Chemokine-mediated redirection of T cells constitutes a critical mechanism of glucocorticoid therapy in autoimmune CNS responses.
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.
Institute for Cellular and Molecular Immunology, University of Göttingen Medical School, Humboldtallee 34, 37073, Göttingen, Germany.
Nils
N
Schweingruber
Henrike J
HJ
Fischer
Lisa
L
Fischer
Jens
J
van den Brandt
Anna
A
Karabinskaya
Verena
V
Labi
Andreas
A
Villunger
Benedikt
B
Kretzschmar
Peter
P
Huppke
Mikael
M
Simons
Jan P
JP
Tuckermann
Alexander
A
Flügel
Fred
F
Lühder
Holger M
HM
Reichardt
D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D018925:Chemokines / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology
D018925:Chemokines; D005938:Glucocorticoids; D018696:Neuroprotective Agents