Clinical response to glatiramer acetate correlates with modulation of IFN- and IL-4 expression in multiple sclerosis

¹ UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
² School of Medicine, University of Maryland, Baltimore, MD, USA

^* To whom correspondence should be addressed.

	Abstract

Objective To determine whether glatiramer acetate (GA)-induced lymphoproliferation and IFN- and IL-4 modulation correlate with the clinical response in multiple sclerosis (MS).

Background GA therapy involves the induction of anti-inflammatory cytokine shifts. However, it is not known whether this response correlates with the clinical outcome.

Methods Thirty-six relapsing-remitting (RR) MS patients were treated with GA for at least two years, and classified clinically as GA-responders (GA-R=22) or hypo/non-responders (GA-HR/NR=14). Proliferation of peripheral blood mononuclear cells (PBMC) to GA and Tetanus toxoid (TT), as well as IL-4 and IFN- ELISPOT, were performed.

Findings There was no difference in PBMC proliferation to GA or TT between GA-R and GA-HR/NR before and during treatment (P>0.05). The mean number of IFN- ELISPOTS in unstimulated, TT and anti-CD3/CD28-stimulated PBMC was lower among GA-R (unstimulated: GA-R=10.1±6.21 (n=22) versus GA-HR/NR=17.8±12.7 (n=14), P=0.04; TT-GA-R=12.2±4.06 (n=12) versus GA-HR/NR=26.8±21.0 (n=8), P=0.028; anti-CD-3/CD28 GA-R=217.3±140.4 (n=22) versus GA-HR/NR=368.5±170.1 (n=14), P=0.006). In contrast, the number of IL-4 ELISPOTS remained unchanged in the GA-R group, but was progressively reduced in the GA-HR/NR group during GA therapy (GA-HR/NR IL-4: pre-Rx: 59±34 versus 22±11 at 12 months (n=6), P=0.0429). The IL-4/IFN- ratio in anti-CD3/CD28-stimulated PBMC was significantly higher among GA-R compared to GA-HR/NR (P=0.0474).

Interpretation Lymphoproliferation to GA did not differentiate GA-R from GA-HR/NR. However, reduced IFN- expression and stable IL-4 expression in anti-CD3/CD28-stimulated PBMC, and an increased IL-4/IFN- ratio was associated with favorable clinical response. More data are needed to validate the prospective use of IL-4/IFN- expression in PBMC as a biomarker of clinical response to GA for individual patients.

Key Words: multiple sclerosis, glatiramer acetate, interferon-gamma, Interleukin-4

First published on March 15, 2007, doi:10.1177/1352458506074510

Multiple Sclerosis 2007;13:754.

A more recent version of this article appeared on July 1, 2007


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