Adoptive Transfer of Human Gingiva-Derived Mesenchymal Stem Cells Ameliorates Collagen-Induced Arthritis via Suppression of Th1 and Th17 Cells and Enhancement of Regulatory T Cell Differentiation

被引:204
作者
Chen, Maogen [1 ,2 ]
Su, Wenru [1 ]
Lin, Xiaohong [1 ,3 ]
Guo, Zhiyong [2 ]
Wang, Julie [1 ]
Zhang, Qunzhou [1 ]
Brand, David [4 ,5 ]
Ryffel, Bernhard [6 ,7 ]
Huang, Jiefu [2 ]
Liu, Zhongmin [8 ]
He, Xiaoshun [2 ]
Le, Anh D. [1 ]
Zheng, Song Guo [1 ,6 ,7 ,8 ]
机构
[1] Univ So Calif, Los Angeles, CA 90033 USA
[2] Sun Yat Sen Univ, Affiliated Hosp 1, Guangzhou 510275, Guangdong, Peoples R China
[3] Shantou Univ, Affiliated Hosp 1, Shantou, Peoples R China
[4] Memphis VA Med Ctr, Memphis, TN USA
[5] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA
[6] Univ Orleans, Orleans, France
[7] CNRS, UMR6218, F-45071 Orleans, France
[8] Tongji Univ, Shanghai East Hosp, Shanghai 200092, Peoples R China
来源
ARTHRITIS AND RHEUMATISM | 2013年 / 65卷 / 05期
基金
中国国家自然科学基金;
关键词
RHEUMATOID-ARTHRITIS; TGF-BETA; AUTOIMMUNE ARTHRITIS; IMMUNE SUPPRESSION; CUTTING EDGE; TREG CELLS; EXPRESSION; ADENOSINE; CD39; OSTEOCLASTOGENESIS;
D O I
10.1002/art.37894
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
Objective Current approaches offer no cures for rheumatoid arthritis (RA). Accumulating evidence has revealed that manipulation of bone marrowderived mesenchymal stem cells (BM-MSCs) may have the potential to control or even prevent RA, but BM-MSCbased therapy faces many challenges, such as limited cell availability and reduced clinical feasibility. This study in mice with established collagen-induced arthritis (CIA) was undertaken to determine whether substitution of human gingiva-derived mesenchymal stem cells (G-MSCs) would significantly improve the therapeutic effects. Methods CIA was induced in DBA/1J mice by immunization with type II collagen and Freund's complete adjuvant. G-MSCs were injected intravenously into the mice on day 14 after immunization. In some experiments, intraperitoneal injection of PC61 (anti-CD25 antibody) was used to deplete Treg cells in arthritic mice. Results Infusion of G-MSCs in DBA/1J mice with CIA significantly reduced the severity of arthritis, decreased the histopathology scores, and down-regulated the production of inflammatory cytokines (interferon- and interleukin-17A). Infusion of G-MSCs also resulted in increased levels of CD4+CD39+FoxP3+ cells in arthritic mice. These increases were noted early after infusion in the spleens and lymph nodes, and later after infusion in the synovial fluid. The FoxP3+ Treg cells that were increased in frequency mainly consisted of Helios-negative cells. When Treg cells were depleted, infusion of G-MSCs partially interfered with the progression of CIA. Pretreatment of G-MSCs with a CD39 or CD73 inhibitor significantly reversed the protective effect of G-MSCs on CIA. Conclusion The role of G-MSCs in controlling the development and severity of CIA mostly depends on CD39/CD73 signals and partially depends on the induction of CD4+CD39+FoxP3+ Treg cells. G-MSCs provide a promising approach for the treatment of autoimmune diseases.
引用
收藏
页码:1181 / 1193
页数:13
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