title: 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.
abstract: OBJECTIVE
  Current approaches offer no cures for rheumatoid arthritis (RA). Accumulating evidence has revealed that manipulation of bone marrow-derived mesenchymal stem cells (BM-MSCs) may have the potential to control or even prevent RA, but BM-MSC-based 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-γ 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.
  
  
  CONCLUSIONS
  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.
authors: University of Southern California, Los Angeles 90033, USA.
authors: Maogen
authors: M
authors: Chen
authors: Wenru
authors: W
authors: Su
authors: Xiaohong
authors: X
authors: Lin
authors: Zhiyong
authors: Z
authors: Guo
authors: Julie
authors: J
authors: Wang
authors: Qunzhou
authors: Q
authors: Zhang
authors: David
authors: D
authors: Brand
authors: Bernhard
authors: B
authors: Ryffel
authors: Jiefu
authors: J
authors: Huang
authors: Zhongmin
authors: Z
authors: Liu
authors: Xiaoshun
authors: X
authors: He
authors: Anh D
authors: AD
authors: Le
authors: Song Guo
authors: SG
authors: Zheng
mesh_terms: D015720:5'-Nucleotidase / Q000276:immunology; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D001081:Apyrase / Q000276:immunology; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002454:Cell Differentiation; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology; D005881:Gingiva / Q000166:cytology; D006801:Humans; D016219:Immunotherapy, Adoptive; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008811:Mice, Inbred DBA; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D015720:5'-Nucleotidase; C548241:NT5E protein, human; D001081:Apyrase; C067869:CD39 antigen
references: J Immunol. 2006 Sep 1;177(5):2765-9
references: 16920910
references: Blood. 2007 Aug 15;110(4):1225-32
references: 17449799
references: Arthritis Rheum. 2012 Aug;64(8):2548-58
references: 22605463
references: J Immunol. 2010 May 15;184(10):5885-94
references: 20382885
references: J Immunol. 2010 Sep 1;185(5):2675-9
references: 20679534
references: Biol Blood Marrow Transplant. 2005 May;11(5):321-34
references: 15846285
references: Stem Cells. 2010 Oct;28(10):1856-68
references: 20734355
references: Arthritis Rheum. 2009 Apr;60(4):1006-19
references: 19333946
references: Stem Cells Dev. 2012 Apr 10;21(6):937-47
references: 21689066
references: J Immunol. 2004 Feb 1;172(3):1531-9
references: 14734731
references: Ann Rheum Dis. 2012 Sep;71(9):1567-1572
references: 22764040
references: Blood. 2005 Feb 15;105(4):1815-22
references: 15494428
references: Stem Cell Res Ther. 2011 Feb 21;2(1):10
references: 21338517
references: J Mol Cell Biol. 2010 Jun;2(3):164-9
references: 20430855
references: J Immunol. 2010 Apr 1;184(7):3433-41
references: 20181882
references: Arthritis Rheum. 2005 Jul;52(7):2212-21
references: 15986351
references: J Exp Med. 2007 Jun 11;204(6):1257-65
references: 17502665
references: J Immunol. 2012 Jul 15;189(2):500; author reply 500-1
references: 22773660
references: Stem Cells Dev. 2004 Jun;13(3):263-71
references: 15186722
references: Nature. 2003 May 15;423(6937):356-61
references: 12748655
references: Immunity. 2011 Oct 28;35(4):622-32
references: 22018472
references: Stem Cells Dev. 2011 Dec;20(12):2093-102
references: 21361847
references: Ann Rheum Dis. 2009 May;68(5):744-50
references: 18480308
references: Blood. 2002 May 15;99(10):3838-43
references: 11986244
references: Ann Rheum Dis. 2011 Sep;70(9):1671-6
references: 21623002
references: Cell. 2008 May 30;133(5):775-87
references: 18510923
references: Arthritis Rheum. 2004 Sep;50(9):2775-85
references: 15457445
references: Arthritis Res Ther. 2010;12(6):R210
references: 21080925
references: J Immunol. 2011 Nov 1;187(9):4654-66
references: 21967895
references: J Immunol. 2012 Feb 1;188(3):976-80
references: 22198953
references: Am J Transplant. 2009 Oct;9(10):2303-11
references: 19656134
references: Arthritis Rheum. 2011 Jun;63(6):1668-80
references: 21384335
references: J Immunol. 2004 May 1;172(9):5213-21
references: 15100259
references: Nat Protoc. 2007;2(5):1269-75
references: 17546023
references: J Mol Cell Biol. 2012 Feb;4(1):22-8
references: 22107826
references: Stem Cells. 2011 Nov;29(11):1849-60
references: 21987520
references: Ann Rheum Dis. 2010 Aug;69(8):1511-8
references: 20498199
references: Blood. 2007 Nov 15;110(10):3691-4
references: 17684157
references: J Immunol. 2006 Nov 15;177(10):6780-6
references: 17082591
references: Biochem Biophys Res Commun. 2010 Mar 12;393(3):377-83
references: 20138833
references: J Immunol. 2009 Dec 15;183(12):7787-98
references: 19923445