Anti-inflammatory pathways of catecholaminergic, tyrosine hydroxylase (TH) - positive cells in human and experimental arthritis

在患者和小鼠的炎症滑膜组织中，申请者S组在先前的工作中发现了酪氨酸羟化酶(TH)阳性细胞(TH+细胞)。申请人S小组在类风湿性关节炎(RA)和骨关节炎患者中描述了这些细胞具有强大的抗炎潜力。在研究单位最近的工作中，间充质干细胞(MSC)来源的TH+细胞在实验性II型胶原诱导的关节炎模型中具有很强的抗炎作用。然而，确切的交感信号通路(无论是肾上腺素能、多巴胺能还是嘌呤能[即腺苷])或这些交感TH+细胞的特定靶细胞尚不清楚。该项目将利用RA/OA患者和关节炎小鼠的细胞材料描绘负责原代和MSC来源的TH+细胞抗炎作用的交感通路。该项目还将揭示在人类和老鼠身上起抗炎作用的靶细胞。交感神经通路的知识将被用于治疗实验性关节炎的动物，以便充分表征TH+细胞的临床改善效果。最后，将交感神经分化技术应用于RA患者的人淋巴细胞，以产生TH+淋巴细胞。这些分化的细胞可以作为基于细胞的治疗的平台(使用MSC来源的TH+细胞或TH+淋巴细胞治疗RA)。

In inflamed synovial tissue of patients and mice, tyrosine hydroxylase (TH) - positive cells (TH+ cells) were discovered in previous work in the applicant s group. These cells have a strong anti-inflammatory potential as described by the applicant s group in patients with rheumatoid arthritis (RA) and osteoarthritis. In recent work within Research Unit, mesenchymal stem cell (MSC) - derived TH+ cells had strong anti-inflammatory effects in the model of experimental collagen type II -induced arthritis. However, the exact sympathetic signalling pathway (whether adrenergic, dopaminergic, or purinergic [i.e., adenosine]) or the specific target cell of these sympathetic TH+ cells are not known.This project will delineate the sympathetic pathway responsible for anti-inflammatory effects of primary and MSC-derived TH+ cells using cell material of patients with RA / OA and arthritic mice. This project will also reveal the target cell responsible for anti-inflammatory effects in humans and mice. Knowledge of the sympathetic pathway will be used to treat animals with experimental arthritis in order to fully characterize the clinical ameliorating effect of TH+ cells. Finally, sympathetic differentiation techniques are applied to human lymphocytes of patients with RA to generate TH+ lymphocytes. These differentiated cells can be used as a platform for a cell-based therapy (use of MSC-derived TH+ cells or TH+ lymphocytes to treat RA).