title: Effect of mesenchymal precursor cells on the systemic inflammatory response and endothelial dysfunction in an ovine model of collagen-induced arthritis.
abstract: OBJECTIVE
  Mesenchymal precursor cells (MPC) are reported to possess immunomodulatory properties that may prove beneficial in autoimmune and other inflammatory conditions. However, their mechanism of action is poorly understood. A collagen-induced arthritis model has been previously developed which demonstrates local joint inflammation and systemic inflammatory changes. These include not only increased levels of inflammatory markers, but also vascular endothelial cell dysfunction, characterised by reduced endothelium-dependent vasodilation. This study aimed to characterise the changes in systemic inflammatory markers and endothelial function following the intravenous administration of MPC, in the ovine model.
  
  
  METHODS
  Arthritis was induced in sixteen adult sheep by administration of bovine type II collagen into the hock joint following initial sensitisation. After 24h, sheep were administered either 150 million allogeneic ovine MPCs intravenously, or saline only. Fibrinogen and serum amyloid-A were measured in plasma to assess systemic inflammation, along with pro-inflammatory and anti-inflammatory cytokines. Animals were necropsied two weeks following arthritis induction. Coronary and digital arterial segments were mounted in a Mulvaney-Halpern wire myograph. The relaxant response to endothelium-dependent and endothelium-independent vasodilators was used to assess endothelial dysfunction.
  
  
  CONCLUSIONS
  Arthritic sheep treated with MPC demonstrated a marked spike in plasma IL-10, 24h following MPC administration. They also showed significantly reduced plasma levels of the inflammatory markers, fibrinogen and serum amyloid A, and increased HDL. Coronary arteries from RA sheep treated with MPCs demonstrated a significantly greater maximal relaxation to bradykinin when compared to untreated RA sheep (253.6 ± 17.1% of pre-contracted tone vs. 182.3 ± 27.3% in controls), and digital arteries also demonstrated greater endothelium-dependent vasodilation. This study demonstrated that MPCs given intravenously are able to attenuate systemic inflammatory changes associated with a monoarthritis, including the development of endothelial dysfunction.
authors.affiliation: Faculty of Veterinary Science, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Dooley
authors.affiliation: Faculty of Veterinary Science, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Anwar
authors.initials: A
authors.lastname: Abdalmula
authors.affiliation: Faculty of Veterinary Science, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Washington
authors.affiliation: Faculty of Veterinary Science, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Claire
authors.initials: C
authors.lastname: Kaufman
authors.affiliation: Faculty of Veterinary Science, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Tudor
authors.affiliation: Mesoblast Ltd, Melbourne, Victoria, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Ghosh
authors.affiliation: Mesoblast Ltd, Melbourne, Victoria, Australia.
authors.forename: Silviu
authors.initials: S
authors.lastname: Itescu
authors.affiliation: Faculty of Veterinary Science, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Wayne G
authors.initials: WG
authors.lastname: Kimpton
authors.affiliation: Faculty of Veterinary Science, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Simon R
authors.initials: SR
authors.lastname: Bailey
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D001920:Bradykinin / Q000494:pharmacology; D002417:Cattle; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005340:Fibrinogen / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D012756:Sheep; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000685:Serum Amyloid A Protein; D014665:Vasodilator Agents; D016753:Interleukin-10; D005340:Fibrinogen; D001920:Bradykinin