Tian W Z, Navikas V, Matusevicius D, Söderström M, Fredrikson S, Hedlund G, Link H
Division of Neurology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Acta Neurol Scand. 1998 Aug;98(2):94-101. doi: 10.1111/j.1600-0404.1998.tb01726.x.
Multiple sclerosis (MS) is characterized by high levels of circulating mononuclear cells (MNC) that respond to myelin proteins like myelin basic protein (MBP) in vitro by expressing mRNA of both pro-inflammatory cytokines, e.g. interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and lymphotoxin (LT) that may make MS worse, and anti-inflammatory cytokines like IL-4, IL-10 and transforming growth factor-beta (TGF-beta) that may act beneficially. Substances that down-regulate cytokines such as TNF-alpha or promote IL-10 or TGF-beta can be anticipated to affect MS beneficially.
In situ hybridization to detect and enumerate IFN-gamma, TNF-alpha, LT, IL-4, IL-10 and TGF-beta mRNA expressing blood MNC after stimulation with myelin basic protein (MBP), control antigens and without antigen in presence and absence of Linomide (roquinimex, LS-2616) was employed. In parallel, ELISPOT assay to detect MBP- and PHA-reactive IFN-gamma secreting blood MNC+/-Linomide was used.
Here we report that Linomide, a synthetic immunomodulator, at concentrations effective in vivo reduces the number of MBP-reactive TNF-alpha and increases MBP-reactive IL-10 and TGF-beta mRNA expressing MNC from MS patients' blood when analysed in vitro. Compared to dexamethasone, Linomide up-regulated levels of blood MNC expressing mRNA of TGF-beta after culture in presence of MBP.
Changes of cytokine balance towards a production of anti-inflammatory cytokines could be a desirable effect to be evaluated in future drug studies of Linomide-like substances. At present, Linomide is not evaluable in MS clinical trials due to side-effects.
多发性硬化症（MS）的特征是循环单核细胞（MNC）水平升高，这些细胞在体外对髓鞘蛋白如髓鞘碱性蛋白（MBP）有反应，通过表达促炎细胞因子（如干扰素-γ（IFN-γ）、肿瘤坏死因子-α（TNF-α）和淋巴毒素（LT），这些可能会使MS病情加重）以及抗炎细胞因子（如IL-4、IL-10和转化生长因子-β（TGF-β），这些可能起有益作用）的mRNA。可以预期，下调细胞因子如TNF-α或促进IL-10或TGF-β的物质会对MS产生有益影响。
采用原位杂交技术，在有和没有林米地（罗喹美克，LS-2616）存在的情况下，检测并用髓鞘碱性蛋白（MBP）、对照抗原以及无抗原刺激后表达IFN-γ、TNF-α、LT、IL-4、IL-10和TGF-β mRNA的血液MNC并进行计数。同时，使用ELISPOT试验检测有或无林米地时MBP和PHA反应性分泌IFN-γ的血液MNC。
我们在此报告，一种合成免疫调节剂林米地，在体内有效的浓度下，体外分析时可减少MS患者血液中MBP反应性TNF-α的数量，并增加表达MBP反应性IL-10和TGF-β mRNA的MNC数量。与地塞米松相比，在MBP存在的情况下培养后，林米地上调了血液MNC中表达TGF-β mRNA的水平。
细胞因子平衡向抗炎细胞因子产生的变化可能是未来类似林米地物质药物研究中值得评估的理想效果。目前，由于副作用，林米地无法在MS临床试验中进行评估。
