e5793ba78833923883ecd4d1a452b470 pmc_34944573.pdf f4a582ceb0a8360eddeb7dd8ad42bc7cbf5e3adc pmc_34944573.pdf ce3f0b677bd45e5e9400a85a88ff78cd4e4a3b2f0bff086504962e2801eb8a54 pmc_34944573.pdf Title: Combined Therapy of Vitamin D3-Tolerogenic Dendritic Cells and Interferon- in a Preclinical Model of Multiple Sclerosis Subject: 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. Keywords: combined therapy; antigen-specific therapies; immunomodulatory; multiple sclerosis Author: Bibiana Quirant-Sánchez, María José Mansilla, Juan Navarro-Barriuso, Silvia Presas-Rodríguez, Aina Teniente-Serra, Federico Fondelli, Cristina Ramo-Tello and Eva Martínez-Cáceres Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Nov 24 12:33:33 2021 CET ModDate: Wed Nov 24 12:45:32 2021 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2487128 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- IOJCNK+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 HHFREY+EURM7 Type 1 Builtin yes yes no 15 0 KORLVE+VnURWPalladioL Type 1 Custom yes yes no 19 0 HXXNNJ+URWPalladioL-Ital Type 1 Custom yes yes no 23 0 FOEKSI+URWPalladioL-Bold Type 1 Custom yes 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yes yes no 148 0 KPKLEE+PalatinoLinotype TrueType WinAnsi yes yes no 151 0 KPKLFG+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 154 0 KPKLEC+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 165 0 KPKLED+PalatinoLinotype CID TrueType Identity-H yes yes yes 168 0 KPKLEE+PalatinoLinotype TrueType WinAnsi yes yes no 174 0 KPKLFG+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 177 0 KPKNKK+PalatinoLinotype,BoldItalic TrueType WinAnsi yes yes no 180 0 KPKLEC+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 190 0 KPKLEE+PalatinoLinotype TrueType WinAnsi yes yes no 193 0 KPKLFG+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 196 0 KPKLEC+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 207 0 KPKLEE+PalatinoLinotype TrueType WinAnsi yes yes no 210 0 KPKLFG+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 213 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2022-03-22 02:26:59 CET RepresentationInformation: pmc_34944573.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) 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Title: Phenotype Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Children: Item: Title: The Phenotype of Monocyte-Derived Dendritic Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: The Phenotype of Peripheral Blood Mononuclear Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: The Phenotype of Splenocytes from C57BL/6J Mice Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Animals Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Bone Marrow-Derived Dendritic Cells Generation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Induction of EAE and Clinical Follow-Up Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: In Vivo Treatment of EAE Mice Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Antigen-Specific T Cell Reactivity and Cytokine Secretion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Children: Item: Title: The Combination of VitD3-tolDC and IFN-Beta Treatment Enhances the Suppressive Ability of VitD3-tolDC and IFN-Beta Monotherapies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Treatment with VitD3-tolDC Reduces the Activation of T Lymphocytes from RRMS Patients Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: VitD3-tolDC+IFN-Beta Culture Induces the Differentiation of Th2 Lymphocytes Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: Antigen-Specific VitD3-tolDC Administration in Combination with IFN-Beta Treatment Improves EAE Clinical Signs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: VitD3-tolDC-MOG Treatment Reduces Antigen-Specific T Cell Reactivity Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Info: Title: Combined Therapy of Vitamin D3-Tolerogenic Dendritic Cells and Interferon- in a Preclinical Model of Multiple Sclerosis Author: Bibiana Quirant-Sánchez, María José Mansilla, Juan Navarro-Barriuso, Silvia Presas-Rodríguez, Aina Teniente-Serra, Federico Fondelli, Cristina Ramo-Tello and Eva Martínez-Cáceres Subject: 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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