new source of DCs (dendritic cells), which can generate more potent antigen-specific immune responses and anti-tumour effects. CBSCs and PBMCs (peripheral blood mononuclear cells) were collected, cultured and differentiated into DCs. Surface markers, secreting cytokines, antigen-presentation activity, antigen-specific cell-mediated immunity and cytotoxic killing effects induced by these two DC origins were evaluated and compared. CBSCs were expanded ~17-fold by ex vivo culture. The expression of surface markers in CBSC-derived DCs were higher than those in PBMC-derived DCs treated with LPS (lipopolysaccharide). The CBSC-derived DCs mainly secreted IL (interleukin)-6, IL-10 and TNF (tumour necrosis factor)-α, whereas PBMC-derived DCs mainly secreted IL-5 and IFN (interferon)-γ. The CBSC-derived DCs had better antigen-presentation abilities when stimulated with LPS or TNF-α, induced higher numbers of IFN-γ-secreting antigen-specific CD8+ T-cells, as assessed using an ELISpot (enzyme-linked immunosorbent spot) assay, and stimulated more potent antigen-specific CTL (cytotoxic T-cell) activities (P<0.01, one-way ANOVA). CBSC-derived DCs had quicker and greater ERK (extracellular-signal-regulated kinase) and Akt phosphorylation, and weaker p38 phosphorylation, than PBMC-derived DCs when stimulated with LPS. In conclusion, CBSC-derived DCs have the ability to induce stronger antigen-specific immunity and more potent anti-tumour effects and therefore could be a good source of DCs for use in DC-based cancer vaccines and immunotherapy.

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