Jung Stefan, Siglienti Ines, Grauer Oliver, Magnus Tim, Scarlato Guglielmo, Toyka Klaus
Klinische Forschungsgruppe für Multiple Sklerose an der Neurologischen Klinik, Julius-Maximilians-Universität Würzburg, Germany.
J Neuroimmunol. 2004 Mar;148(1-2):63-73. doi: 10.1016/j.jneuroim.2003.11.014.
Glatiramer acetate (GLAT) is a mixture of basic polypeptides that have been shown to suppress experimental autoimmune encephalomyelitis (EAE). As Copaxone, GLAT is approved for the treatment of relapsing-remitting multiple sclerosis (MS). Different immunomechanisms have been suggested to contribute to the beneficial effects of GLAT which rely on blockade of MHC class II molecules or cross-recognition with myelin basic protein (MBP). Because GLAT could also inhibit experimental autoimmunity not related to myelin proteins, we searched for additional, less-restricted immunomodulatory actions of GLAT. Using freshly isolated resident peritoneal macrophages from naive Lewis rats, it is shown that GLAT profoundly modulates cytokine secretion of the cells. In unseparated macrophages (MPhi) and MPhi of low density, GLAT enhanced constitutive and LPS-induced production of interleukin 10 (IL-10) while LPS-induced synthesis of tumor necrosis factor-alpha (TNF-alpha) was dose-dependently suppressed by GLAT. Although both basic proteins GLAT and MBP facilitated adherence of MPhi, MBP had opposite effects on cytokine production suggesting unique properties of GLAT. In contrast to MPhi, peritoneal mast cells produced only little amounts of cytokines. The inductive effect of GLAT on IL-10 production by antigen-presenting cells was also observed in bone marrow-derived rat dendritic cells (DCs) which, unlike MPhi, were not suppressed in their production of TNF-alpha. Induction of IL-10 in different antigen-presenting cells is a new immunomodulatory mechanism of GLAT. In part, it goes along with the inhibition of TNF-alpha and may be a common basis for the known beneficial effects of GLAT on various cellular autoimmune responses including MS.
醋酸格拉替雷（GLAT）是一种碱性多肽混合物，已被证明可抑制实验性自身免疫性脑脊髓炎（EAE）。作为考帕松，GLAT被批准用于治疗复发缓解型多发性硬化症（MS）。已提出不同的免疫机制有助于GLAT的有益作用，这依赖于对MHC II类分子的阻断或与髓鞘碱性蛋白（MBP）的交叉识别。由于GLAT也可抑制与髓鞘蛋白无关的实验性自身免疫，我们寻找了GLAT其他限制较少的免疫调节作用。使用从未接触过抗原的Lewis大鼠新鲜分离的驻留腹膜巨噬细胞，结果表明GLAT可深刻调节细胞的细胞因子分泌。在未分离的巨噬细胞（MPhi）和低密度MPhi中，GLAT增强了白细胞介素10（IL-10）的组成性分泌和脂多糖（LPS）诱导的分泌，而LPS诱导的肿瘤坏死因子-α（TNF-α）合成则被GLAT剂量依赖性抑制。尽管GLAT和MBP这两种碱性蛋白都促进了MPhi的黏附，但MBP对细胞因子产生的影响相反，表明GLAT具有独特的特性。与MPhi不同，腹膜肥大细胞仅产生少量细胞因子。在骨髓来源的大鼠树突状细胞（DCs）中也观察到GLAT对抗抗原呈递细胞产生IL-10的诱导作用，与MPhi不同，DCs产生TNF-α的能力未被抑制。在不同抗原呈递细胞中诱导IL-10是GLAT的一种新的免疫调节机制。部分原因是它与TNF-α的抑制作用同时出现，可能是GLAT对包括MS在内的各种细胞自身免疫反应已知有益作用的共同基础。
