Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Blocking the Granulocyte Macrophage Colony Stimulating Factor Receptor Alpha Chain Prevents Mechanical Hypersensitivity in a Mouse Model of Inflammatory Pain.
Hatcher, John P., Whitworth, Justine, Anderson, Ian K., Chessell, Iain P., Sleeman, Matthew A.
Over the last decade the GM-CSF pathway has been proposed as playing a pivotal role in the pathology of rheumatoid arthritis (RA) by promoting macrophage and neutrophil activation, survival and differentiation. Consequently a number of clinical studies are underway in RA targeting either GM-CSFR or GM-CSF. Recently it has also been shown that GM-CSF may have a role in peripheral pain sensation in models of cancer pain. As refractory pain remains a significant problem in many individuals with RA, we have investigated the role of GM-CSFR blockade in a mouse model of inflammatory pain. Objective: In these studies we aimed to characterize the role of GM-CSFR alpha in inflammatory pain by blocking GM-CSF signalling using a neutralising antibody to the GM-CSF receptor.
Mechanical hypersensitivity was determined using a mouse incapacitance tester. Mice were placed into the apparatus such as each hind paw was located on one of two weight bearing sensors. Weight bearing was calculated by measurement of ipsilateral and contralateral weights in grams over a period of 4s. Following the establishment of baseline readings mice received a single intra-plantar administration of Complete Freunds Adjuvant (FCA) (30ml of 1mg/ml). 24 hrs later mice underwent pre-dose testing for changes in mechanical hypersensitivity as described above. Mice were then randomly allocated into treatment groups of 9/10 with approximately equal ipsilateral/contralateral ratios and were administered one of the following treatments; PBS vehicle (10ml/kg), CAT-004, the isotype control (30mg/kg) or CAM-3003, a GM-CSFR antibody (3, 10 or 30mg/kg). All doses were administered intra-peritoneally. Mice were re-tested for changes in mechanical hypersensitivity at 4hr, 1, 2, 3 and 7 days post dose as described above.
FCA caused a mechanical hypersensitivity which manifested as a reduction in the ipsilateral/contralateral ratio when compared to naive readings. The administration of CAT-004 did not produce any significant reversal of the FCA induced hypersensitivity at any time point when compared to PBS vehicle control. CAM-3003 (3, 10 and 30mg/kg) caused a reversal of the FCA induced hypersensitivity (vs CAT 004 control) which reached significance 1 day post dose for all treatment groups. Significance was maintained out till 2 days post dose for the 30mg/kg group. No significant inhibition of mechanical hypersensitivity was observed following administration of 3mg/kg or 10mg/kg CAM-3003 when compared with isotype control (CAT-004).
This study demonstrates that inhibiting GM-CSF signalling is effective in a mouse inflammatory pain mouse model, supporting continued development of agents targeting GM-CSFR for this therapeutic area.
To cite this abstract, please use the following information:
Hatcher, John P., Whitworth, Justine, Anderson, Ian K., Chessell, Iain P., Sleeman, Matthew A.; Blocking the Granulocyte Macrophage Colony Stimulating Factor Receptor Alpha Chain Prevents Mechanical Hypersensitivity in a Mouse Model of Inflammatory Pain. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2092