Dooley Laura M, Abdalmula Anwar, Washington Elizabeth A, Kaufman Claire, Tudor Elizabeth M, Ghosh Peter, Itescu Silviu, Kimpton Wayne G, Bailey Simon R
Faculty of Veterinary Science, The University of Melbourne, Parkville, Victoria, Australia.
Mesoblast Ltd, Melbourne, Victoria, Australia.
PLoS One. 2015 May 7;10(5):e0124144. doi: 10.1371/journal.pone.0124144. eCollection 2015.
Mesenchymal precursor cells (MPC) are reported to possess immunomodulatory properties that may prove beneficial in autoimmune and other inflammatory conditions. However, their mechanism of action is poorly understood. A collagen-induced arthritis model has been previously developed which demonstrates local joint inflammation and systemic inflammatory changes. These include not only increased levels of inflammatory markers, but also vascular endothelial cell dysfunction, characterised by reduced endothelium-dependent vasodilation. This study aimed to characterise the changes in systemic inflammatory markers and endothelial function following the intravenous administration of MPC, in the ovine model.
Arthritis was induced in sixteen adult sheep by administration of bovine type II collagen into the hock joint following initial sensitisation. After 24h, sheep were administered either 150 million allogeneic ovine MPCs intravenously, or saline only. Fibrinogen and serum amyloid-A were measured in plasma to assess systemic inflammation, along with pro-inflammatory and anti-inflammatory cytokines. Animals were necropsied two weeks following arthritis induction. Coronary and digital arterial segments were mounted in a Mulvaney-Halpern wire myograph. The relaxant response to endothelium-dependent and endothelium-independent vasodilators was used to assess endothelial dysfunction.
Arthritic sheep treated with MPC demonstrated a marked spike in plasma IL-10, 24h following MPC administration. They also showed significantly reduced plasma levels of the inflammatory markers, fibrinogen and serum amyloid A, and increased HDL. Coronary arteries from RA sheep treated with MPCs demonstrated a significantly greater maximal relaxation to bradykinin when compared to untreated RA sheep (253.6 ± 17.1% of pre-contracted tone vs. 182.3 ± 27.3% in controls), and digital arteries also demonstrated greater endothelium-dependent vasodilation. This study demonstrated that MPCs given intravenously are able to attenuate systemic inflammatory changes associated with a monoarthritis, including the development of endothelial dysfunction.
据报道，间充质前体细胞（MPC）具有免疫调节特性，这可能在自身免疫性疾病和其他炎症性疾病中发挥有益作用。然而，其作用机制尚不清楚。先前已建立了胶原诱导的关节炎模型，该模型可显示局部关节炎症和全身炎症变化。这些变化不仅包括炎症标志物水平升高，还包括血管内皮细胞功能障碍，其特征为内皮依赖性血管舒张功能降低。本研究旨在表征在绵羊模型中静脉注射MPC后全身炎症标志物和内皮功能的变化。
对16只成年绵羊进行初次致敏后，将牛II型胶原注射到跗关节中诱导关节炎。24小时后，给绵羊静脉注射1.5亿个同种异体绵羊MPC，或仅注射生理盐水。测量血浆中的纤维蛋白原和血清淀粉样蛋白A，以及促炎和抗炎细胞因子，以评估全身炎症。关节炎诱导两周后对动物进行尸检。将冠状动脉和指动脉段安装在Mulvaney-Halpern线肌动描记器中。使用对内皮依赖性和非内皮依赖性血管舒张剂的舒张反应来评估内皮功能障碍。
用MPC治疗的关节炎绵羊在注射MPC后24小时血浆IL-10显著升高。它们还显示炎症标志物纤维蛋白原和血清淀粉样蛋白A的血浆水平显著降低，高密度脂蛋白增加。与未治疗的类风湿性关节炎绵羊相比，用MPC治疗的类风湿性关节炎绵羊的冠状动脉对缓激肽的最大舒张反应显著更大（预收缩张力的253.6±17.1%，而对照组为182.3±27.3%），指动脉也表现出更大的内皮依赖性血管舒张。本研究表明，静脉注射MPC能够减轻与单关节炎相关的全身炎症变化，包括内皮功能障碍的发展。
