2. Academic Validation
  3. Granulocyte macrophage colony-stimulating factor receptor α expression and its targeting in antigen-induced arthritis and inflammation

Granulocyte macrophage colony-stimulating factor receptor α expression and its targeting in antigen-induced arthritis and inflammation

  • Arthritis Res Ther. 2016 Dec 1;18(1):287. doi: 10.1186/s13075-016-1185-9.
Andrew D Cook 1,  Cynthia Louis 2,  Matthew J Robinson 3,  Reem Saleh 2,  Matthew A Sleeman 3 4,  John A Hamilton 2
Affiliations

Affiliations

  • 1 Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, 3050, Australia. [email protected].
  • 2 Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, 3050, Australia.
  • 3 Department of Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Granta Park, Cambridge, CB21 6GH, UK.
  • 4 , Present Address: Regeneron, 777 Old Saw Mill River Rd, Tarrytown, NY, USA.
PMID: 27908288 DOI: 10.1186/s13075-016-1185-9
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Animal models; Arthritis; Granulocyte macrophage colony-stimulating factor; Inflammation; Macrophages; Targeting.

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