FRI0007 MOSPD2: A NOVEL THERAPEUTIC TARGET FOR THE TREATMENT OF RHEUMATOID ARTHRITIS

N. Yacov, Y. Salem, O. Prophate-Meira, P. Kafri, E. Breitbart, I. Mendel
2020 Annals of the Rheumatic Diseases  
Background:Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with an unknown etiology that affects the joints. B and T lymphocytes are major drivers of arthritis, mediated through their secretion of antibodies against self-antigens and the production of pro-inflammatory cytokines. Nevertheless, innate immune cells play an important role in disease progression, and recruitment of blood monocytes/macrophages was highly correlated with tissue damage in RA patients1,2. Once
more » ... ltrated into the joint, monocytes can produce proinflammatory cytokines and chemokines that further escalate the inflammatory process and tissue damage. Consistent with that, genetic and pharmacological intervention targeting CCR2 and CCR5, chemokine receptors which are abundantly expressed on monocytes, was shown to reduce disease severity in multiple preclinical models of RA3. Blocking monocyte migration in RA can be therefore an attractive therapeutic approach, if implied in a manner that can overcome the redundancy of chemokine receptors and ligands.Motile sperm domain-containing protein 2 (MOSPD2) is a 518 amino acids single-pass membrane protein to which no function was ascribed up until recently. Assessment of MOSPD2 in immune cell subsets showed it is expressed by monocytes and neutrophils. We previously discovered that MOSPD2 regulates human monocyte and neutrophil migration in a chemokine-agnostic manner4.Objectives:Using anti MOSPD2 mAbs, the role of MOSPD2 in mouse monocyte migration in-vitro and RA progression in mice was assessed.Methods:In-vitro, MCP-1 and SDF-1 chemokines were used to induce migration of mouse splenic monocytes through a trans-well plate in the presence of anti MOSPD2 mAbs. In-vivo, DBA-1 mice were injected with type II collagen on days 0 and 21 to induce arthritis. Mice were then treated twice a week with anti MOSPD2 mAb, anti TNF-α or an isotype control antibody until study end (day 42). Animals were monitored for arthritis score, and upon sacrifice, hind limb joints were examined for pathology.Results:Anti MOSPD2 mAbs significantly inhibited migration of mouse monocytes in-vitro. Treatment with anti MOSPD2 mAb after disease was already initiated, limited disease progression and significantly ameliorated clinical manifestation at the climax phase of the disease by more than 50% compared with isotype control and anti TNF-α treatment. Pathological examination revealed that treatment with anti MOSPD2 mAb reduced pannus formation and joint inflammation.Conclusion:The results further support the involvement of monocytes in RA pathogenesis and highlight the key role MOSPD2 plays in this disease. Accordingly, targeting of monocyte migration using anti MOSPD2 mAbs may hold promise as a treatment for various chronic inflammatory diseases, including RA.References:[1]Tak PP et al., (1997) Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum 40:217.[2]Mulherin D et al., (1996) Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum 39:115.[3]Zhao, Q et al., (2010) Dual targeting of CCR2 and CCR5: therapeutic potential for immunologic and cardiovascular diseases. J. Leukoc. Biol. 88: 41.[4]Mendel et al., 2017 Identification of Motile Sperm Domain-Containing Protein 2 as Regulator of Human Monocyte Migration. J Immunol. 198: 2125.Disclosure of Interests:None declared
doi:10.1136/annrheumdis-2020-eular.1978 fatcat:e7o5piwvqnhwlirlji6zjub7we