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Acta Neuropathologica

, Volume 127, Issue 5, pp 713–729 | Cite as

Chemokine-mediated redirection of T cells constitutes a critical mechanism of glucocorticoid therapy in autoimmune CNS responses

  • Nils Schweingruber
  • Henrike J. Fischer
  • Lisa Fischer
  • Jens van den Brandt
  • Anna Karabinskaya
  • Verena Labi
  • Andreas Villunger
  • Benedikt Kretzschmar
  • Peter Huppke
  • Mikael Simons
  • Jan P. Tuckermann
  • Alexander Flügel
  • Fred Lühder
  • Holger M. Reichardt
Original Paper

Abstract

Glucocorticoids (GCs) are the standard therapy for treating multiple sclerosis (MS) patients suffering from an acute relapse. One of the main mechanisms of GC action is held to be the induction of T cell apoptosis leading to reduced lymphocyte infiltration into the CNS, yet our analysis of experimental autoimmune encephalomyelitis (EAE) in three different strains of genetically manipulated mice has revealed that the induction of T cell apoptosis is not essential for the therapeutic efficacy of GCs. Instead, we identified the redirection of T cell migration in response to chemokines as a new therapeutic principle of GC action. GCs inhibited the migration of T cells towards CCL19 while they enhanced their responsiveness towards CXCL12. Importantly, blocking CXCR4 signaling in vivo by applying Plerixafor® strongly impaired the capacity of GCs to interfere with EAE, as revealed by an aggravated disease course, more pronounced CNS infiltration and a more dispersed distribution of the infiltrating T cells throughout the parenchyma. Our observation that T cells lacking the GC receptor were refractory to CXCL12 further underscores the importance of this pathway for the treatment of EAE by GCs. Importantly, methylprednisolone pulse therapy strongly increased the capacity of peripheral blood T cells from MS patients of different subtypes to migrate towards CXCL12. This indicates that modulation of T cell migration is an important mechanistic principle responsible for the efficacy of high-dose GC therapy not only of EAE but also of MS.

Keywords

Multiple sclerosis EAE MS patients Glucocorticoids Apoptosis CXCR4 

Notes

Acknowledgments

We would like to thank Martina Weig, Birgit Curdt, Regine Kruse, Nancy Meyer, Amina Bassibas and Julian Koch for technical assistance, Cathy Ludwig for language corrections, Jerry Adams for vav-Bcl-2 tg mice and Meike Schaffrinski and Florian Klemm for help with buffy coats. This work was supported by grants from the Deutsche Forschungsgemeinschaft (Lu634/8-1, Tu220/3-1, FOR 1336, SFB-TRR 43/B11 & B13), the Bundesministerium für Bildung und Forschung (UNDERSTAND MS) and the Austrian Science Fund (FWF), grant Y212-B13.

Conflict of interest

The authors declare that they have no conflict of interests.

Supplementary material

401_2014_1248_MOESM1_ESM.pdf (350 kb)
Supplementary material 1 (PDF 350 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Nils Schweingruber
    • 1
    • 2
  • Henrike J. Fischer
    • 1
  • Lisa Fischer
    • 2
  • Jens van den Brandt
    • 1
    • 7
  • Anna Karabinskaya
    • 1
  • Verena Labi
    • 3
    • 8
  • Andreas Villunger
    • 3
  • Benedikt Kretzschmar
    • 4
  • Peter Huppke
    • 5
  • Mikael Simons
    • 4
  • Jan P. Tuckermann
    • 6
  • Alexander Flügel
    • 2
  • Fred Lühder
    • 2
  • Holger M. Reichardt
    • 1
  1. 1.Institute for Cellular and Molecular ImmunologyUniversity of Göttingen Medical SchoolGöttingenGermany
  2. 2.Department of Neuroimmunology, Institute for Multiple Sclerosis Research, The Hertie Foundation and MPI for Experimental MedicineUniversity of Göttingen Medical SchoolGöttingenGermany
  3. 3.Division of Developmental Immunology, BiocenterMedical University of InnsbruckInnsbruckAustria
  4. 4.Department of NeurologyUniversity of Göttingen Medical SchoolGöttingenGermany
  5. 5.Department of Pediatrics and Pediatric NeurologyUniversity of Göttingen Medical SchoolGöttingenGermany
  6. 6.Institute for General Zoology and EndocrinologyUniversity of UlmUlmGermany
  7. 7.University of Greifswald Medical SchoolGreifswaldGermany
  8. 8.Max-Delbrück-Center for Molecular MedicineBerlinGermany

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