title: Granulocyte macrophage colony-stimulating factor receptor α expression and its targeting in antigen-induced arthritis and inflammation.
abstract: Blockade of granulocyte macrophage colony-stimulating factor (GM-CSF) and its receptor (GM-CSFRα) is being successfully tested in trials in rheumatoid arthritis (RA) with clinical results equivalent to those found with neutralization of the current therapeutic targets, TNF and IL-6. To explore further the role of GM-CSF as a pro-inflammatory cytokine, we examined the effect of anti-GM-CSFRα neutralization on myeloid cell populations in antigen-driven arthritis and inflammation models and also compared its effect with that of anti-TNF and anti-IL-6.
  
  
  
  Cell population changes upon neutralization by monoclonal antibodies (mAbs) in the antigen-induced arthritis (AIA) and antigen-induced peritonitis (AIP) models were monitored by flow cytometry and microarray. Adoptive transfer of monocytes into the AIP cavity was used to assess the GM-CSF dependence of the development of macrophages and monocyte-derived dendritic cells (Mo-DCs) at a site of inflammation.
  
  
  
  Therapeutic administration of a neutralizing anti-GM-CSF mAb, but not of an anti-colony-stimulating factor (anti-CSF)-1 or an anti-CSF-1R mAb, ameliorated AIA disease. Using the anti-GM-CSFRα mAb, the relative surface expression of different inflammatory myeloid populations was found to be similar in the inflamed tissues in both the AIA and AIP models; however, the GM-CSFRα mAb, but not neutralizing anti-TNF and anti-IL-6 mAbs, preferentially depleted Mo-DCs from these sites. In addition, we were able to show that locally acting GM-CSF upregulated macrophage/Mo-DC numbers via GM-CSFR signalling in donor monocytes.
  
  
  
  Our findings suggest that GM-CSF blockade modulates inflammatory responses differently to TNF and IL-6 blockade and may provide additional insight into how targeting the GM-CSF/GM-CSFRα system is providing efficacy in RA.
authors.affiliation: Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, 3050, Australia. adcook@unimelb.edu.au.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cook
authors.affiliation: Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, 3050, Australia.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Louis
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Granta Park, Cambridge, CB21 6GH, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Robinson
authors.affiliation: Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, 3050, Australia.
authors.forename: Reem
authors.initials: R
authors.lastname: Saleh
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Granta Park, Cambridge, CB21 6GH, UK.|, Present Address: Regeneron, 777 Old Saw Mill River Rd, Tarrytown, NY, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Sleeman
authors.affiliation: Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, 3050, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Hamilton
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*
chemical_list: D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Animal models; Arthritis; Granulocyte macrophage colony-stimulating factor; Inflammation; Macrophages; Targeting