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      Leukemia inhibitory factor tips the immune balance towards regulatory T cells in multiple sclerosis.

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          Abstract

          Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), for which current treatments are unable to prevent disease progression. Based on its neuroprotective and neuroregenerating properties, leukemia inhibitory factor (LIF), a member of the interleukin-6 (IL-6) cytokine family, is proposed as a novel candidate for MS therapy. However, its effect on the autoimmune response remains unclear. In this study, we determined how LIF modulates T cell responses that play a crucial role in the pathogenesis of MS. We demonstrate that expression of the LIF receptor was strongly increased on immune cells of MS patients. LIF treatment potently boosted the number of regulatory T cells (Tregs) in CD4(+) T cells isolated from healthy controls and MS patients with low serum levels of IL-6. Moreover, IL-6 signaling was reduced in the donors that responded to LIF treatment in vitro. Our data together with previous findings revealing that IL-6 inhibits Treg development, suggest an opposing function of LIF and IL-6. In a preclinical animal model of MS we shifted the LIF/IL-6 balance in favor of LIF by CNS-targeted overexpression. This increased the number of Tregs in the CNS during active autoimmune responses and reduced disease symptoms. In conclusion, our data show that LIF downregulates the autoimmune response by enhancing Treg numbers, providing further impetus for the use of LIF as a novel treatment for MS and other autoimmune diseases.

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          Author and article information

          Journal
          Brain Behav. Immun.
          Brain, behavior, and immunity
          1090-2139
          0889-1591
          Mar 2015
          : 45
          Affiliations
          [1 ] Department of Immunology, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590 Diepenbeek, Belgium.
          [2 ] Laboratory for Neurobiology and Gene Therapy, Katholieke Universiteit Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium.
          [3 ] de Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 75, 1200 Brussels, Belgium.
          [4 ] Department of Immunology, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590 Diepenbeek, Belgium; Department of Molecular Cell Biology and Immunology, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
          [5 ] Department of Immunology, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590 Diepenbeek, Belgium; Revalidatie & MS-Centrum, Boemerangstraat 2, 3900 Overpelt, Belgium.
          [6 ] Department of Immunology, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590 Diepenbeek, Belgium. Electronic address: niels.hellings@uhasselt.be.
          Article
          S0889-1591(14)00552-2
          10.1016/j.bbi.2014.11.010
          25514345
          9e39bd2e-5911-4ce1-91f1-9cbe95ca6a3b
          Copyright © 2014 Elsevier Inc. All rights reserved.

          Leukemia inhibitory factor,Multiple sclerosis,Regulatory T cells,Therapeutics

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