Treatment of Experimental Arthritis by Inducing Immune Tolerance With Human Adipose-Derived Mesenchymal Stem Cells
Treatment of Experimental Arthritis by Inducing Immune Tolerance With Human Adipose-Derived Mesenchymal Stem Cells
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DOI：
10.1002/art.24405
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发表时间：
2009-04-01
影响因子：
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通讯作者：
Delgado, Mario
中科院分区：
文献类型：
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作者：
Gonzalez, Manuel A.;Gonzalez-Rey, Elena;Delgado, Mario
目标。类风湿性关节炎（RA）是一种慢性自身免疫性疾病，由免疫自身耐受性丧失引起，以慢性关节炎症为特征。成体间充质干细胞（MSCs）最近被发现抑制效应T细胞反应，并在各种免疫疾病中有有益的作用。本研究的目的是研究一种基于人脂肪源性间充质干细胞（AD-MSCs）的治疗RA的新策略。DBA/1胶原诱导关节炎小鼠发病后用人AD-MSCs治疗，并测定临床评分。通过测量关节和血清中不同炎症介质的水平来确定炎症反应。th1介导的自身反应反应通过测定自身抗原刺激下引流淋巴结细胞的增殖反应和细胞因子谱来评估。测定Treg细胞数量及对自身反应性Th1细胞的抑制能力。全身输注人AD-MSCs可显著降低实验性关节炎的发生率和严重程度。这种治疗效果是通过下调两种有害疾病成分介导的：th1驱动的自身免疫反应和炎症反应。人AD-MSCs减少了各种炎症细胞因子和趋化因子的产生，降低了抗原特异性Th1/Th17细胞的扩增，并诱导了淋巴结和关节中抗炎白细胞介素-10的产生。人AD-MSCs还诱导了抗原特异性CD4+CD25+FoxP3+ Treg细胞的新生，具有抑制自身反应性T效应反应的能力。人AD-MSCs通过诱导Treg细胞的产生/激活而成为免疫耐受的关键调节因子，因此是基于细胞治疗RA的有吸引力的候选者。
Objective. Rheumatoid arthritis (RA) is a chronic autoimmune disease caused by loss of immunologic self tolerance and characterized by chronic joint inflammation. Adult mesenchymal stem cells (MSCs) were recently found to suppress effector T cell responses and to have beneficial effects in various immune disorders. The purpose of this study was to examine a new therapeutic strategy for RA based on the administration of human adipose-derived MSCs (AD-MSCs).Methods. DBA/1 mice with collagen-induced arthritis were treated with human AD-MSCs after disease onset, and clinical scores were determined. Inflammatory response was determined by measuring the levels of different mediators of inflammation in the joints and serum. The Th1-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with the autoantigen. The number of Treg cells and the suppressive capacity on self-reactive Th1 cells were also determined.Results. Systemic infusion of human AD-MSCs significantly reduced the incidence and severity of experimental arthritis. This therapeutic effect was mediated by down-regulating the 2 deleterious disease components: the Th1-driven autoimmune and inflammatory responses. Human AD-MSCs decreased the production of various inflammatory cytokines and chemokines, decreased antigen-specific Th1/Th17 cell expansion, and induced the production of antiinflammatory interleukin-10 in lymph nodes and joints. Human AD-MSCs also induced de novo generation of antigen-specific CD4+CD25+FoxP3+ Treg cells with the capacity to suppress self-reactive T effector responses.Conclusion. Human AD-MSCs emerge as key regulators of immune tolerance by inducing the generation/activation of Treg cells and are thus attractive candidates for a cell-based therapy for RA.