Expression and functional activity of chemokine receptors in glatiramer acetate-specific T cells isolated from multiple sclerosis patient receiving the drug glatiramer acetate.
The purpose of the current study is to examine the surface expression of chemokine receptors and the chemotaxis toward the respective chemokines of glatiramer acetate (GA)-specific CD4(+) T cells isolated from the blood and the cerebrospinal fluid (CSF) of a multiple sclerosis (MS) patient. Four clones were selected, two isolated from the peripheral blood and two from the CSF. CCR4 and CXCR3 were expressed on all four clones. Both blood-derived clones also expressed CCR5 and, to a lesser extent, CCR6. Similarly, one CSF clone expressed CCR5 and CCR6. In contrast, CCR1, CCR2, CCR3, CCR7, CCR9, CCR10, CXCR1, CXCR4, CXCR5, CXCR6, and CCR6 were either expressed on few cells or were not expressed at all on all four clones examined. The expression of chemokine receptors was corroborated with the ability of the cells to respond chemotactically to the corresponding chemokines, CCL5/RANTES, CCL20/MIP-3α, CCL22/MDC and CXCL10/IP-10. Both the receptor expression and chemotaxis were reduced upon activation with PMA and ionomycin. The shared expression of chemokine receptors and the migration patterns suggest that GA-reactive cells have migrated from the blood into the CSF, and that local reactivation within the inflamed CSF may downregulate the expression of chemokine receptors and hence impede their migration intrathecally. The results may also explain the beneficial synergistic effects of combining immunosuppressive drugs with GA in MS patients.
Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
Rune Alexander
RA
Høglund
Anne Lise
AL
Hestvik
Trygve
T
Holmøy
Azzam A
AA
Maghazachi
D000328:Adult; D001769:Blood / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002555:Cerebrospinal Fluid / Q000276:immunology; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology*; D000068717:Glatiramer Acetate; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D010455:Peptides / Q000008:administration & dosage*; D054398:Receptors, CCR4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054399:Receptors, CCR6 / Q000276:immunology* / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C515354:CCR4 protein, human; C106311:CCR6 protein, human; D018925:Chemokines; D010455:Peptides; D054398:Receptors, CCR4; D019713:Receptors, CCR5; D054399:Receptors, CCR6; D054367:Receptors, CXCR3; D015759:Ionomycin; D000068717:Glatiramer Acetate; D013755:Tetradecanoylphorbol Acetate