González Manuel A, Gonzalez-Rey Elena, Rico Laura, Büscher Dirk, Delgado Mario
Cellerix SA, Tres Cantos, and Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
Arthritis Rheum. 2009 Apr;60(4):1006-19. doi: 10.1002/art.24405.
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).
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.
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.
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.
类风湿关节炎（RA）是一种由免疫自身耐受性丧失引起的慢性自身免疫性疾病，其特征为慢性关节炎症。最近发现成人间充质干细胞（MSCs）可抑制效应T细胞反应，并对各种免疫紊乱具有有益作用。本研究的目的是探讨基于人脂肪来源的间充质干细胞（AD-MSCs）给药的RA新治疗策略。
胶原诱导性关节炎的DBA/1小鼠在疾病发作后用人AD-MSCs进行治疗，并确定临床评分。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。通过确定用自身抗原刺激的引流淋巴结细胞的增殖反应和细胞因子谱来评估Th1介导的自身反应性反应。还确定了调节性T细胞（Treg细胞）的数量以及对自身反应性Th1细胞的抑制能力。
全身输注人AD-MSCs显著降低了实验性关节炎的发病率和严重程度。这种治疗效果是通过下调两种有害的疾病成分介导的：Th1驱动的自身免疫和炎症反应。人AD-MSCs减少了各种炎性细胞因子和趋化因子的产生，减少了抗原特异性Th1/Th17细胞的扩增，并在淋巴结和关节中诱导了抗炎性白细胞介素-10的产生。人AD-MSCs还诱导了具有抑制自身反应性T效应反应能力的抗原特异性CD4+CD25+FoxP3+ Treg细胞的重新生成。
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RA细胞治疗的有吸引力的候选者。
