Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus.

Autor: Cole S; Immunology, Janssen Research, 1400 McKean Road, Spring House, PA, 19477, USA., Walsh A; Immunology, Janssen Research, 1400 McKean Road, Spring House, PA, 19477, USA., Yin X; Immunology, Janssen Research, 1400 McKean Road, Spring House, PA, 19477, USA., Wechalekar MD; Rheumatology Unit, Repatriation General Hospital and Flinders University, Adelaide, Australia., Smith MD; Rheumatology Unit, Repatriation General Hospital and Flinders University, Adelaide, Australia., Proudman SM; Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia and Discipline of Medicine, University of Adelaide, Adelaide, Australia., Veale DJ; Center for Arthritis and Rheuamatic Diseases, St. Vincent's University Hospital, University College Dublin, Elm Park, Dublin 4, Ireland., Fearon U; Molecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Trinity College London, Dublin 24, Ireland., Pitzalis C; Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK., Humby F; Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK., Bombardieri M; Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK., Axel A; Oncology, Janssen Research, 1400 McKean Road, Spring House, PA, 19477, USA., Adams H 3rd; Oncology, Janssen Research, 1400 McKean Road, Spring House, PA, 19477, USA., Chiu C; Oncology, Janssen Research, 1400 McKean Road, Spring House, PA, 19477, USA., Sharp M; Oncology, Janssen Research, 1400 McKean Road, Spring House, PA, 19477, USA., Alvarez J; Oncology, Janssen Research, 1400 McKean Road, Spring House, PA, 19477, USA., Anderson I; Immunology, Janssen Research, 1400 McKean Road, Spring House, PA, 19477, USA., Madakamutil L; Immunology, Janssen Research, 1400 McKean Road, Spring House, PA, 19477, USA., Nagpal S; Immunology, Janssen Research, 1400 McKean Road, Spring House, PA, 19477, USA. snagpal2@its.jnj.com., Guo Y; Immunology, Janssen Research, 1400 McKean Road, Spring House, PA, 19477, USA. yguo49@its.jnj.com.
Jazyk: angličtina
Zdroj: Arthritis research & therapy [Arthritis Res Ther] 2018 May 02; Vol. 20 (1), pp. 85. Date of Electronic Publication: 2018 May 02.
DOI: 10.1186/s13075-018-1578-z
Abstrakt: Background: Plasmablasts and plasma cells play a key role in many autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). This study was undertaken to evaluate the potential of targeting CD38 as a plasma cell/plasmablast depletion mechanism by daratumumab in the treatment of patients with RA and SLE.
Methods: RNA-sequencing analysis of synovial biopsies from various stages of RA disease progression, flow cytometry analysis of peripheral blood mononuclear cells (PBMC) from patients with RA or SLE and healthy donors, immunohistochemistry assessment (IHC) of synovial biopsies from patients with early RA, and ex vivo immune cell depletion assays using daratumumab (an anti-CD38 monoclonal antibody) were used to assess CD38 as a therapeutic target.
Results: We demonstrated that the plasma cell/plasmablast-related genes CD38, XBP1, IRF4, PRDM1, IGJ and TNFSF13B are significantly up-regulated in synovial biopsies from patients with arthralgia, undifferentiated arthritis (UA), early RA and established RA as compared to healthy controls and control patients with osteoarthritis. In addition, the highest CD38 expression was observed on plasma cells and plasmablasts compared to natural killer (NK) cells, classical dendritic cells (DCs), plasmacytoid DCs (pDCs) and T cells, in blood from healthy controls and patients with SLE and RA. Furthermore, IHC showed CD38 staining in the same region as CD3 and CD138 staining in synovial tissue biopsies from patients with early RA. Most importantly, our data show for the first time that daratumumab effectively depletes plasma cells/plasmablasts in PBMC from patients with SLE and RA in a dose-dependent manner ex vivo.
Conclusion: These results indicate that CD38 may be a potential target for RA disease interception and daratumumab should be evaluated clinically for the treatment of both RA and SLE.
Databáze: MEDLINE
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