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Abstract
Background: Glatiramer acetate (GA, Copaxone®), a mixture of polymers comprising four amino acids, is approved for treatment of relapsing-remitting multiple sclerosis and clinically isolated syndrome. GA mediates its activity by induction of GA-specific T cells that shift the T cell balance from a dominant proinflammatory phenotype (Th1/Th17) to an anti-inflammatory phenotype (Th2/Treg).
Objective: To characterize the functional pathways by which GA acts on immune cells, the authors conducted gene expression profiling using glatiramoid-stimulated splenocytes.
Methods: Mice were immunized with GA and harvested splenocytes were reactivated ex vivo with GA or a purported generic GA. Gene expression profiles and functional pathways were evaluated in reactivated splenocytes.
Results: Overall, 1,474 genes were significantly upregulated or downregulated by GA. The main functional pathways induced by GA were: increased proliferation and activation of immune cells including T and B lymphocytes, stimulation of antigen presenting cells and differentiation of effector T lymphocytes. T-helper cell differentiation was the most significant canonical pathway associated with gene transcripts altered by GA. These expression patterns were not observed when splenocytes were activated with generic GA.
Conclusion: GA-induced functional pathways coincide with known mechanisms of GA activity in MS patients and further support the unique therapeutic effect of this drug.
Acknowledgments
All authors contributed extensively to the paper; R Schwartz designed the study; I Perevozkin performed the animal experiments; S Bakshi and I Perevozkin generated the data; S Bakshi, R Schwartz, V Chalifa-Caspi, I Plaschkes and M Gurevich analyzed the data; V Chalifa-Caspi and I Plaschkes performed statistical analyses; M Gurevich performed functional gene expression analyses and S Bakshi, R Schwartz, M Gurevich and V Chalifa-Caspi drafted and edited the manuscript. S Truten of Medical Communication Co., Inc., Wynnewood, PA, USA assisted with manuscript development.