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An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
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Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal

Mattias N D Svensson1,2, Martina Zoccheddu1, Shen Yang1

  • 1Department of Medicine, Altman Clinical and Translational Research Institute, University of California, San Diego, La Jolla, CA 92093, USA.

Science Advances
|July 9, 2020
PubMed

Insights

This study shows that targeting fibroblast-like synoviocytes (FLS) with a novel decoy protein, Ig1&2, can reduce rheumatoid arthritis (RA) symptoms in mice. Combining Ig1&2 with TNF inhibitors offers a synergistic approach to RA treatment without increased immunosuppression.

Area of Science:

  • Immunology
  • Rheumatology
  • Molecular Biology

Background:

  • Fibroblast-like synoviocytes (FLS) are key drivers of rheumatoid arthritis (RA) pathology.
  • Current disease-modifying antirheumatic drugs (DMARDs) rely on systemic immunosuppression.
  • Targeting FLS offers a potential strategy to complement DMARDs for improved RA control without added immunosuppression.

Purpose of the Study:

  • To evaluate the therapeutic potential of immunoglobulin-like domains 1 and 2 (Ig1&2), a decoy protein activating receptor tyrosine phosphatase sigma (PTPRS), for RA treatment.
  • To investigate the expression of PTPRS in RA FLS and the effect of Ig1&2 on FLS migration.
  • To assess the efficacy of Ig1&2 in a murine arthritis model and its potential synergy with TNF inhibitors.

Main Methods:

  • Assessed PTPRS expression in synovial lining FLS from RA patients.
  • Tested Ig1&2's effect on migration of RA and osteoarthritis FLS.
  • Administered Fc-fusion Ig1&2 in a mouse model of arthritis.
  • Investigated the regulatory pathway of PTPRS by tumor necrosis factor (TNF) and the impact of TNF inhibition.

Main Results:

  • PTPRS expression is enriched in synovial lining RA FLS.
  • Ig1&2 significantly reduced migration of RA FLS but not osteoarthritis FLS.
  • Fc-fusion Ig1&2 treatment attenuated arthritis in mice without compromising innate or adaptive immunity.
  • TNF down-regulates PTPRS in FLS via a PI3K-dependent pathway; TNF inhibition increases PTPRS expression in arthritic joints.
  • Combination therapy with sub-therapeutic doses of TNF inhibitor and Fc-Ig1&2 synergistically reversed arthritis in mice.

Conclusions:

  • Ig1&2 demonstrates potential as an FLS-targeted therapy for RA.
  • The combination of FLS-targeted therapy (Ig1&2) and immunosuppressive DMARDs (TNF inhibitors) shows synergistic efficacy in preclinical models.
  • This approach offers a promising strategy for managing RA with potentially reduced systemic immunosuppression.

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