Cytokine production in T lymphocyte–microglia interaction is attenuated by glatiramer acetate: a mechanism for therapeutic efficacy in multiple sclerosis

Abstract

The efficacy of glatiramer acetate in multiple sclerosis (MS) is thought to involve the production of Th2 regulatory lymphocytes that secrete anti-inflammatory cytokines; however, other mechanisms cannot be excluded Given that activated T lymphocytes infiltrate into the CNS and become in dose proximity to microglia, we evaluated whether glatiramer acetate affects the potential interaction between T cells and microglia. We report that the co-culture of activated T lymphocytes with microglia led to the induction of several cytokines, and that these were reduced by glatiramer acetate treatment Morphological transformation of bipolar/ramified microglia into an activated ameboid form was attenuated by glatiramer acetate. These results reveal a novel mechanism for glatiramer acetate: the impairment of activated T cells to effectively interact with microglia to produce cytokines. The net result of a non-inflammatory milieu within the CNS, in spite of T cell infiltration, may help account for the amelioration of disease activity in MS patients on glatiramer acetate therapy.

Type 2 Monocyte and Microglia Differentiation Mediated by Glatiramer Acetate Therapy in Patients with Multiple Sclerosis

“…Although our results confirm recent reports that GA can directly modulate human APC responses in vitro (41,42) and extend this observation to ex vivo human monocytes, it is not known whether APCs actually encounter such concentrations of GA in vivo (43). Higher levels of GA may be present at sites of injection or in Represented as the average mean fluorescent intensity Ϯ SD; n ϭ 3-5 independent experiments.…”

Glatiramer acetate increases IL-1 receptor antagonist but decreases T cell-induced IL-1β in human monocytes and multiple sclerosis

“…It is thus likely that this mechanism is highly relevant to the pathogenesis and persistence of chronic/sterile inflammation in diseases such as MS. The effect of GA on cytokine production induced by contact with stimulated T cells in human microglial cells was previously demonstrated (16). Stimulated T cells that were pretreated with GA induced lower levels of TNF, IL-1␤, and IL-6 in human microglial cells and phorbol 12-myristate 13-acetate (PMA)/IFN␥-treated U937 monocytic cells.…”

“…Besides triggering proinflammatory cytokine production, contact-mediated activation of monocytes induces the production and/or shedding of cytokine inhibitors such as sIL-1Ra and soluble receptors of IL-1 and TNF (15). The importance of T cell contact-mediated activation of monocytic cells in MS was further demonstrated in vitro in cocultures of T cells and microglial cells (16,17).…”

Cytokines in Multiple Sclerosis – Possible Targets for Immune Therapies

“…Increased secretion of IL-10 and reduced production of IL-12 from monocytes was reported under GA treatment [19]. In humans, GA impairs interactions between activated T-cells and microglia thus suppressing induction of several pro-inflammatory cytokines [20]. CNS infiltration of GAspecific T-cells results in increased expression of IL-4, TGFbeta and IL-10.…”