Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal.,Science Advances

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Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal.
Science Advances ( IF 13.6 ) Pub Date : 2020-06-26 , DOI: 10.1126/sciadv.aba4353
Mattias N D Svensson _{1,

2} , Martina Zoccheddu ₁ , Shen Yang ₁ , Gyrid Nygaard ₁ , Christian Secchi _{1,

2,

3} , Karen M Doody ₂ , Kamil Slowikowski _{4,

5,

6,

7,

8} , Fumitaka Mizoguchi _{4,

9} , Frances Humby ₁₀ , Rebecca Hands ₁₀ , Eugenio Santelli _{1,

2} , Cristiano Sacchetti _{1,

2} , Kuninobu Wakabayashi ₁₁ , Dennis J Wu ₁ , Christopher Barback _{12,

13} , Rizi Ai ₁₄ , Wei Wang ₁₄ , Gary P Sims ₁₅ , Piotr Mydel _{16,

17} , Tsuyoshi Kasama ₁₁ , David L Boyle ₁ , Francesco Galimi ₃ , David Vera _{12,

13} , Michel L Tremblay _{18,

19,

20} , Soumya Raychaudhuri _{4,

5,

6,

7,

21,

22} , Michael B Brenner ₄ , Gary S Firestein ₁ , Costantino Pitzalis ₁₀ , Anna-Karin H Ekwall _{23,

24} , Stephanie M Stanford _{1,

2} , Nunzio Bottini _{1,

2}

Affiliation

Department of Medicine, Altman Clinical and Translational Research Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Division of Cellular Biology, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
Department of Biomedical Sciences, National Institute of Biostructures and Biosystems, University of Sassari Medical School, 07100 Sassari, Italy.
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Partners HealthCare Personalized Medicine, Boston, MA 02115, USA.
Program in Medical and Population Genetics, Broad Institute of Massachusetts Technical Institute and Harvard University, Cambridge, MA 02138, USA.
Bioinformatics and Integrative Genomics, Harvard University, Cambridge, MA 02138, USA.
Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8519, Japan.
Centre for Experimental Medicine and Rheumatology, John Vane Science Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
Division of Rheumatology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
Department of Radiology, University of California, La Jolla, CA 92093, USA.
UCSD Molecular Imaging Program, University of California, La Jolla, CA 92093, USA.
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
Respiratory, Inflammation and Autoimmunity, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA.
Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, The Laboratory Building, 5th Floor, 5021 Bergen, Norway.
Department of Microbiology, Jagiellonian University, Kraków, Poland.
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada.
Department of Biochemistry, McGill University, Montréal, Québec H3A 1A3, Canada.
Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada.
Rheumatology Unit, Karolinska Institutet, Stockholm S-171 76, Sweden.
Institute of Inflammation and Repair, University of Manchester, Manchester M13 9PT, UK.
Department of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Centre for Bone and Arthritis Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Fibroblast-like synoviocytes (FLS) are joint-lining cells that promote rheumatoid arthritis (RA) pathology. Current disease-modifying antirheumatic agents (DMARDs) operate through systemic immunosuppression. FLS-targeted approaches could potentially be combined with DMARDs to improve control of RA without increasing immunosuppression. Here, we assessed the potential of immunoglobulin-like domains 1 and 2 (Ig1&2), a decoy protein that activates the receptor tyrosine phosphatase sigma (PTPRS) on FLS, for RA therapy. We report that PTPRS expression is enriched in synovial lining RA FLS and that Ig1&2 reduces migration of RA but not osteoarthritis FLS. Administration of an Fc-fusion Ig1&2 attenuated arthritis in mice without affecting innate or adaptive immunity. Furthermore, PTPRS was down-regulated in FLS by tumor necrosis factor (TNF) via a phosphatidylinositol 3-kinase–mediated pathway, and TNF inhibition enhanced PTPRS expression in arthritic joints. Combination of ineffective doses of TNF inhibitor and Fc-Ig1&2 reversed arthritis in mice, providing an example of synergy between FLS-targeted and immunosuppressive DMARD therapies.

中文翻译：

滑膜细胞靶向治疗与 TNF 抑制在关节炎逆转中协同作用。

成纤维细胞样滑膜细胞 (FLS) 是促进类风湿性关节炎 (RA) 病理学的关节内衬细胞。目前的缓解疾病的抗风湿药 (DMARDs) 通过全身免疫抑制发挥作用。FLS 靶向方法可能与 DMARDs 相结合，在不增加免疫抑制的情况下改善对 RA 的控制。在这里，我们评估了免疫球蛋白样结构域 1 和 2 (Ig1&2)（一种可激活 FLS 上的受体酪氨酸磷酸酶 sigma (PTPRS) 的诱饵蛋白）用于 RA 治疗的潜力。我们报告 PTPRS 表达在滑膜衬里 RA FLS 中富集，并且 Ig1&2 减少了 RA 的迁移，但不减少骨关节炎 FLS。在不影响先天性或适应性免疫的情况下，给予 Fc 融合 Ig1&2 可减轻小鼠关节炎。此外，PTPRS 在 FLS 中被肿瘤坏死因子 (TNF) 通过磷脂酰肌醇 3-激酶介导的途径下调，TNF 抑制增强了关节炎关节中 PTPRS 的表达。无效剂量的 TNF 抑制剂和 Fc-Ig1&2 的组合逆转了小鼠的关节炎，提供了 FLS 靶向和免疫抑制 DMARD 疗法之间协同作用的例子。

更新日期：2020-06-26

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