PLoS One. 2013 Apr 22;8(4):e62237. doi: 10.1371/journal.pone.0062237. Print 2013.
BACKGROUND:Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease. It is thought to be mediated by CD4(+) Th1/Th17 cells. More recently, cells of the innate immune system such as dendritic cells (DCs) and natural killer (NK) cells have been in focus. Glatiramer acetate (GA) is an approved drug for treating MS patients.
METHODOLOGY PRINCIPAL FINDINGS: In the current study we examined the activities of NK and DCs in nine relapsing remitting MS patients for up to one year after initiation of GA treatment. We observed that NK cells isolated from most of these patients have increased cytotoxic activity against K562 cells. Further analysis showed that the same NK cells lysed both autologous immature (i) and mature (m) DCs. In most patients this increased activity was correlated with increased NK cell activating cytotoxicity receptors such as NKp30, NKp44, NKp46 and NKG2D, and reduced expression of the inhibitory molecule CD158 on the surface of these NK cells. The expression of HLA-DR was increased on iDCs and mDCs in the majority of the patients, but no consistency was observed for the expression of HLA-I or HLA-E. Also, the co-stimulatory receptors CD80, CD83 or CD86 expression was down-regulated on iDCs and mDCs in most cases. Further, the expression of CCR6 was increased on mDCs at later time points of therapy (between 32-48 weeks).
CONCLUSIONS SIGNIFICANCE: Our results are the first showing the effects of GA treatment on NK cells in MS patients, which may impact future use of this and other drugs to treat this disease.
Sellner J, Koczi W, Harrer A, Oppermann K,
Obregon-Castrillo E, Pilz G, Wipfler P, Afazel S, Haschke-Becher E,
Trinka E, Kraus J.
Clin Exp Immunol. 2013 Apr. doi: 10.1111/cei.12125. [Epub ahead of print]
An altered expression pattern of adhesion molecules (AM) on the surface of immune cells is a premise for their extravasation into the central nervous system (CNS) and the formation of acute brain lesions in multiple sclerosis (MS). We evaluated the impact of glatiramer acetate (GA) on cell-bound and soluble AM in the peripheral blood of patients with relapsing-remitting MS (RRMS). Fifteen patients treated de-novo with GA were studied on four occasions over a period of 12 months. Surface levels of ICAM-1, ICAM-3, LFA-1 and VLA-4 were assessed in T cells (CD3+CD8+, CD3+CD4+), B cells, natural killer (NK) cells, natural killer T cells (NKT) and monocytes by 5-colour flow cytometry. Soluble E-selectin, ICAM-1, ICAM-3, PECAM-1, P-selectin and VCAM-1 were determined with a fluorescent bead-based immunoassay. The pro-migratory pattern in RRMS was verified by comparison with healthy controls and was characterized by an up-regulation of LFA-1 (CD3+CD4+ T cells, B cells), VLA-4 (CD3+CD8+ T cells, NK cells), ICAM-1 (B cells) and ICAM-3 (NK cells). Effects of GA treatment were most pronounced after 6 months and included attenuated levels of LFA-1 (CD3+CD4+) and VLA-4 (CD3+CD4+, CD3+CD8+, NK, NKT, monocytes). Further effects included a lowering of ICAM-1 and ICAM-3 levels in almost all immune cell subsets. Soluble AM levels in RRMS did not differ from healthy controls and remained unaltered after GA treatment. The de-regulated pro-migratory expression profile of cell-bound AM is altered by GA treatment. While this alteration may contribute to the beneficial action of the drug, the prolonged development and unselective changes indicate more secondary immune regulatory phenomena related to these effects.