Glatiramer acetate treatment effects on gene expression in monocytes of multiple sclerosis patients

Abstract

BackgroundGlatiramer acetate (GA) is a mixture of synthetic peptides used in the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). The aim of this study was to investigate the effects of GA therapy on the gene expression of monocytes.MethodsMonocytes were isolated from the peripheral blood of eight RRMS patients. The blood was obtained longitudinally before the start of GA therapy as well as after one day, one week, one month and two months. Gene expression was measured at the mRNA level by microarrays.ResultsMore than 400 genes were identified as up-regulated or down-regulated in the course of therapy, and we analyzed their biological functions and regulatory interactions. Many of those genes are known to regulate lymphocyte activation and proliferation, but only a subset of genes was repeatedly differentially expressed at different time points during treatment.ConclusionsOverall, the observed gene regulatory effects of GA on monocytes were modest and not stable over time. However, our study revealed several genes that are worthy of investigation in future studies on the molecular mechanisms of GA therapy.

Analytical workflow profiling gene expression in murine macrophages

“…60 Direct association in the literature between macrophages and the underexpressed gene Ptprcap was less clear, although it has been found in the monocyte precursors to macrophages. 61 However, Ptprcap is known as a CD45-associate, regulating the interaction of CD45 with other proteins. As CD45 regulates apoptosis, this may explain the relationship to immune-challenge.…”

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

“…Glatiramer Acetate (GA; copolymer 1), a mixture of synthetic peptides mimicking myelin basic protein, used as a first-line treatment option for RR-MS, inhibits a tryptophanyl-tRNA synthetase known to modulate angiogenic signalling [206,207]. The selective adhesion molecule inhibitor Natalizumab, which binds integrin-α4 on endothelial cells and blocks the VCAM-1 driven transmigration of immune cells sensitized against myelin antigen from the vessel lumen to the neuropil across the BBB, precludes VEGF-induced angiogenesis [208,209].…”

“…In a stroke model, exogenous VEGF administration increases neurogenesis of the SVZ, only after 28 days, without concomitant angiogenesis, demonstrating that a specific VEGF isoform could protect neurons independently of the endothelial cell influence [231]. In the EAE model, despite several reports of an improved clinical score after early VEGF inhibition, one study [232] demonstrated that pertussis toxin stimulated VEGF expression and that VEGF neuroprotection could Fingolimod Gilenya [210][211][212] Glatiramer acetate Copaxone [206,207] Interferon β-1a Avonex, Rebif [84,204,205] Interferon β-1b Betaferon, Extavia Mitoxantrone Novantrone [216] Natalizumab Tysabri [208,209] Teriflunomide Aubagio Only indirect evidence derived from antilymphocytes activity be responsible for milder disease. VEGF may have different effects in different cell types depending on different splice variants [233].…”

Unnatural amino acids improve affinity and modulate immunogenicity: Developing peptides to treat MHC type II autoimmune disorders

“…APLs do not need to displace all of the antigens in order to function: they need only occupy sufficient MHC receptors that their anti‐inflammatory response balances the pro‐inflammatory response elicited from the antigen . However, no traditional APL has reached the clinic although there are a number of candidates, such as glatiramer triacetate, that may have some APL activity in addition to other mechanisms of action. HLABs on the other hand rely on near complete displacement of the natural antigen.…”