Wedel Johannes, Hottenrott Maximillia C, Stamellou Eleni, Breedijk Annette, Tsagogiorgas Charalambos, Hillebrands Jan-Luuk, Yard Benito A
Departments of Medicine, Nephrology, Endocrinology, Diabetology, Rheumatology and.
Anesthesia and Critical Care, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; and.
J Leukoc Biol. 2014 Sep;96(3):453-62. doi: 10.1189/jlb.3A0813-455R. Epub 2014 Jun 13.
Recently, we developed a nonhemodynamic dopamine derivative, NOD, which has profound anti-inflammatory effects in vitro. As NOD also protects rats from ischemic AKI, the present study tested whether NOD is able to modulate cellular immunity for potential use as a T cell-suppressive agent. To this end, T cells were stimulated by anti-CD3/CD28 or PMA/ionomycin in the presence or absence of different concentrations of NOD. T cell proliferation, activation markers, intracellular cytokine expression, and activation of transcription factors were assessed. Whereas T cell proliferation was inhibited significantly by NOD at Day 3, proliferation was restored at Day 7 or later depending on the NOD concentration used. Inhibition of proliferation was reflected by a diminished CD25 expression and switch from naive to memory T cells. Early TCR activation events were unaffected, yet NF-κB and AP-1 were strongly inhibited by NOD. The inhibitory effect of NOD seemed to be dependent on its redox activity, as NOT, a redox-inactive NOD derivate, did not influence proliferation. NOD displayed synergistic effects with CNIs on T cell proliferation. Our data demonstrate that NOD displays T cell-suppressive activity. In keeping with its anti-inflammatory action and its beneficial effect on ischemia-induced AKI, NOD may be an interesting drug candidate to prevent CNI-related side-effects.
最近，我们研发了一种非血流动力学多巴胺衍生物NOD，它在体外具有显著的抗炎作用。由于NOD还能保护大鼠免受缺血性急性肾损伤，本研究测试了NOD是否能够调节细胞免疫，以作为一种T细胞抑制药物。为此，在存在或不存在不同浓度NOD的情况下，用抗CD3/CD28或佛波酯/离子霉素刺激T细胞。评估了T细胞增殖、活化标志物、细胞内细胞因子表达和转录因子的活化情况。虽然在第3天NOD显著抑制了T细胞增殖，但根据所用NOD浓度的不同，在第7天或之后增殖得以恢复。增殖的抑制表现为CD25表达减少以及从初始T细胞向记忆T细胞的转变。早期TCR激活事件未受影响，但NOD强烈抑制了NF-κB和AP-1。NOD的抑制作用似乎取决于其氧化还原活性，因为氧化还原无活性的NOD衍生物NOT对增殖没有影响。NOD与钙调神经磷酸酶抑制剂（CNIs）对T细胞增殖具有协同作用。我们的数据表明NOD具有T细胞抑制活性。鉴于其抗炎作用以及对缺血诱导的急性肾损伤的有益作用，NOD可能是一种预防CNI相关副作用的有前景的候选药物。
