Regenerative Medicine Institute, National Centre for Biomedical Engineering Science and College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland;
National Centre for Biomedical Engineering Science and College of Science, National University of Ireland, Galway, Galway, Ireland; and.
Am J Physiol Renal Physiol. 2014 Dec 15;307(12):F1412-26. doi: 10.1152/ajprenal.00024.2014. Epub 2014 Oct 22.
Mesenchymal stem cells (MSCs) suppress T helper (Th)17 cell differentiation and are being clinically pursued for conditions associated with aberrant Th17 responses. Whether such immunomodulatory effects are enhanced by coadministration of MSCs with other agents is not well known. In the present study, individual and combined effects of MSCs and the vitamin D receptor (VDR) agonist paricalcitol on Th17 induction were investigated in vitro and in a mouse model of sterile kidney inflammation (unilateral ureteral obstruction). In vitro, MSCs and paricalcitol additively suppressed Th17 differentiation, although only MSCs suppressed expression of Th17-associated transcriptions factors. Combined administration of MSCs and paricalcitol resulted in an early (day 3) reduction of intrarenal CD4(+) and CD8(+) T cells, CD11b(+)/lymphocyte antigen 6G(+) neutrophils, and inflammatory (lymphocyte antigen 6C(hi)) monocytes as well as reduced transcript for IL-17 compared with untreated animals. Later (day 8), obstructed kidneys of MSC/paricalcitol double-treated mice, but not mice treated with either intervention alone, had reduced tubular injury and interstitial fibrosis as well as lower numbers of neutrophils and inflammatory monocytes and an increase in the ratio between M2 (CD206(+)) and M1 (CD206(-)) macrophages compared with control mice. Adjunctive therapy with VDR agonists may enhance the immunosuppressive properties of MSCs in the setting of pathogenic Th17-type immune responses and related inflammatory responses.
间充质干细胞 (MSCs) 抑制辅助性 T 细胞 17（Th17）细胞分化，目前正在临床研究用于治疗与 Th17 反应异常相关的疾病。但与其他药物联合应用时，MSCs 是否会增强这种免疫调节作用尚不清楚。本研究在体外和无菌性肾炎症（单侧输尿管梗阻）小鼠模型中，研究了 MSCs 和维生素 D 受体 (VDR) 激动剂帕立骨化醇单独及联合应用对 Th17 诱导的影响。体外实验结果表明，MSCs 和帕立骨化醇可协同抑制 Th17 分化，尽管只有 MSCs 能抑制 Th17 相关转录因子的表达。MSCs 和帕立骨化醇联合给药可导致早期（第 3 天）减少肾内 CD4(+) 和 CD8(+) T 细胞、CD11b(+)/淋巴细胞抗原 6G(+) 中性粒细胞和炎症（淋巴细胞抗原 6C(hi)）单核细胞，以及与未治疗动物相比，IL-17 的转录减少。晚期（第 8 天），MSC/帕立骨化醇双重治疗的小鼠梗阻肾脏，而不是单独接受任何一种干预的小鼠，其肾小管损伤和间质纤维化减少，中性粒细胞和炎症性单核细胞数量减少，M2（CD206(+)) 和 M1（CD206(-)) 巨噬细胞的比例增加，与对照组相比。在致病 Th17 型免疫反应和相关炎症反应中，VDR 激动剂的辅助治疗可能增强 MSCs 的免疫抑制特性。
