Affiliations: Multiple Sclerosis Center, Sheba Medical Center,
Tel-Hashomer, and Sackler School of Medicine, Tel-Aviv University, Israel
Note: [] Corresponding author: A. Achiron, MD, PhD, Multiple Sclerosis
Center, Sheba Medical Center, Tel-Hashomer, 52621, Israel. Tel.: +972 3
5303811; Fax: +972 3 5348186; E-mail: achiron@post.tau.ac.il
Abstract: Background: Glatiramer acetate (GA, Copaxone®) has beneficial
effects on the clinical course of relapsing-remitting multiple sclerosis
(RRMS). However, the exact molecular mechanisms of GA effects are only
partially understood. Objective: To characterized GA molecular effects in RRMS patients
within 3 months of treatment by microarray profiling of peripheral blood
mononuclear cells (PBMC). Methods: Gene-expression profiles were determined in RRMS patients
before and at 3 months after initiation of GA treatment using Affimetrix
(U133A-2) microarrays containing 14,500 well-characterized human genes. Most
informative genes (MIGs) of GA-induced biological convergent pathways operating
in RRMS were constructed using gene functional annotation, enrichment analysis
and pathway reconstruction bioinformatic softwares. Verification at the mRNA
and protein level was performed by qRT-PCR and FACS. Results: GA induced a specific gene expression molecular signature
that included altered expression of 480 genes within 3 months of treatment; 262
genes were up-regulated, and 218 genes were down-regulated. The main convergent
mechanisms of GA effects were related to antigen-activated apoptosis,
inflammation, adhesion, and MHC class-I antigen presentation. Conclusions: Our findings demonstrate that GA treatment induces
alternations of immunomodulatory gene expression patterns that are important
for suppression of disease activity already at three months of treatment and
can be used as molecular markers of GA activity.
