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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0802046v1 183/2/841    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Luther, C. Articles by Tolosa, E. PubMed PubMed Citation Articles by Luther, C. Articles by Tolosa, E.

Prednisolone Treatment Induces Tolerogenic Dendritic Cells and a Regulatory Milieu in Myasthenia Gravis Patients¹

Claudia Luther^2,3,*, Eleni Adamopoulou^4,, Christina Stoeckle^4,*, Verena Brucklacher-Waldert⁵, Daniela Rosenkranz^*, Lars Stoltze^*, Sigrid Lauer^*, Simone Poeschel^*, Arthur Melms^* and Eva Tolosa^3,5,*

^* Department of General Neurology and Neurodegenerative Disorders, Hertie Institute for Clinical Brain Research, Tübingen University Hospital, Germany; and Medical Clinic and Policlinic II, Julius-Maximilian University of Würzburg, Germany

FOXP3-expressing naturally occurring CD4⁺CD25^high T regulatory cells (Treg) are relevant in the control of autoimmunity, and a defect in this cell population has been observed in several human autoimmune diseases. We hypothesized that altered functions of peripheral Treg cells might play a role in the immunopathogenesis of myasthenia gravis, a T cell-dependent autoimmune disease characterized by the presence of pathogenic autoantibodies specific for the nicotinic acetylcholine receptor. We report in this study a significant decrease in the in vitro suppressive function of peripheral Treg cells isolated from myasthenia patients in comparison to those from healthy donors. Interestingly, Treg cells from prednisolone-treated myasthenia gravis patients showed an improved suppressive function compared with untreated patients, suggesting that prednisolone may play a role in the control of the peripheral regulatory network. Indeed, prednisolone treatment prevents LPS-induced maturation of monocyte-derived dendritic cells by hampering the up-regulation of costimulatory molecules and by limiting secretion of IL-12 and IL-23, and enhancing IL-10. In addition, CD4⁺ T cells cultured in the presence of such tolerogenic dendritic cells are hyporesponsive and can suppress autologous CD4⁺ T cell proliferation. The results shown in this study indicate that prednisolone treatment promotes an environment that favors immune regulation rather than inflammation.

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 the German Research Council (SFB 685 and GK 794), the Fortüne Program of the University of Tübingen and the Myasthenia Gravis Foundation.

² Current address: Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, Canada.

³ Address correspondence and reprint requests to Drs. Claudia Luther and Eva Tolosa, Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, Canada. E-mail addresses: cluther{at}bccrc.ca and eva.tolosa{at}zmnh.uni-hamburg.de

⁴ E.A. and C.S. contributed equally to this study.

⁵ Current address: Institute for Neuroimmunology and Clinical Multiple Sclerosis Research, University Clinic Eppendorf, Hamburg, Germany.

⁶ Abbreviations used in this paper: Treg, regulatory T cell; iTreg, induced Treg; nTreg, naturally occurring Treg; Tr1, type 1 Treg; MG, myasthenia gravis; AchR, acetylcholine receptor; pred, prednisolone; DC, dendritic cell; DC_pred,LPS, prednisolone-treated, LPS-stimulated DC; DC_imm, immature DC; DC_mat, mature DC; HD, healthy donor; t-MG, treated MG patient; ut-MG, untreated MG patient; Aza, azathioprine; Tresp, responder T cell; MFI, median fluorescence intensity; mo-DC, monocyte-derived DC; FOXP3, forkhead box transcription factor 3.

⁷ The online version of this article contains supplemental material.