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

UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA

K. Costello

School of Medicine, University of Maryland, Baltimore, MD, USA

M. Chen

School of Medicine, University of Maryland, Baltimore, MD, USA

A. Said

School of Medicine, University of Maryland, Baltimore, MD, USA

K.P. Johnson

School of Medicine, University of Maryland, Baltimore, MD, USA

S. Dhib-Jalbut

UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA, jalbutsu{at}umdnj.edu

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. Multiple Sclerosis 2007; 13: 754-762. http://msj.sagepub.com

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

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