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

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