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      Animal models of multiple sclerosis—Potentials and limitations

      a , a , b , * , a

      Progress in Neurobiology

      Elsevier Ltd.

      APC, antigen-presenting cell, AT-EAE, adoptive transfer EAE, BBB, blood–brain barrier, BDNF, brain-derived neurotrophic factor, CD, cluster of differentiation, CNS, central nervous system, CNTF, ciliary neurotrophic factor, EAE, experimental autoimmune encephalomyelitis, HLA, human leukocyte antigen, Ig, immunoglobulin, IL, interleukin, IFN, interferon, IVIg, intravenous immunoglobulin, mAb, monoclonal antibody, MBP, myelin basic protein, MHC, major histocompatibility complex, MOG, myelin oligodendrocyte glycoprotein, MP, methylprednisolone, MRI, magnetic resonance imaging, MS, multiple sclerosis, NK, natural killer, ODC, oligodendrocyte, QTL, quantitative trait locus, PLP, proteolipid protein, Tc, cytotoxic T cell, TCR, T cell receptor, TGF, transforming growth factor, Th cell, helper T cell, TNF, tumor necrosis factor, Animal model, Autoimmunity, Experimental autoimmune encephalomyelitis, Immunogenetics, Immunomodulatory therapy, Multiple sclerosis

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          Research highlights

          ▶ The classical MOG 35-55-EAE is complemented by novel cortical and toxic MS models. ▶ Putative autoantigens of EAE/MS include myelin and axonal glycoproteins and lipids. ▶ MS risk genes involve DRB1*1501 and more than 10 novel candidate genes. ▶ Treg and Th17 cells deserve close attention in EAE/MS pathogenesis. ▶ Oral disease-modifiers and monoclonal antibodies show great promise for MS therapy.

          Abstract

          Experimental autoimmune encephalomyelitis (EAE) is still the most widely accepted animal model of multiple sclerosis (MS). Different types of EAE have been developed in order to investigate pathogenetic, clinical and therapeutic aspects of the heterogenic human disease. Generally, investigations in EAE are more suitable for the analysis of immunogenetic elements (major histocompatibility complex restriction and candidate risk genes) and for the study of histopathological features (inflammation, demyelination and degeneration) of the disease than for screening of new treatments. Recent studies in new EAE models, especially in transgenic ones, have in connection with new analytical techniques such as microarray assays provided a deeper insight into the pathogenic cellular and molecular mechanisms of EAE and potentially of MS. For example, it was possible to better delineate the role of soluble pro-inflammatory (tumor necrosis factor-α, interferon-γ and interleukins 1, 12 and 23), anti-inflammatory (transforming growth factor-β and interleukins 4, 10, 27 and 35) and neurotrophic factors (ciliary neurotrophic factor and brain-derived neurotrophic factor). Also, the regulatory and effector functions of distinct immune cell subpopulations such as CD4 + Th1, Th2, Th3 and Th17 cells, CD4 +FoxP3 + Treg cells, CD8 + Tc1 and Tc2, B cells and γδ + T cells have been disclosed in more detail. The new insights may help to identify novel targets for the treatment of MS. However, translation of the experimental results into the clinical practice requires prudence and great caution.

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          Most cited references 303

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          IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells.

          On activation, naive T cells differentiate into effector T-cell subsets with specific cytokine phenotypes and specialized effector functions. Recently a subset of T cells, distinct from T helper (T(H))1 and T(H)2 cells, producing interleukin (IL)-17 (T(H)17) was defined and seems to have a crucial role in mediating autoimmunity and inducing tissue inflammation. We and others have shown that transforming growth factor (TGF)-beta and IL-6 together induce the differentiation of T(H)17 cells, in which IL-6 has a pivotal function in dictating whether T cells differentiate into Foxp3+ regulatory T cells (T(reg) cells) or T(H)17 cells. Whereas TGF-beta induces Foxp3 and generates T(reg) cells, IL-6 inhibits the generation of T(reg) cells and induces the production of IL-17, suggesting a reciprocal developmental pathway for T(H)17 and T(reg) cells. Here we show that IL-6-deficient (Il6-/-) mice do not develop a T(H)17 response and their peripheral repertoire is dominated by Foxp3+ T(reg) cells. However, deletion of T(reg) cells leads to the reappearance of T(H)17 cells in Il6-/- mice, suggesting an additional pathway by which T(H)17 cells might be generated in vivo. We show that an IL-2 cytokine family member, IL-21, cooperates with TGF-beta to induce T(H)17 cells in naive Il6-/- T cells and that IL-21-receptor-deficient T cells are defective in generating a T(H)17 response.
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            Risk alleles for multiple sclerosis identified by a genomewide study.

            Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis. We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis. A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1x10(-4)); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001). An additional 40 SNPs with less stringent P values (<0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor alpha gene (IL2RA) were strongly associated with multiple sclerosis (P=2.96x10(-8)), as were a nonsynonymous SNP in the interleukin-7 receptor alpha gene (IL7RA) (P=2.94x10(-7)) and multiple SNPs in the HLA-DRA locus (P=8.94x10(-81)). Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis. Copyright 2007 Massachusetts Medical Society.
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              Autoimmune T cell responses in the central nervous system.

              Autoreactive T cell responses have a crucial role in central nervous system (CNS) diseases such as multiple sclerosis. Recent data indicate that CNS autoimmunity can be mediated by two distinct lineages of CD4+ T cells that are defined by the production of either interferon-gamma or interleukin-17. The activity of these CD4+ T cell subsets within the CNS influences the pathology and clinical course of disease. New animal models show that myelin-specific CD8+ T cells can also mediate CNS autoimmunity. This Review focuses on recent progress in delineating the pathogenic mechanisms, regulation and interplay between these different T cell subsets in CNS autoimmunity.
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                Author and article information

                Contributors
                Journal
                Prog Neurobiol
                Prog. Neurobiol
                Progress in Neurobiology
                Elsevier Ltd.
                0301-0082
                1873-5118
                15 June 2010
                November 2010
                15 June 2010
                : 92
                : 3
                : 386-404
                Affiliations
                [a ]Department of Neurology, University of Rostock, Germany
                [b ]Department of Neurology, Heinrich-Heine-University, Moorenstr. 5, 40225 Duesseldorf, Germany
                Author notes
                [* ]Corresponding author. Tel.: +49 211 8117880; fax: +49 211 8118469. Hans-Peter.Hartung@ 123456uni-duesseldorf.de
                Article
                S0301-0082(10)00117-6
                10.1016/j.pneurobio.2010.06.005
                7117060
                20558237
                Copyright © 2010 Elsevier Ltd. All rights reserved.

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