醋酸格拉替雷的临床反应与多发性硬化症中γ干扰素和白细胞介素-4表达的调节相关。

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

作者信息

Valenzuela R M, Costello K, Chen M, Said A, Johnson K P, Dhib-Jalbut S

机构信息

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

出版信息

Mult Scler. 2007 Jul;13(6):754-62. doi: 10.1177/1352458506074510. Epub 2007 Mar 15.

DOI:10.1177/1352458506074510

PMID:17613604

Abstract

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.

摘要

目的

确定醋酸格拉替雷（GA）诱导的淋巴细胞增殖以及IFN-γ和IL-4调节是否与多发性硬化症（MS）的临床反应相关。

背景

GA治疗涉及诱导抗炎细胞因子转变。然而，尚不清楚这种反应是否与临床结果相关。

方法

36例复发缓解型（RR）MS患者接受GA治疗至少两年，并根据临床情况分为GA反应者（GA-R = 22例）或低反应/无反应者（GA-HR/NR = 14例）。对外周血单个核细胞（PBMC）对GA和破伤风类毒素（TT）的增殖以及IL-4和IFN-γ酶联免疫斑点法进行检测。

结果

在治疗前和治疗期间，GA-R组和GA-HR/NR组PBMC对GA或TT的增殖无差异（P>0.05）。在未刺激、TT刺激和抗CD3/CD28刺激的PBMC中，GA-R组IFN-γ酶联免疫斑点的平均数量较低（未刺激：GA-R = 10.1±6.21（n = 22），GA-HR/NR = 17.8±12.7（n = 14），P = 0.04；TT-GA-R = 12.2±4.06（n = 12），GA-HR/NR = 26.8±21.0（n = 8），P = 0.028；抗CD-3/CD28 GA-R = 217.3±140.4（n = 22），GA-HR/NR = 368.5±170.1（n = 14），P = 0.006）。相比之下，GA-R组中IL-4酶联免疫斑点的数量保持不变，但在GA治疗期间GA-HR/NR组中逐渐减少（GA-HR/NR IL-4：治疗前：59±34，12个月时为22±11（n = 6），P = 0.0429）。与GA-HR/NR组相比，GA-R组中抗CD3/CD28刺激的PBMC中IL-4/IFN-γ比值显著更高（P = 0.0474）。