Inserm, Unité 844, Montpellier, France.
PLoS One. 2010 Dec 7;5(12):e14247. doi: 10.1371/journal.pone.0014247.
Based on their capacity to suppress immune responses, multipotent mesenchymal stromal cells (MSC) are intensively studied for various clinical applications. Although it has been shown in vitro that the immunomodulatory effect of MSCs mainly occurs through the secretion of soluble mediators, the mechanism is still not completely understood. The aim of the present study was to better understand the mechanisms underlying the suppressive effect of MSCs in vivo, using cells isolated from mice deficient in the production of inducible nitric oxide synthase (iNOS) or interleukin (IL)-6 in the murine model of collagen-induced arthritis.
In the present study, we show that primary murine MSCs from various strains of mice or isolated from mice deficient for iNOS or IL-6 exhibit different immunosuppressive potential. The immunomodulatory function of MSCs was mainly attributed to IL-6-dependent secretion of prostaglandin E2 (PGE2) with a minor role for NO. To address the role of these molecules in vivo, we used the collagen-induced arthritis as an experimental model of immune-mediated disorder. MSCs effectively inhibited collagen-induced inflammation during a narrow therapeutic window. In contrast to wild type MSCs, IL-6-deficient MSCs and to a lesser extent iNOS-deficient MSCs were not able to reduce the clinical signs of arthritis. Finally, we show that, independently of NO or IL-6 secretion or Treg cell induction, MSCs modulate the host response by inducing a switch to a Th2 immune response.
Our data indicate that mscs mediate their immunosuppressive effect via two modes of action: locally, they reduce inflammation through the secretion of anti-proliferative mediators, such as NO and mainly PGE2, and systemically they switch the host response from a Th1/Th17 towards a Th2 immune profile.
基于其抑制免疫反应的能力，多能间充质基质细胞（MSC）被广泛研究用于各种临床应用。尽管已经在体外表明 MSC 的免疫调节作用主要通过可溶性介质的分泌来实现，但机制仍不完全清楚。本研究的目的是使用胶原诱导关节炎小鼠模型中产生诱导型一氧化氮合酶（iNOS）或白细胞介素（IL）-6 的细胞，更好地理解 MSC 体内抑制作用的机制。
在本研究中，我们表明，来自不同品系小鼠的原代鼠 MSC 或来自 iNOS 或 IL-6 缺陷小鼠的 MSC 具有不同的免疫抑制潜力。MSC 的免疫调节功能主要归因于 IL-6 依赖性前列腺素 E2（PGE2）的分泌，而 NO 的作用较小。为了研究这些分子在体内的作用，我们使用胶原诱导关节炎作为免疫介导的疾病的实验模型。MSC 在狭窄的治疗窗口内有效抑制胶原诱导的炎症。与野生型 MSC 相比，IL-6 缺陷型 MSC 且在较小程度上 iNOS 缺陷型 MSC 不能减轻关节炎的临床症状。最后，我们表明，MSC 通过诱导 Th2 免疫反应的转换，独立于 NO 或 IL-6 分泌或 Treg 细胞诱导，调节宿主反应。
我们的数据表明，MSC 通过两种作用模式发挥其免疫抑制作用：局部地，它们通过分泌抗增殖介质（如 NO 和主要的 PGE2）来减少炎症；系统性地，它们将宿主反应从 Th1/Th17 转向 Th2 免疫特征。
