Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy.
Neuroimmunomodulation. 2012;19(5):283-92. doi: 10.1159/000336981. Epub 2012 Apr 3.
We investigated dopaminergic inhibition of CD4+CD25(high) regulatory T lymphocytes (Treg) in relapsing-remitting multiple sclerosis (MS) patients treated with interferon (IFN)-β.
MS patients were prospectively studied at baseline and during 1 year of IFN-β, and compared with healthy controls (HCs). Treg were separated by immunomagnetic sorting and the effect of dopamine (DA) on Treg was assessed in coculture experiments with homologous effector T lymphocytes (Teff). Tyrosine hydroxylase (TH), dopaminergic receptors (DR) D3 and D5, and forkhead box protein P3 (FoxP3) mRNA were assessed by real-time PCR. Circulating CD4+ T cell subsets were assessed by flow cytometry.
In coculture experiments, Treg inhibition of Teff proliferation was reduced by DA in HCs and completely abolished in MS patients at baseline. However, in patients after 12 months of IFN-β, Teff proliferation was impaired and DA had no more effect on Treg. In comparison to cells from HCs, Treg from MS patients at baseline had increased mRNA for DR D5 and TH (but not for DR D3). During treatment with IFN-β, both DR D5 and TH mRNA decreased down to values lower than those of cells from HCs. In comparison to HCs, MS patients had a higher frequency of circulating Treg, both at baseline and after IFN-β, while FoxP3 mRNA levels in Treg were similar in patients and HCs and did not show major changes during IFN-β.
Dopaminergic inhibition of Treg in MS patients is suppressed during IFN-β treatment. Treg play a key role in the suppression of autoimmunity, thus the effect may have a therapeutic repercussion.
我们研究了在接受干扰素（IFN）-β治疗的复发性缓解型多发性硬化症（MS）患者中，多巴胺对 CD4+CD25（高）调节性 T 淋巴细胞（Treg）的抑制作用。
前瞻性研究了 MS 患者在 IFN-β治疗前和治疗 1 年时的情况，并与健康对照（HCs）进行了比较。通过免疫磁珠分选分离 Treg，并在同源效应 T 淋巴细胞（Teff）的共培养实验中评估多巴胺（DA）对 Treg 的影响。通过实时 PCR 评估酪氨酸羟化酶（TH）、多巴胺受体（DR）D3 和 D5、叉头框蛋白 P3（FoxP3）mRNA。通过流式细胞术评估循环 CD4+T 细胞亚群。
在共培养实验中，DA 降低了 HCs 中 Treg 对 Teff 增殖的抑制作用，而在 MS 患者的基线时完全消除了这种抑制作用。然而，在接受 IFN-β治疗 12 个月后，Teff 增殖受损，DA 对 Treg 不再有影响。与 HCs 的细胞相比，MS 患者基线时的 Treg 中 DR D5 和 TH 的 mRNA 表达增加（但 DR D3 没有增加）。在接受 IFN-β治疗期间，DR D5 和 TH mRNA 均下降至低于 HCs 细胞的水平。与 HCs 相比，MS 患者在基线时和接受 IFN-β治疗后循环 Treg 的频率均较高，而 Treg 中的 FoxP3 mRNA 水平在患者和 HCs 中相似，在 IFN-β治疗期间没有发生重大变化。
在 IFN-β治疗期间，MS 患者的 Treg 被多巴胺抑制。Treg 在抑制自身免疫中起关键作用，因此这种作用可能具有治疗意义。
