Do Th2 cells mediate the effects of glatiramer acetate in experimental autoimmune encephalomyelitis?

Mechanisms underlying the clinical benefits of glatiramer acetate (GA) for patients with multiple sclerosis (MS) remain elusive. A prevailing hypothesis is that GA can induce Th2-polarized T cells, which cross-recognize myelin-specific epitopes and can inhibit myelin-reactive autoaggression in Th1 T cells, a process referred to as 'bystander suppression.' To test whether the efficacy of GA is indeed mediated by Th2 T cells, we have utilized an animal model for MS: experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. GA therapy conferred moderate protection from EAE. GA-reactive T cells from these mice were not Th2 polarized, and the Th1 cytokine reduction of myelin-reactive T cells in GA-treated mice was comparable to that in untreated control mice. Significantly, the protective effects of GA against EAE were also observed in IL-4-, IL-10-deficient and IL-4/IL-10 double-deficient mice. Similar to wild-type mice, GA therapy in IL-4- and IL-10-deficient mice was associated with diminished myelin-reactive T cell expansion and reduced production of myelin antigen-induced IFN-gamma and tumor necrosis factor-alpha. Thus, despite the absence of two prominent Th2 cytokines, IL-4 and IL-10, either alone or combined, GA was still beneficial in suppressing EAE. Our results caution against the notion that Th2 cells and bystander suppression account for the effect of GA on EAE and suggest that an alternative mechanism may operate in GA-treated MS patients.