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THU0042 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
  1. S. Garcia1,
  2. L. M. Hartkamp1,
  3. M. W. Tang1,
  4. I. van Es1,
  5. H. Lin2,
  6. L. Long2,
  7. E. L. Masteller2,
  8. B. R. Wong2,
  9. P. P. Tak1,3,
  10. K. A. Reedquist1
  1. 1Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
  2. 2Five Prime Therapeutics, Inc., South San Francisco, United States
  3. 3Currently also Glaxosmithkline, Stevanage, United Kingdom

Abstract

Background Disease activity and response to therapy in RA correlates with changes in synovial macrophage numbers and their products. M-CSF or interleukin (IL)-34 stimulation of their common receptor CSFR1 promotes macrophage differentiation, activation and osteoclastogenesis, but M-CSF and IL-34 play distinct roles in murine development. 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 rheumatoid arthritis (RA) are unknown.

Objectives To determine the roles of M-CSF and IL-34 in huma macrophage activation, and human and murine models of RA.

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 ECs 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 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.

Conclusions 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 RA.

Disclosure of Interest S. Garcia: None Declared, L. Hartkamp: None Declared, M. W. Tang: None Declared, I. van Es: None Declared, H. Lin Shareholder of: stock options in Five Prime Therapeutics, Inc., Employee of: Five Prime Therapeutics, Inc., L. Long Shareholder of: stock options in Five Prime Therapeutics, Inc., Employee of: Five Prime Therapeutics, Inc., E. Masteller Shareholder of: stock options in Five Prime Therapeutics, Inc., Employee of: Five Prime Therapeutics, Inc., B. Wong Shareholder of: stock options in Five Prime Therapeutics, Inc., Employee of: Five Prime Therapeutics, Inc., P. Tak Employee of: GlaxoSmithKline, K. Reedquist Grant/research support from: Five Prime Therapeutics, Inc.

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