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01.12.2018 | Research article | Ausgabe 1/2018 Open Access

Arthritis Research & Therapy 1/2018

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

Zeitschrift:
Arthritis Research & Therapy > Ausgabe 1/2018
Autoren:
Suzanne Cole, Alice Walsh, Xuefeng Yin, Mihir D. Wechalekar, Malcolm D. Smith, Susanna M. Proudman, Douglas J. Veale, Ursula Fearon, Costantino Pitzalis, Frances Humby, Michele Bombardieri, Amy Axel, Homer Adams III, Christopher Chiu, Michael Sharp, John Alvarez, Ian Anderson, Loui Madakamutil, Sunil Nagpal, Yanxia Guo
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13075-018-1578-z) contains supplementary material, which is available to authorized users.

Abstract

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.
Zusatzmaterial
Additional file 1: Figure S1. Dose-dependent ex vivo depletion of plasma cells by daratumumab in PBMC samples. (A) Representative FACS plot of combined plasma cells. Pre-gated on live singlet CD3−CD56−CD19low/midCD20−lymphocytes. From left to right, plot shows the representative plasma cell population (CD27hiCD138+) at 1 μg/ml isotype control, 0.0003 μg/ml daratumumab, 0.01μg/ml daratumumab and 1μg/ml daratumumab, respectively. Number in the quadrant shows the absolute number of plasma cells at each condition. (B) Quantification of plasma cells at 72 h post-culture with isotype control or daratumumab (Dara) at indicated concentrations. (C) Dose-response of plasma cell depletion by daratumumab in combined samples from patients with SLE or RA and healthy controls. (D) Representative quantification of CD38 MFI on remaining plasma cells at 72 h post-culture with isotype control or daratumumab at indicated concentrations. (E) Dose-response of CD38 down-regulation on plasma cells by daratumumab in all samples combined as in C-D. For each individual donor at each daratumumab concentration, triplicate wells were combined for quantification in B and D and then normalized to isotype control in C and E. (F) Representative quantification of CD38 MFI on CD56+CD16+ NK cells at 72 h post-culture with isotype control or daratumumab at indicated concentrations. (G) Dose response of CD38 MFI down-regulation on NK cells by daratumumab in patients with SLE or RA and healthy controls combined. Data shown represent four patients with SLE, four with RA and four healthy controls. (PDF 401 kb)
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