Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor α in collagen-induced arthritis
Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor α in collagen-induced arthritis
复制标题
DOI：
10.1002/art.21012
复制
发表时间：
2005-05-01
影响因子：
--
通讯作者：
Noël, D
中科院分区：
文献类型：
--
作者：
Djouad, F;Fritz, V;Noël, D
Objective.成体间充质干细胞（MSC）代表了治疗应用，如组织工程和细胞治疗的有前途的工具。最近的数据表明，由于它们的免疫抑制性质，MSC可能对增强同种异体造血移植和预防移植物抗宿主病感兴趣。使用类风湿性关节炎（RA）的小鼠模型，本研究调查了MSC的免疫抑制特性是否可以具有治疗价值，以抑制反应性T细胞在自身免疫性疾病，如RA。在胶原诱导性关节炎（CIA）小鼠中，我们在免疫或加强注射时注射不同剂量的C3 MSC，随后评估临床和免疫学参数。在体外混合淋巴细胞反应中，加入或不加入肿瘤坏死因子α（TNF α），测定MSCs的免疫抑制特性。在CIA关节炎模型中，MSC没有带来任何益处。临床和免疫学研究结果均表明，MSC与Th 1应答的加重有关。使用表达β-淀粉酶的MSC，我们无法在膝关节的关节环境中检测到标记细胞，这表明症状的恶化不太可能是由于MSC在关节中的归巢。体外实验表明，TNF α的加入足以逆转MSCs对T细胞增殖的免疫抑制作用，这一观察结果与IL-6分泌的增加有关。我们的数据表明，环境参数，特别是那些与炎症，可能会影响骨髓间充质干细胞的免疫抑制特性。
Objective. Adult mesenchymal stem cells (MSCs) represent promising tools for therapeutic applications such as tissue engineering and cellular therapy. Recent data suggest that, due to their immunosuppressive nature, MSCs may be of interest to enhance allogeneic hematopoietic engraftment and prevent graft-versus-host disease. Using a murine model of rheumatoid arthritis (RA), this study investigated whether the immunosuppressive properties of MSCs could be of therapeutic value to inhibit reactive T cells in autoimmune diseases such as RA.Methods. In mice with collagen-induced arthritis (CIA), we injected various doses of C3 MSCs at the time of immunization or booster injection, and subsequently evaluated the clinical and immunologic parameters. The immunosuppressive properties of MSCs were determined in vitro in mixed lymphocyte reactions with or without the addition of tumor necrosis factor a (TNF alpha).Results. In the CIA model of arthritis, MSCs did not confer any benefit. Both the clinical and the immunologic findings suggested that MSCs were associated with accentuation of the Th1 response. Using luciferase-expressing MSCs, we were unable to detect labeled cells in the articular environment of the knee, suggesting that worsening of the symptoms was unlikely due to the homing of MSCs in the joints. Experiments in vitro showed that the addition of TNF alpha was sufficient to reverse the immunosuppressive effect of MSCs on T cell proliferation, and this observation was associated with an increase in interleukin-6 secretion.Conclusion. Our data suggest that environmental parameters, in particular those related to inflammation, may influence the immunosuppressive properties of MSCs.