Abstract
The immune system is homeostatically regulated to maintain a balance between triggering of inflammatory responses and protecting against self-directed autoimmunity. In autoimmune diseases, such as multiple sclerosis, this balance is disrupted. T regulatory cells, characterised by the expression of the cell surface marker CD25 and the transcription factor FoxP3, play a key role in maintaining this balance by suppression of the activity of effector T cells principally through cell-cell contact. These inhibitory effects of Treg cells appear to be impaired in multiple sclerosis. Facilitating the activity of Treg cells may thus be a promising therapeutic strategy for treatment of multiple sclerosis. Glatiramer acetate stimulates proliferation of CD4+CD25+ FoxP3+ Treg cells and their transmigration across the blood brain barrier in in vitro models. These Treg cells may cross-react with myelin within the nervous system to turn off encephalitogenic effector T cells. In multiple sclerosis, glatiramer acetate can induce a phenotypic shift in T cell populations towards CD4+CD25+ Treg cells in vitro, whereas it has been demonstrated in vivo that glatiramer acetate exposure induces a population of CD8+ suppressor T cells that regulate CD4+ T cell proliferation. In addition, glatiramer acetate down-regulates the expression of the Toll-like receptor TLR9, which may be involved in an innate immunity component of autoimmune disease, in a mouse EAE model. Upstream promotion of Treg cell differentiation by blockade of the co-stimulatory molecule CD154 may also be of benefit in preventing autoimmune disease, as illustrated by a promising exploratory Phase I study in multiple sclerosis.
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Kasper, L.H., Haque, A. & Haque, S. Regulatory mechanisms of the immune system in multiple sclerosis. T regulatory cells: turned on to turn off. J Neurol 254 (Suppl 1), I10–I14 (2007). https://doi.org/10.1007/s00415-007-1003-z
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DOI: https://doi.org/10.1007/s00415-007-1003-z