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

OBJECTIVE: To determine whether glatiramer acetate (GA)-induced lymphoproliferation and IFN-gamma 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-gamma 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-gamma 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-gamma 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-gamma expression and stable IL-4 expression in anti-CD3/CD28-stimulated PBMC, and an increased IL-4/IFN-gamma ratio was associated with favorable clinical response. More data are needed to validate the prospective use of IL-4/IFN-gamma expression in PBMC as a biomarker of clinical response to GA for individual patients.