title: Mesenchymal stem cell therapy in proteoglycan induced arthritis.
abstract: OBJECTIVE
  To explore the immunosuppressive effect and mechanism of action of intraperitoneal (ip) and intra-articular (ia) mesenchymal stem cell (MSC) injection in proteoglycan induced arthritis (PGIA).
  
  
  METHODS
  MSC were administered ip or ia after establishment of arthritis. We used serial bioluminescence imaging (BLI) to trace luciferase-transfected MSC. Mice were sacrificed at different time points to examine immunomodulatory changes in blood and secondary lymphoid organs.
  
  
  RESULTS
  Both ip and local ia MSC injection resulted in a beneficial clinical and histological effect on established PGIA. BLI showed that MSC ip and ia in arthritic mice are largely retained for several weeks in the peritoneal cavity or injected joint respectively, without signs of migration. Following MSC treatment pathogenic PG-specific IgG2a antibodies in serum decreased. The Th2 cytokine IL-4 was only upregulated in PG-stimulated lymphocytes from spleens in ip treated mice and in lymphocytes from draining lymph nodes in ia treated mice. An increase in production of IL-10 was seen with equal distribution. Although IFN-γ was also elevated, the IFN-γ/IL-4 ratio in MSC treated mice was opposite to the ratio in (untreated) active PGIA.
  
  
  CONCLUSIONS
  MSC treatment, both ip and ia, suppresses PGIA, a non-collagen induced arthritis model. MSC are largely retained for weeks in the injection region. MSC treatment induced at the region of injection a deviation of PG-specific immune responses, suggesting a more regulatory phenotype with production of IL-4 and IL-10, but also of IFN-γ, and a systemic decrease of pathogenic PG-specific IgG2a antibodies. These findings underpin the potential of MSC treatment in resistant arthritis.
authors.affiliation: Department of Pediatric Immunology and Laboratory of Translational Immunology, Center for Molecular and Cellular Intervention (CMCI), Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: J F
authors.initials: JF
authors.lastname: Swart
authors.affiliation: Department of Pediatric Immunology and Laboratory of Translational Immunology, Center for Molecular and Cellular Intervention (CMCI), Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: de Roock
authors.affiliation: Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: F M
authors.initials: FM
authors.lastname: Hofhuis
authors.affiliation: Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Rozemuller
authors.affiliation: Department of Pediatric Immunology and Laboratory of Translational Immunology, Center for Molecular and Cellular Intervention (CMCI), Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: van den Broek
authors.affiliation: Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Moerer
authors.affiliation: Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Broere
authors.affiliation: Department of Pediatric Immunology and Laboratory of Translational Immunology, Center for Molecular and Cellular Intervention (CMCI), Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: van Wijk
authors.affiliation: Department of Pediatric Immunology and Laboratory of Translational Immunology, Center for Molecular and Cellular Intervention (CMCI), Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Kuis
authors.affiliation: Department of Pediatric Immunology and Laboratory of Translational Immunology, Center for Molecular and Cellular Intervention (CMCI), Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: B J
authors.initials: BJ
authors.lastname: Prakken
authors.affiliation: Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: A C M
authors.initials: AC
authors.lastname: Martens
authors.affiliation: Department of Pediatric Immunology and Laboratory of Translational Immunology, Center for Molecular and Cellular Intervention (CMCI), Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: N M
authors.initials: NM
authors.lastname: Wulffraat
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000628:therapy*; D005260:Female; D007108:Immune Tolerance / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007270:Injections, Intra-Articular; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008163:Luminescent Measurements; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011509:Proteoglycans / Q000276:immunology / Q000633:toxicity; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D000906:Antibodies; D007074:Immunoglobulin G; D011509:Proteoglycans; D015847:Interleukin-4; D007371:Interferon-gamma
keywords: DMARDs (biologic); Juvenile Idiopathic Arthritis; Rheumatoid Arthritis; Treatment