Gene expression analysis reveals functional pathways of glatiramer acetate activation

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.

Keywords::

• functional pathways
• gene expression
• glatiramer acetate
• glatiramoid
• microarray
• T cells

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.

Notes