Colony-Stimulating Factor (CSF) Receptor 1 Blockade Overcomes Overlapping Effects of M-CSF and Interleukin-34 On Myeloid Differentiation and Gene Expression to Reduce Inflammation in Human and Murine Models of Rheumatoid Arthritis

Samuel Garcia¹, Linda M. Hartkamp², Inge E. van Es², Haishan Lin³, Li Long³, Emma L. Masteller³, Brian R. Wong³, Paul P. Tak⁴ and Kris A. Reedquist², ¹Department of Experimental Immunology, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, Netherlands, ²Department of Experimental Immunology, Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, ³Five Prime Therapeutics, Inc., South San Francisco, CA, ⁴Department of Experimental Immunology, Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam and GlaxoSmithKline, Amsterdam, Netherlands

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: animal models and rheumatoid arthritis, cytokines, interleukins (IL), macrophages, rheumatoid arthritis, synovium

Session Information

Title: Cytokines, Mediators, and Gene Regulation

Session Type: Abstract Submissions (ACR)

Background/Purpose: Disease activity and response to therapy in RA correlates with changes in synovial macrophage numbers and their products. M-CSF or IL-34 stimulation of their receptor CSFR1 promotes macrophage differentiation, activation and osteoclastogenesis. Pharmacological inhibition of CSFR1 is beneficial in animal models of arthritis but the relative contributions of M-CSF, IL-34 and their receptor to inflammation in RA are unknown.

Methods: M-CSF, IL-34, and cellular markers were detected by immunohistochemistry and digital image analysis in synovial tissue from 18 biological-naïve RA patients, 14 PsA patients, and 4 controls without inflammatory disease (2 healthy donors and 2 OA patients). Gene expression in M-CSF and IL-34 –differentiated human macrophages was assessed by FACS analysis and q-PCR arrays. RA synovial explants were incubated with M-CSF, IL-34, control antibody (Ab), or a humanized CSFR1-blocking Ab. Prophylactic effects of control and CSFR1-blocking Ab were examined in murine collagen-induced arthritis (CIA).

Results: Expression of M-CSF and IL-34 was similar in RA and PsA synovial tissue, but lower in controls (p< 0.05). M-CSF expression was restricted to endothelial cells and IL-34 was observed in sublining mononuclear cells and intimal lining layer cells. CXCL5, CXCL6, FN1, COL1A1, COL6A1-2, COL14A1, COL15A1, MMP7, MMP8 and MMP9 mRNA expression was significantly upregulated in macrophages differentiated in M-CSF compared to IL-34, while CXCL7, CXCL9, CXCL10, CXCL11, CXCL12, LAMA1, and MMP2 were significantly downregulated. M-CSF or IL-34 had no effect on RA synovial explant IL-6 production, but anti-CSFR1 Ab dose-dependently reduced IL-6 production. Treatment with anti-CSFR1 Ab in CIA significantly reduced paw swelling and joint destruction.

Conclusion: M-CSF and IL-34 are expressed in topographically distinct regions of inflamed synovial tissue and differentially effect macrophage capacity to attract inflammatory cells and remodel tissue. Simultaneous inhibition of CSFR1 interactions with both M-CSF and IL-34 suppresses inflammatory activation of RA synovial tissue and pathology in CIA, suggesting a novel therapeutic strategy for the treatment of RA.

Disclosure:

S. Garcia,
None;

L. M. Hartkamp,
None;

I. E. van Es,
None;

H. Lin,