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Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis

OBJECTIVE: Previous work has suggested that the granulocyte macrophage colony stimulating factor (GM-CSF)–GM-CSF receptor α axis (GM-CSFRα) may provide a new therapeutic target for the treatment of rheumatoid arthritis (RA). Therefore, we investigated the cellular expression of GM-CSFRα in RA synovi...

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Autores principales: Greven, D E A, Cohen, E S, Gerlag, D M, Campbell, J, Woods, J, Davis, N, van Nieuwenhuijze, A, Lewis, A, Heasmen, S, McCourt, M, Corkill, D, Dodd, A, Elvin, J, Statache, G, Wicks, I P, Anderson, I K, Nash, A, Sleeman, M A, Tak, P P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602263/
https://www.ncbi.nlm.nih.gov/pubmed/24936585
http://dx.doi.org/10.1136/annrheumdis-2014-205234
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author Greven, D E A
Cohen, E S
Gerlag, D M
Campbell, J
Woods, J
Davis, N
van Nieuwenhuijze, A
Lewis, A
Heasmen, S
McCourt, M
Corkill, D
Dodd, A
Elvin, J
Statache, G
Wicks, I P
Anderson, I K
Nash, A
Sleeman, M A
Tak, P P
author_facet Greven, D E A
Cohen, E S
Gerlag, D M
Campbell, J
Woods, J
Davis, N
van Nieuwenhuijze, A
Lewis, A
Heasmen, S
McCourt, M
Corkill, D
Dodd, A
Elvin, J
Statache, G
Wicks, I P
Anderson, I K
Nash, A
Sleeman, M A
Tak, P P
author_sort Greven, D E A
collection PubMed
description OBJECTIVE: Previous work has suggested that the granulocyte macrophage colony stimulating factor (GM-CSF)–GM-CSF receptor α axis (GM-CSFRα) may provide a new therapeutic target for the treatment of rheumatoid arthritis (RA). Therefore, we investigated the cellular expression of GM-CSFRα in RA synovial tissue and investigated the effects of anti-GM-CSFRα antibody treatment in vitro and in vivo in a preclinical model of RA. METHODS: We compared GM-CSFRα expression on macrophages positive for CD68 or CD163 on synovial biopsy samples from patients with RA or psoriatic arthritis (PsA) to disease controls. In addition, we studied the effects of CAM-3003, an anti-GM-CSFR antibody in a collagen induced arthritis model of RA in DBA/1 mice. The pharmacokinetic profile of CAM-3003 was studied in naïve CD1(ICR) mice (see online supplement) and used to interpret the results of the pharmacodynamic studies in BALB/c mice. RESULTS: GM-CSFRα was expressed by CD68 positive and CD163 positive macrophages in the synovium, and there was a significant increase in GM-CSFRα positive cells in patients in patients with RA as well as patients with PsA compared with patients with osteoarthritis and healthy controls. In the collagen induced arthritis model there was a dose dependent reduction of clinical arthritis scores and the number of F4/80 positive macrophages in the inflamed synovium after CAM-3003 treatment. In BALB/c mice CAM-3003 inhibited recombinant GM-CSF mediated margination of peripheral blood monocytes and neutrophils. CONCLUSIONS: The findings support the ongoing development of therapies aimed at interfering with GM-CSF or its receptor in various forms of arthritis, such as RA and PsA.
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spelling pubmed-46022632015-10-21 Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis Greven, D E A Cohen, E S Gerlag, D M Campbell, J Woods, J Davis, N van Nieuwenhuijze, A Lewis, A Heasmen, S McCourt, M Corkill, D Dodd, A Elvin, J Statache, G Wicks, I P Anderson, I K Nash, A Sleeman, M A Tak, P P Ann Rheum Dis Basic and Translational Research OBJECTIVE: Previous work has suggested that the granulocyte macrophage colony stimulating factor (GM-CSF)–GM-CSF receptor α axis (GM-CSFRα) may provide a new therapeutic target for the treatment of rheumatoid arthritis (RA). Therefore, we investigated the cellular expression of GM-CSFRα in RA synovial tissue and investigated the effects of anti-GM-CSFRα antibody treatment in vitro and in vivo in a preclinical model of RA. METHODS: We compared GM-CSFRα expression on macrophages positive for CD68 or CD163 on synovial biopsy samples from patients with RA or psoriatic arthritis (PsA) to disease controls. In addition, we studied the effects of CAM-3003, an anti-GM-CSFR antibody in a collagen induced arthritis model of RA in DBA/1 mice. The pharmacokinetic profile of CAM-3003 was studied in naïve CD1(ICR) mice (see online supplement) and used to interpret the results of the pharmacodynamic studies in BALB/c mice. RESULTS: GM-CSFRα was expressed by CD68 positive and CD163 positive macrophages in the synovium, and there was a significant increase in GM-CSFRα positive cells in patients in patients with RA as well as patients with PsA compared with patients with osteoarthritis and healthy controls. In the collagen induced arthritis model there was a dose dependent reduction of clinical arthritis scores and the number of F4/80 positive macrophages in the inflamed synovium after CAM-3003 treatment. In BALB/c mice CAM-3003 inhibited recombinant GM-CSF mediated margination of peripheral blood monocytes and neutrophils. CONCLUSIONS: The findings support the ongoing development of therapies aimed at interfering with GM-CSF or its receptor in various forms of arthritis, such as RA and PsA. BMJ Publishing Group 2015-10 2014-06-16 /pmc/articles/PMC4602263/ /pubmed/24936585 http://dx.doi.org/10.1136/annrheumdis-2014-205234 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Basic and Translational Research
Greven, D E A
Cohen, E S
Gerlag, D M
Campbell, J
Woods, J
Davis, N
van Nieuwenhuijze, A
Lewis, A
Heasmen, S
McCourt, M
Corkill, D
Dodd, A
Elvin, J
Statache, G
Wicks, I P
Anderson, I K
Nash, A
Sleeman, M A
Tak, P P
Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis
title Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis
title_full Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis
title_fullStr Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis
title_full_unstemmed Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis
title_short Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis
title_sort preclinical characterisation of the gm-csf receptor as a therapeutic target in rheumatoid arthritis
topic Basic and Translational Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602263/
https://www.ncbi.nlm.nih.gov/pubmed/24936585
http://dx.doi.org/10.1136/annrheumdis-2014-205234
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