Brain Advance Access originally published online on April 16, 2004
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Brain, Vol. 127, No. 6, 1370-1378, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh163
Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in vitro and in vivo
1 Institute for Clinical Neuroimmunology, Klinikum Großhadern, Ludwig Maximilians University, Munich, 2 Marianne-Strauss-Klinik, Berg, 3 Institute of Medical Statistics and Epidemiology, Technical University, Munich and 4 Department of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried, Germany
Correspondence to: Dr R. Hohlfeld, Institute for Clinical Neuroimmunology, Marchioninistrasse 15, D-81377 Munich, Germany. E-mail: hohlfeld{at}neuro.mpg.de
It is widely assumed that glatiramer acetate (GA), an approved agent for the immunomodulatory treatment of multiple sclerosis, acts primarily as an antigen for T lymphocytes. Recent studies, however, indicated that in vitro, GA directly inhibits dendritic cells, a rare but potent type of professional antigen-presenting cell (APC). To investigate whether these in vitro observations are relevant to the actions of GA in vivo, we studied the effects of GA on monocytes, the major type of circulating APC. In a first series of experiments, we investigated the effects of GA on monocyte reactivity in vitro. Monocytes were stimulated with ligands for Toll-like receptor (TLR)-2 (peptidoglycan and lipoteichoic acid), TLR-4 [lipopolysaccharide (LPS)] and TLR-5 (flagellin), as well as two proinflammatory cytokines (interferon-
and granulocyte–monocyte colony-stimulating factor). Monocyte activation was measured by induction of the surface markers signalling lymphocytic activation molecule (SLAM), CD25 and CD69 (detected by cytofluorometry), and by production of monocyte-derived tumour necrosis factor (TNF)-
(detected by enzyme-linked immunospot assay). GA had a broad inhibitory effect on all measures of monocyte reactivity, regardless of which stimulator was used. It is unlikely that this reflects a simple toxic effect, because monocyte viability and CD14 expression were unaffected. In a second series of experiments, we investigated the properties of monocytes cultured ex vivo from eight GA-treated multiple sclerosis patients, eight untreated multiple sclerosis patients and eight healthy subjects. We found that LPS-induced SLAM expression and TNF- production were significantly reduced in monocytes from GA-treated patients compared with controls. These results demonstrate for the first time that GA inhibits monocyte reactivity in vitro and in vivo, significantly extending the current concept of the mechanism of action of GA.
Key Words: multiple sclerosis; glatiramer acetate; immunotherapy; monocyte; ex vivo assay
Abbreviations: APC= antigen-presenting cell; DC = dendritic cell; EDSS = Expanded Disability Status Scale; Elispot = enzyme-linked immunospot; FACS = fluorescence activated cell sorting; GM-CSF = granulocyte–monocyte colony-stimulating factor; GA = glatiramer acetate; IFN = interferon; IL = interleukin; LPS = lipopolysaccharide; LTA = lipoteichoic acid; PBMC = peripheral blood mononuclear cell; PGN = peptidoglycan; SLAM = signalling lymphocytic activation molecule; TLR = Toll-like receptor; TNF = tumour necrosis factor
Received December 3, 2003. Revised February 4, 2004. Accepted February 5, 2004.
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