Glatiramer acetate and IFN-beta act on dendritic cells in multiple sclerosis.
Glatiramer acetate (GA; Copolymer 1; Copaxone) and interferon-beta (IFN-beta) modulate the course of multiple sclerosis (MS), but probably by different mechanisms. GA, a mixture of synthetic peptides, is believed to act as an altered peptide ligand with inhibitory effects on autoreactive T cells and promoting Th2 cells. It is unknown whether GA affects dendritic cells (DCs), which, besides strong antigen presenting capacity, orchestrate Th1 and Th2 responses. IFN-beta inhibits IL-12 production by DCs over unknown mechanisms. This study was designed to investigate in vitro effects of GA and IFN-beta on the development and function of DCs from MS patients and healthy controls, and to explore their possible synergistic effects on DCs. DCs were generated from adherent blood mononuclear cells (MNCs). GA or IFN-beta or both, when added at initiation of DC cultures, rapidly promoted the development of adherent MNCs into floating, activated DCs as reflected by up-regulation of HLA-DR and CD86 expression. IFN-beta, but not GA, induced IL-3R expression on DCs. Compared to DCs from healthy controls, MS patients' DCs expressed higher levels of the myeloid DC marker CD1a and produced lower amounts of IL-10. GA reduced IL-12 production by DCs. IFN-beta also reduced IL-12, but increased IL-10 production by DCs from both MS patients and healthy controls. GA and IFN-beta synergistically suppressed CD1a and enhanced CD86 expression on MS DCs. These findings document novel mechanisms of action of GA and IFN-beta at the DC level in MS.
Hussien
Y
Y
Neuroimmunology Unit, Division of Neurology, Karolinska Institute, Huddinge University Hospital, SE-141 86, Stockholm, Sweden.
Sanna
A
A
Söderström
M
M
Link
H
H
Huang
Y M
YM
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000328:Adult; D015703:Antigens, CD / Q000032:analysis / Q000096:biosynthesis; D018949:Antigens, CD1 / Q000032:analysis; D051940:B7-2 Antigen; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D000068717:Glatiramer Acetate; D006801:Humans; D016130:Immunophenotyping; D016899:Interferon-beta / Q000008:administration & dosage*; D016753:Interleukin-10 / Q000032:analysis / Q000096:biosynthesis; D018664:Interleukin-12 / Q000032:analysis / Q000096:biosynthesis; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000096:biosynthesis; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000188:drug therapy* / Q000276:immunology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology; D010455:Peptides / Q000008:administration & dosage*; D016185:Receptors, Interleukin-3 / Q000032:analysis; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D018949:Antigens, CD1; D051940:B7-2 Antigen; C419393:CD1a antigen; C497964:CD86 protein, human; D008562:Membrane Glycoproteins; D010455:Peptides; D016185:Receptors, Interleukin-3; D016753:Interleukin-10; D018664:Interleukin-12; D000068717:Glatiramer Acetate; D016899:Interferon-beta