title: Blocking stroke-induced immunodeficiency increases CNS antigen-specific autoreactivity but does not worsen functional outcome after experimental stroke.
abstract: Stroke-induced immunodepression (SIDS) is an essential cause of poststroke infections. Pharmacological inhibition of SIDS appears promising in preventing life-threatening infections in stroke patients. However, SIDS might represent an adaptive mechanism preventing autoreactive immune responses after stroke. To address this, we used myelin oligodendrocyte glycoprotein (MOG) T-cell receptor transgenic (2D2) mice where >80% of peripheral CD4(+) T cells express a functional receptor for MOG. We investigated in a murine model of middle cerebral artery occlusion the effect of blocking SIDS by inhibiting body's main stress axes, the sympathetic nervous system (SNS) with propranolol and the hypothalamic-pituitary-adrenal axis (HPA) with mifepristone. Blockade of both stress axes robustly reduced infarct volumes, decreased infection rate, and increased long-term survival of 2D2 and C57BL/6J wild-type mice. Despite these protective effects, blockade of SIDS increased CNS antigen-specific Type1 T helper cell (Th1) responses in the brains of 2D2 mice 14 d after middle cerebral artery occlusion. One month after experimental stroke, 2D2 mice developed signs of polyradiculitis, which were diminished by SIDS blockade. Adoptive transfer of CD4(+) T cells, isolated from 2D2 mice, into lymphocyte-deficient Rag-1KO mice did not reveal differences between SIDS blockade and vehicle treatment in functional long-term outcome after stroke. In conclusion, inhibiting SIDS by pharmacological blockade of body's stress axes increases autoreactive CNS antigen-specific T-cell responses in the brain but does not worsen functional long-term outcome after experimental stroke, even in a mouse model where CNS antigen-specific autoreactive T-cell responses are boosted.
authors.affiliation: Center for Stroke Research, Department for Experimental Neurology.
authors.forename: Christine
authors.initials: C
authors.lastname: Römer
authors.affiliation: Center for Stroke Research, Department for Experimental Neurology.
authors.forename: Odilo
authors.initials: O
authors.lastname: Engel
authors.affiliation: Center for Stroke Research, Department for Experimental Neurology.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Winek
authors.affiliation: Department of Neurology, Medical University of Graz, 8010 Graz, Austria, and.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hochmeister
authors.affiliation: Center for Stroke Research, Department for Experimental Neurology.
authors.forename: Tian
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Department of Neurology, University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Royl
authors.affiliation: Department of Neurology, NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 10098 Berlin, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Klehmet
authors.affiliation: Center for Stroke Research, Department for Experimental Neurology, Department of Neurology, NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 10098 Berlin, Germany, German Center for Neurodegenerative Diseases, 10117 Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.affiliation: Institute of Medical Immunology, and.
authors.forename: Christian
authors.initials: C
authors.lastname: Meisel
authors.affiliation: Center for Stroke Research, Department for Experimental Neurology, Department of Neurology, NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 10098 Berlin, Germany, andreas.meisel@charite.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meisel
mesh_terms: D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000503:physiopathology; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C571327:Mog protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D011948:Receptors, Antigen, T-Cell; C064658:RAG-1 protein
keywords: CNS autoreactivity; immunosuppression; mifepristone; murine stroke; propranolol; stroke-induced immunodeficiency syndrome