Glatiramer acetate induces a Th2-biased response and crossreactivity with myelin basic protein in patients with MS.
Glatiromer 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 11 MS patients treated with GA from 1-19 months. Interferon-gamma and IL-5 (markers of Th1 and Th2 responses respectively) were assayed by ELISA in GA-specific T-cell lines (TCL) supernatants. Th1/Th2 bias was 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-gamma 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 Th1 was decreased, whereas those classified as Th2 increased on-treatment as compared to pre-treatment. Some GA-specific TCL, (approximately 25%) generated during treatment secreted predominantly IL-5 in response to MBP and the immunodominant MBP peptide 83-99, indicating that these crossreactive antigens can act as partial agonists for GA-reactive TCL. These results strongly suggest that the mechanism of action of GA in MS involves the induction of crossreactive GA-specific T cells with a predominant Th2 cytokine profile.
Chen
M
M
University of Maryland School of Medicine, Baltimore 21201, USA.
Gran
B
B
Costello
K
K
Johnson
K
K
Martin
R
R
Dhib-Jalbut
S
S
D002460:Cell Line; D003429:Cross Reactions; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D000068717:Glatiramer Acetate; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015848:Interleukin-5 / Q000096:biosynthesis; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology*; D004676:Myelin Basic Protein / Q000276:immunology*; D010455:Peptides / Q000494:pharmacology*; D012044:Regression Analysis; D013601:T-Lymphocytes / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*
D016207:Cytokines; D007166:Immunosuppressive Agents; D015848:Interleukin-5; D004676:Myelin Basic Protein; D010455:Peptides; D000068717:Glatiramer Acetate