Inhibition of Autoimmune Disease by the Immunomodulator Linomide Correlates with the Ability to Activate Macrophages
Inhibition of Autoimmune Disease by the Immunomodulator Linomide Correlates with the Ability to Activate Macrophages
复制标题
DOI：
10.3109/08916930008994093
复制
发表时间：
2000-01
期刊：
影响因子：
3.5
通讯作者：
E. Dahlén;Mikael Andersson;K. Dawe;A. C. Tellander;C. Brunmark;A. Björk;G. Hedlund
中科院分区：
文献类型：
--
作者：
E. Dahlén;Mikael Andersson;K. Dawe;A. C. Tellander;C. Brunmark;A. Björk;G. Hedlund
Linomide是一种有效的免疫调节剂，已被证明可以抑制几种自身免疫性疾病动物模型中的自身免疫，包括实验性自身免疫性脑脊髓炎（EAE）。Linomide的作用机制尚不清楚，但是，已经提出调节抗原呈递细胞（APC）的功能，这可能是抑制自身免疫性疾病的原因。在本研究中，我们已经能够表明，Linomide治疗SJL/N小鼠上调了巨噬细胞和B细胞上几种活化标志物的细胞表面表达。因此，我们发现以下标记物（表示为对照的%）在Linomide处理后显著上调：巨噬细胞上的MHC II类（260%）、Ly-6 A/E（520%）、CD 11 a（280%）、CD 54（190%）和CD 80（200%）和B细胞上的Ly-6 A/E（250%）和CD 11 a（150%）。获得这些效果所需的Linomide的持续时间和剂量与EAE抑制所需的相似。通过将结构修饰引入Linomide分子中制备了几种Linomide类似物，从而产生了许多对EAE具有不同作用的化合物。我们发现化合物抑制EAE的能力与其上调巨噬细胞上MHC II类的能力之间存在线性关系（p<0.001），因此能够抑制EAE的化合物也上调MHC II类表达，而不抑制EAE的化合物则不能。这些结果表明，药物介导的不同APC功能的激活可能在自身免疫中具有保护作用。
Linomide is a potent immunomodulator that has been shown to inhibit autoimmunity in several animal models of autoimmune disease, including experimental autoimmune encephalomyelitis (EAE). Linomide's mechanism of action is unknown, however, it has been suggested to modulate the function of antigen presenting cells (APC) and that this may account for the inhibition of autoimmune disease. In this study we have been able to show that Linomide treatment of SJL/N mice upregu-lates the cell surface expression of several activation markers on macrophages and B cells. Thus, we found the following markers, expressed as a % of control, to be significantly upreg-ulated following Linomide treatment; MHC class II (260%), Ly-6A/E (520%), CDlla (280%), CD54 (190%) and CD80 (200%) on macrophages and Ly-6A/E (250%) and CDlla (150%) on B cells. The duration and dosage of Linomide required to obtain these effects is similar to those required for EAE inhibition. Several Linomide analogues were made by the introduction of structural modifications into the Linomide molecule, resulting in a number of compounds with varying effects on EAE. We found a linear relationship between the compound's ability to inhibit EAE and its ability to upregulate MHC class II on macrophages (p<0.001), such that compounds which were able to inhibit EAE also upregulated MHC class II expression, whereas those that did not inhibit EAE were unable to do so. These results suggest that drug-mediated activation of distinct APC functions may be protective in autoimmunity