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The journal of immunology : official journal of the American Association of Immunologists v.197 no.7, 2016년, pp.2598 - 2609   SCI SCIE
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ERβ-Dependent Direct Suppression of Human and Murine Th17 Cells and Treatment of Established Central Nervous System Autoimmunity by a Neurosteroid

Aggelakopoulou, Maria (Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 115 27, Greece ); Kourepini, Evangelia (Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 115 27, Greece ); Paschalidis, Nikolaos (Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 115 27, Greece ); Simoes, Davina C. M. (Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 115 27, Greece ); Kalavrizioti, Dimitra (Division of Hematology, Department of Internal Medicine, University of Patras Medical School, Rion 265 00, Greece ); Dimisianos, Nikolaos (and ); Papathanasopoulos, Panagiotis (Department of Neurology, Patras University Hospital, Patras 265 00, Greece ); Mouzaki, Athanasia (Department of Neurology, Patras University Hospital, Patras 265 00, Greece ); Panoutsakopoulou, Vily (Division of Hematology, Department of Internal Medicine, University of Patras Medical School, Rion 265 00, Greece );
  • 초록  

    Multiple sclerosis (MS), an autoimmune disease of the CNS, is mediated by autoreactive Th cells. A previous study showed that the neurosteroid dehydroepiandrosterone (DHEA), when administered preclinically, could suppress progression of relapsing-remitting experimental autoimmune encephalomyelitis (EAE). However, the effects of DHEA on human or murine pathogenic immune cells, such as Th17, were unknown. In addition, effects of this neurosteroid on symptomatic disease, as well as the receptors involved, had not been investigated. In this study, we show that DHEA suppressed peripheral responses from patients with MS and reversed established paralysis and CNS inflammation in four different EAE models, including the 2D2 TCR-transgenic mouse model. DHEA directly inhibited human and murine Th17 cells, inducing IL-10–producing regulatory T cells. Administration of DHEA in symptomatic mice induced regulatory CD4 + T cells that were suppressive in an IL-10–dependent manner. Expression of the estrogen receptor β by CD4 + T cells was necessary for DHEA-mediated EAE amelioration, as well as for direct downregulation of Th17 responses. TGF-β1 as well as aryl hydrocarbon receptor activation was necessary for the expansion of IL-10–producing T cells by DHEA. Thus, our studies demonstrate that compounds that inhibit pathogenic Th17 responses and expand functional regulatory cells could serve as therapeutic agents for autoimmune diseases, such as MS.


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