88f5a6bfeaf5fbc2c43cddf392c7cf2c pmc_11204061.pdf 9ab33fbbfb125153aef3c3aecae4268a60ad5d32 pmc_11204061.pdf a221b87e482cc8ee99b73e7f757b17ac2101ea54ba9166573ebf5ede337a6a37 pmc_11204061.pdf Title: IL-6 Inhibition as a Therapeutic Target in Aged Experimental Autoimmune Encephalomyelitis Subject: Multiple sclerosis (MS) onset at an advanced age is associated with a higher risk of developing progressive forms and a greater accumulation of disability for which there are currently no effective disease-modifying treatments. Immunosenescence is associated with the production of the senescence-associated secretory phenotype (SASP), with IL-6 being one of the most prominent cytokines. IL-6 is a determinant for the development of autoimmunity and neuroinflammation and is involved in the pathogenesis of MS. Herein, we aimed to preclinically test the therapeutic inhibition of IL-6 signaling in experimental autoimmune encephalomyelitis (EAE) as a potential age-specific treatment for elderly MS patients. Young and aged mice were immunized with myelin oligodendrocyte protein (MOG)35–55 and examined daily for neurological signs. Mice were randomized and treated with anti-IL-6 antibody. Inflammatory infiltration was evaluated in the spinal cord and the peripheral immune response was studied. The blockade of IL-6 signaling did not improve the clinical course of EAE in an aging context. However, IL-6 inhibition was associated with an increase in the peripheral immunosuppressive response as follows: a higher frequency of CD4 T cells producing IL-10, and increased frequency of inhibitory immune check points PD-1 and Tim-3 on CD4+ T cells and Lag-3 and Tim-3 on CD8+ T cells. Our results open the window to further studies aimed to adjust the anti-IL-6 treatment conditions to tailor an effective age-specific therapy for elderly MS patients. Keywords: experimental autoimmune encephalomyelitis; IL-6; immunosenescence; ageing; innate immunity; multiple sclerosis Author: María Dema, Herena Eixarch, Mireia Castillo, Xavier Montalban and Carmen Espejo Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Wed Jun 19 10:20:53 2024 CEST ModDate: Wed Jun 19 10:24:27 2024 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 13 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1683587 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- WLENKM+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 OLIIGN+VnURWPalladioL Type 1 Custom yes yes yes 16 0 PEKHSO+URWPalladioL-Bold Type 1 Custom yes yes yes 21 0 ZZCWBU+URWPalladioL-Roma Type 1 Custom yes yes yes 27 0 XWYMWJ+URWPalladioL-Ital Type 1 Custom yes yes yes 32 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 48 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 51 0 WBVKDJ+URWPalladioL-BoldItal Type 1 Custom yes yes yes 68 0 QMDDXF+CMSY10 Type 1 Builtin yes yes yes 73 0 GECPAC+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 158 0 GECPAE+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 161 0 GECPAF+PalatinoLinotype CID TrueType Identity-H yes yes yes 164 0 GECPAG+PalatinoLinotype TrueType WinAnsi yes yes no 170 0 GECPBG+PalatinoLinotype TrueType MacRoman yes yes no 173 0 GECPAC+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 273 0 GECPAE+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 276 0 GECPAF+PalatinoLinotype CID TrueType Identity-H yes yes yes 279 0 GECPAG+PalatinoLinotype TrueType WinAnsi yes yes no 285 0 GECPBG+PalatinoLinotype TrueType MacRoman yes yes no 288 0 GEDIMN+CordiaNew TrueType WinAnsi yes yes no 291 0 JVKMOP+EURM10 Type 1 Builtin yes yes yes 308 0 GEDKAH+PalatinoLinotype,BoldItalic TrueType WinAnsi yes yes no 319 0 GECPAC+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 322 0 GECPAE+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 325 0 GECPAF+PalatinoLinotype CID TrueType Identity-H yes yes yes 328 0 GECPAG+PalatinoLinotype TrueType WinAnsi yes yes no 334 0 GECPBG+PalatinoLinotype TrueType MacRoman yes yes no 337 0 GEDIMN+CordiaNew TrueType WinAnsi yes yes no 340 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-09-01 08:12:39 CEST RepresentationInformation: pmc_11204061.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-07-18 02:30:11 CEST Size: 1683587 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 488 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Blocking of IL-6 Signaling Did Not Ameliorate EAE Clinical Outcome in Aged Mice Destination: subsection.2.1 Item: Title: EAE Clinical Parameters at 28 Days Postimmunization in Young and Aged Mice Destination: subsection.2.2 Item: Title: IL-6 Inhibition Enhances Peripheral Immunosuppressive Response in EAE Aged Mice Destination: subsection.2.3 Item: Title: Th Responses and Expression of Immune Checkpoint Inhibitors in Te Cells at 28 dpi in Young and Aged Mice Treated with Anti-IL-6 Antibody or IgG Isotype Destination: subsection.2.4 Item: Title: CD8+ T, NKT and NK Cell Cytotoxic Capacity at 28 dpi in Young and Aged Mice Treated with IgG Isotype or Anti-IL-6 Antibody Destination: subsection.2.5 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Mice Destination: subsection.4.1 Item: Title: EAE Induction and Clinical Follow-Up Destination: subsection.4.2 Item: Title: Experimental Treatment Destination: subsection.4.3 Item: Title: Motor Function Assessment Destination: subsection.4.4 Item: Title: Histopathological Analysis Destination: subsection.4.5 Item: Title: Peripheral Immune Response Analysis Destination: subsection.4.6 Item: Title: Statistical Analysis Destination: subsection.4.7 Item: Title: References Destination: section.5 Info: Title: IL-6 Inhibition as a Therapeutic Target in Aged Experimental Autoimmune Encephalomyelitis Author: María Dema, Herena Eixarch, Mireia Castillo, Xavier Montalban and Carmen Espejo Subject: Multiple sclerosis (MS) onset at an advanced age is associated with a higher risk of developing progressive forms and a greater accumulation of disability for which there are currently no effective disease-modifying treatments. Immunosenescence is associated with the production of the senescence-associated secretory phenotype (SASP), with IL-6 being one of the most prominent cytokines. IL-6 is a determinant for the development of autoimmunity and neuroinflammation and is involved in the pathogenesis of MS. Herein, we aimed to preclinically test the therapeutic inhibition of IL-6 signaling in experimental autoimmune encephalomyelitis (EAE) as a potential age-specific treatment for elderly MS patients. Young and aged mice were immunized with myelin oligodendrocyte protein (MOG)35 55 and examined daily for neurological signs. Mice were randomized and treated with anti-IL-6 antibody. Inflammatory infiltration was evaluated in the spinal cord and the peripheral immune response was studied. The blockade of IL-6 signaling did not improve the clinical course of EAE in an aging context. However, IL-6 inhibition was associated with an increase in the peripheral immunosuppressive response as follows: a higher frequency of CD4 T cells producing IL-10, and increased frequency of inhibitory immune check points PD-1 and Tim-3 on CD4+ T cells and Lag-3 and Tim-3 on CD8+ T cells. Our results open the window to further studies aimed to adjust the anti-IL-6 treatment conditions to tailor an effective age-specific therapy for elderly MS patients. 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