Gene expression analysis reveals functional pathways of glatiramer acetate activation

摘要

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.