| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Institute for Multiple Sclerosis Research, University of Göttingen and Gemeinnützige Hertie-Stiftung, Göttingen;
Department of Cellular and Molecular Immunology, University of Göttingen, Medical School, Göttingen;
Tissue Specific Hormone Action group, Leibniz Institute for Age Research–Fritz Lipmann Institute, Jena; and
Department of Neurology, St. Josef-Hospital, University of Bochum, Bochum, Germany
High-dose glucocorticoid (GC) therapy is widely used to treat multiple sclerosis (MS), but the underlying mechanisms remain debatable. In this study, we investigated the impact of GC administration on experimental autoimmune encephalomyelitis using different GC receptor (GR)-deficient mutants. Heterozygous GR knockout mice were less sensitive to dexamethasone therapy, indicating that the expression level of the receptor determines therapeutic efficacy. Mice reconstituted with homozygous GR knockout fetal liver cells showed an earlier onset of the disease and were largely refractory to GC treatment, indicating that the GR in hematopoietic cells is essential for the beneficial effects of endogenous GCs and dexamethasone. Using cell-type specific GR-deficient mice, we could demonstrate that GCs mainly act on T cells, while modulation of macrophage function was largely dispensable in this context. The therapeutic effects were achieved through induction of apoptosis and down-regulation of cell adhesion molecules in peripheral TH17 and bystander T cells, while similar effects were not observed within the spinal cord. In addition, dexamethasone inhibited T cell migration into the CNS, confirming that peripheral but not CNS-residing T lymphocytes are the essential targets of GCs. Collectively, our findings reveal a highly selective mechanism of GC action in experimental autoimmune encephalomyelitis and presumably multiple sclerosis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from Gemeinnützige Hertie-Stiftung (1.01.1/06/010) and Deutsche Forschungsgemeinschaft (Re1631/1-3, Tu-220/3).
2 F.L. and H.M.R. contributed equally to this work and are listed in alphabetical order.
3 Address correspondence and reprint requests to Dr. Fred Lühder, Institute for Multiple Sclerosis Research, University of Göttingen and Gemeinnützige Hertie-Stiftung, Waldweg 33, 37073 Göttingen, Germany. E-mail address: fred.luehder{at}med.uni-goettingen.de or Dr. Holger Reichardt, Department of Cellular and Molecular Immunology, University of Göttingen, Medical School, Humboldtallee 34, 37073 Göttingen, Germany. E-mail address: hreichardt{at}med.uni-goettingen.de
4 Abbreviations used in this paper: GC, glucocorticoid; MS, multiple sclerosis; BBB, blood-brain barrier; GR, GC receptor; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; Dex, dexamethasone; CHS, contact hypersensitivity; GITR, glucocorticoid-induced tumor necrosis factor receptor family related gene; Treg, regulatory T cell; n.s., nonsignificant.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
