Glatiramer acetate induces a Th2-biased response and crossreactivity with myelin basic protein in patients with MS

Glatiramer acetate (GA) is an approved treatment for multiple sclerosis (MS ). The proposed mechanism of action is the induction of GA-specific T cells characterized by protective anti-inflammatory Th2 response. We tested this hypothesis in II MS patients treated with GA from 1 - 19 months. Interfero n-gamma and IL-5 (markers of Th1 and Th2 responses respectively) were assay ed by ELISA in GA-specific T-cell lines (TCL) supernatants. Th1/Th2 bias wa s defined based on the ratio of IFN-gamma /IL-5 secretion. Fifty-eight pre- treatment and 75 on-treatment GA-specific TCL were generated. On-treatment mean IL-5 levels in GA-TCL increased significantly, whereas those for IFN-g amma were markedly reduced. Consequently, the ratio of IFN gamma /IL-5 also shifted in favor of a Th2 response. The percentage of GA-TCL classified as Th I was decreased, whereas those classified as TH increased on-treatment as compared to pre-treatment. Some GA-specific TC (approximately 25%) gener ated during treatment secreted predominantly IL-5 in response to MBP and th e immunodominant MBP peptide 83-99, indicating that these crossreactive ant igens can act as partial agonists for GA-reactive TCL. These results strong ly suggest that the mechanism of action of GA in MS involves the induction of crossreactive GA-specific T cells with a predominant Th2 cytokine profil e.