O014 Podoplanin (GP38), a marker of synovial inflammation, is an excellent therapeutic target in mouse collagen-induced arthritis

Introduction In patients with rheumatoid arthritis, synovial fibroblasts (SF) highly up-express the surface protein Podoplanin (PDPN) while its ligand, CLEC-2, is brought into the synovial membrane by platelets.1,2 PDPN is also up-expressed by synovial Th17 T cells from arthritic mice.3,4 Interestingly, IL-17 secretion by human Th17 T cells is triggered by direct cellular contacts with SF in a PDPN-dependent manner in vitro.5 PDPN is then an excellent biomarker and a potential regulator of joint inflammation. Despite these observations, in vivo experimental approaches that explore the therapeutic opportunity of targeting PDPN during the disease are missing. Objectives We aimed at refining the understanding of PDPN expression patterns inside the mouse synovium. We explored the therapeutic benefits from an anti-PDPN antibody in mice with auto-immune arthritis. Methods PDPN expression patterns were investigated from freshly isolated TNFa-overexpressing mouse synoviocytes by histology and FACS. The functions of PDPN expressing synoviocytes were sought by cell sorting and quantitative PCR analysis. An anti-PDPN antibody was administrated to collagen-induced arthritis (CIA) mice from day 26 post-immunisation. The CIA mice disease activity was monitored daily until day 42 and their tissues (plasma, synovium, bones, lymph nodes) analysed by ELISA, FACS, histology, micro-CT, T cell in vitro stimulation and multiplex cytokine assays. Results Joint inflammation triggered PDPN up-expression on a pro-inflammatory SF subset with concurrent accumulation of PDPN +anti inflammatory macrophages. These populations disappeared with the resolution of inflammation. Anti-PDPN treated CIA mice were efficiently protected from arthritis as demonstrated by their clinical features, their reduced leucocyte and non-haematopoietic cell accumulations into the joints as well as their attenuated bone erosion and remodelling. The T cell cytokine expression profile was normal in these mice. The anti-collagen auto-antibody plasma titres were significantly reduced in the anti-PDPN treated CIA mice compare to the control group. Conclusions We demonstrated for the first time that PDPN is expressed by pro-inflammatory and anti-inflammatory cell subsets during joint inflammation. Moreover, we are providing strong evidences that an anti-PDPN antibody restrains auto-immune arthritis in mice. This therapeutic benefit provided by the anti-PDPN antibody correlates with a reduction of circulating auto-antibody titres. This observation suggests that the anti-PDPN antibody might interfere with the micro-environment supporting B cell activation and/or plasma cell survival. References . Ekwall AK, et al. Arthritis Res. Ther2011;13:R40. . Del Rey MJ, et al. PLoS One2014;9:e0099607. . Miyamoto Y, et al. Molecular Immunology2013;54:199. . Jones GW, et al. J. Exp. Med2015;212:1793. . Noack M, et al. Arthritis Res. Ther2016;18:148. Disclosure of interest None declared