Teitelbaum D, Brenner T, Abramsky O, Aharoni R, Sela M, Arnon R
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Mult Scler. 2003 Dec;9(6):592-9. doi: 10.1191/1352458503ms963oa.
Glatiramer acetate (GA) previously known as Copolymer 1 (Cop 1), a synthetic amino acid copolymer, suppresses experimental autoimmune encephalomyelitis (EAE) and shows a beneficial effect in relapsing-remitting type of multiple sclerosis (MS). GA acts as a specific immunomodulator by binding to MHC Class II molecules, inducing specific T suppressor (Ts) cells and interfering with T cell responses to myelin antigens. MS patients treated with GA developed GA reactive antibodies, which peaked at three months and decreased at six months. In order to find out whether anti-GA antibodies may neutralize the therapeutic effect of GA, we tested both polyclonal (mouse and human) and monoclonal GA specific antibodies for their ability to interfere with the biological activity of GA in several assay systems. None of the antibodies interfered with GA activities either in vitro (binding to MHC molecules and T cell stimulation) or in vivo (blocking of EAE). Furthermore, 53 samples of sera obtained from 34 MS patients that participated in the open label trial in Israel, and all developed GA specific antibodies, were tested for their ability to inhibit the proliferation response of GA specific Ts cell clone and to interfere with GA competitive inhibition of the response to peptide 84-102 of myelin basic protein (MBP). None of the sera inhibited and some even enhanced the in vitro activities of GA. Furthermore, representative MS sera with high titer of GA reactive antibodies did not neutralize the biological activities of GA and did not inhibit Th2 cytokine secretion by human GA specific clone. These results are consistent with the findings that the therapeutic effect of GA is not affected by GA reactive antibodies and is sustained upon long term treatment.
醋酸格拉替雷（GA），以前称为共聚体1（Cop 1），是一种合成氨基酸共聚物，可抑制实验性自身免疫性脑脊髓炎（EAE），并在复发缓解型多发性硬化症（MS）中显示出有益效果。GA通过与II类主要组织相容性复合体（MHC）分子结合、诱导特异性抑制性T细胞（Ts）并干扰T细胞对髓鞘抗原的反应，从而作为一种特异性免疫调节剂发挥作用。接受GA治疗的MS患者会产生GA反应性抗体，这些抗体在三个月时达到峰值，六个月时下降。为了确定抗GA抗体是否会中和GA的治疗效果，我们在多个检测系统中测试了多克隆（小鼠和人）及单克隆GA特异性抗体干扰GA生物活性的能力。无论是在体外（与MHC分子结合及T细胞刺激）还是在体内（阻断EAE），这些抗体均未干扰GA的活性。此外，对从参与以色列开放标签试验的34例MS患者获得的53份血清样本进行了检测，所有患者均产生了GA特异性抗体，检测这些血清抑制GA特异性Ts细胞克隆增殖反应以及干扰GA对髓鞘碱性蛋白（MBP）84 - 102肽反应的竞争性抑制的能力。没有一份血清具有抑制作用，有些血清甚至增强了GA的体外活性。此外，具有高滴度GA反应性抗体的代表性MS血清并未中和GA的生物活性，也未抑制人GA特异性克隆分泌Th2细胞因子。这些结果与以下发现一致，即GA的治疗效果不受GA反应性抗体的影响，并且在长期治疗后仍能持续。
