Dynamic T-lymphocyte chemokine receptor expression induced by interferon-beta therapy in multiple sclerosis.
Treatment with interferon (IFN)-beta reduces clinical disease activity in multiple sclerosis (MS). Using flow cytometry, an enzyme-linked immunosorbent assay and a real-time polymerase chain reaction, we studied in vivo IFN-beta-induced effects on CD4(+) T-lymphocyte chemokine receptor expression as these influence central nervous system (CNS) transmigration and inflammation. At 'steady state' (>/=1 day after the most recent IFN-beta injection), IFN-beta treatment increased CD4(+) T-cell surface expression of CC chemokine receptor (CCR)4, CCR5 and CCR7 after 3 months of treatment, whereas that of CXC chemokine receptor (CXCR)3 was unaltered. Conversely, at 9-12 h after the most recent IFN-beta injection, CCR4, CCR5 and CCR7 expressions were unaltered, while CXCR3 expression was reduced. CD4(+) T-cell surface expression of CCR4 was significantly lower in untreated MS patients compared with healthy volunteers. Of the plasma chemokines, only CXCL10 was increased by IFN-beta treatment; CCL3, CCL4, CCL5 and CXCL9 were unaltered. CCR5 mRNA expression in blood mononuclear cells correlated with the expression of T-helper type 1 (Th1)-associated genes whereas CCR4 and CCR7 mRNA expression correlated with Th2 and immunoregulatory genes. In conclusion, IFN-beta treatment caused 'steady-state' increases of several chemokine receptors relevant for CD4(+) T-lymphocyte trafficking and function, possibly facilitating lymphocyte migration into the CNS. An important therapeutic effect of IFN-beta treatment may be the normalization of a decreased Th2-related CD4(+) T-cell CCR4 expression in MS patients. Surface chemokine receptor expression and CXCL10 varied according to the timing of blood sampling in relation to the most recent IFN-beta injection. Thus, it is imperative to distinguish acute effects of IFN-beta from steady-state effects.
Krakauer
M
M
Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital, Copenhagen, Denmark. martin.krakauer@dadlnet.dk
Sorensen
P S
PS
Khademi
M
M
Olsson
T
T
Sellebjerg
F
F
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018925:Chemokines / Q000097:blood / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016899:Interferon-beta / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology* / Q000628:therapy*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018925:Chemokines; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D016899:Interferon-beta