Bone marrow stromal cells use TGF-β to suppress allergic responses in a mouse model of ragweed-induced asthma
Bone marrow stromal cells use TGF-β to suppress allergic responses in a mouse model of ragweed-induced asthma
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DOI：
10.1073/pnas.0910720107
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发表时间：
2010-03-23
影响因子：
11.1
通讯作者：
Mezey, Eva
中科院分区：
文献类型：
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作者：
Nemeth, Krisztian;Keane-Myers, Andrea;Mezey, Eva
骨髓基质细胞[BMSC;也称为间充质干细胞（MSC）]有效抑制人类急性移植物抗宿主病和小鼠许多疾病模型中的炎症反应。许多研究得出结论认为，BMSC驱动的免疫调节是通过抑制促炎性Th 1应答介导的，同时使Th 1/Th 2比率向Th 2重新平衡。在这项研究中，使用豚草诱导的小鼠哮喘模型，我们研究了BMSCs是否可以在过敏性，Th 2优势的环境中是有益的。当在抗原激发时静脉注射BMSC时，它们保护动物免受大多数哮喘特异性病理变化的影响，包括抑制肺中嗜酸性粒细胞浸润和过量粘液产生，降低支气管灌洗液中Th 2细胞因子（IL-4，IL-5和IL-13）的水平，并降低血清中Th 2免疫球蛋白（IgG 1和IgE）的水平。为了探讨其作用机制，我们使用了从各种基因敲除小鼠中分离的BMSCs，进行了体内细胞因子阻断，并研究了哮喘血清和豚草攻击动物的支气管肺泡灌洗液对体外BMSCs的影响。我们的研究结果表明，IL-4和/或IL-13激活BMSC中的STAT 6通路，导致其TGF-β产生的增加，这似乎单独或与调节性T细胞一起介导有益效果，其中一些可能被BMSC招募。这些数据表明，除了关注移植物抗宿主病和自身免疫性疾病，过敏性疾病，特别是治疗抵抗性哮喘，也可能是最近发现的细胞治疗方法使用骨髓间充质干细胞的一个可能的目标。
Bone marrow stromal cells [BMSCs; also known as mesenchymal stem cells (MSCs)] effectively suppress inflammatory responses in acute graft-versus-host disease in humans and in a number of disease models in mice. Many of the studies concluded that BMSC-driven immunomodulation is mediated by the suppression of proinflammatory Th1 responses while rebalancing the Th1/Th2 ratio toward Th2. In this study, using a ragweed induced mouse asthma model, we studied if BMSCs could be beneficial in an allergic, Th2-dominant environment. When BMSCs were injected i.v. at the time of the antigen challenge, they protected the animals from the majority of asthma-specific pathological changes, including inhibition of eosinophil infiltration and excess mucus production in the lung, decreased levels of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage, and lowered serum levels of Th2 immunoglobulins (IgG1 and IgE). To explore the mechanism of the effect we used BMSCs isolated from a variety of knockout mice, performed in vivo blocking of cytokines and studied the effect of asthmatic serum and bronchoalveolar lavage from ragweed challenged animals on the BMSCs in vitro. Our results suggest that IL-4 and/or IL-13 activate the STAT6 pathway in the BMSCs resulting in an increase of their TGF-beta production, which seems to mediate the beneficial effect, either alone, or together with regulatory T cells, some of which might be recruited by the BMSCs. These data suggest that, in addition to focusing on graft-versus-host disease and autoimmune diseases, allergic conditions-specifically therapy resistant asthma-might also be a likely target of the recently discovered cellular therapy approach using BMSCs.