Title |
Granulocyte macrophage colony-stimulating factor receptor α expression and its targeting in antigen-induced arthritis and inflammation
|
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Published in |
Arthritis Research & Therapy, December 2016
|
DOI | 10.1186/s13075-016-1185-9 |
Pubmed ID | |
Authors |
Andrew D. Cook, Cynthia Louis, Matthew J. Robinson, Reem Saleh, Matthew A. Sleeman, John A. Hamilton |
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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 33 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 8 | 24% |
Researcher | 4 | 12% |
Student > Bachelor | 3 | 9% |
Student > Master | 3 | 9% |
Student > Doctoral Student | 2 | 6% |
Other | 5 | 15% |
Unknown | 8 | 24% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 10 | 30% |
Immunology and Microbiology | 5 | 15% |
Biochemistry, Genetics and Molecular Biology | 3 | 9% |
Agricultural and Biological Sciences | 3 | 9% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 3% |
Other | 3 | 9% |
Unknown | 8 | 24% |