Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ

摘要

The ability of a remedy to modulate the pathological process in the target organ is crucial for its therapeutic activity. Glatiramer acetate (GA, Copaxone, Copolymer 1), a drug approved for the treatment of multiple sclerosis, induces regulatory T helper 2/3 cells that penetrate the CNS. Here we investigated whether these GA-specif ic T cells can function as suppressor cells with therapeutic potential in the target organ by in situ expression of T helper 2/3 cytokines and neurotrophic factors. GA-specific cells and their in situ expression were detected on the level of whole-brain tissue by using a two-stage double-labeling system: (ⅰ) labeling of the GA-specific T cells, followed by their adoptive transfer, and (ⅱ) detection of the secreted factors in the brain by immunohistolog-ical methods. GA-specific T cells in the CNS demonstrated intense expression of the brain-derived neurotrophic factor and of two antiinflammatory cytokines, IL-10 and transforming growth factor β. No expression of the inflammatory cytokine IFN-γ was observed. This pattern of expression was manifested in brains of normal and experimental autoimmune encephalomyelitis-induced mice to which GA-specific cells were adoptively transferred, but not in control mice. Furthermore, infiltration of GA-induced cells to the brain resulted in bystander expression of IL-10 and transforming growth factor β by resident astrocytes and microglia. The ability of infiltrating GA-specific cells to express antiinflammatory cytokines and neurotrophic factor in the organ in which the pathological processes occur correlates directly with the therapeutic activity of GA in experimental autoimmune encephalomyelitis multiple sclerosis.