Long-term therapy with glatiramer acetate in multiple sclerosis: effect on T-cells

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Abstract
Glatiramer acetate (GA) is an immunotherapeutic drug for multiple sclerosis (MS). Several mechanisms of action have been demonstrated which target and affect T-cells that are specific for myelin antigen epitopes. We measured the in vitro proliferation of GA-responsive T-cells from untreated MS patients and from normal healthy subjects; in addition, we determined the effect of prolonged GA therapy or interferon-b therapy on the in vitro proliferation of GA-responsive T-cells of MS patients. We found that GA induces the proliferation of T-cells isolated from individuals who have not been previously exposed to GA, and that long-term in vivo therapy of MS patients with GA abrogates the GA-induced proliferative response of T-cells. In GA-treated patients, there is no evidence of generalized immunosuppression; both tetanus toxoid and anti-CD3 induced proliferative responses remain unaffected. We propose that prolonged in vivo exposure to GA may result in the eventual induction of anergy or deletion of a population of GA-responsive cells that may also be T-cells that are pathogenic in MS. This mechanism of action, in addition to other mechanisms that have been demonstrated, suggests that GA has pleiotropic effects on the immune system in MS.