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

被引：87

作者：

Cole, Suzanne ^{[1
]}

Walsh, Alice ^{[1
]}

Yin, Xuefeng ^{[1
]}

Wechalekar, Mihir D. ^{[2
,3
]}

Smith, Malcolm D. ^{[2
,3
]}

Proudman, Susanna M. ^{[4
,5
]}

Veale, Douglas J. ^{[6
]}

Fearon, Ursula ^{[7
]}

Pitzalis, Costantino ^{[8
]}

Humby, Frances ^{[8
]}

Bombardieri, Michele ^{[8
]}

Axel, Amy ^{[9
]}

Adams, Homer, III ^{[9
]}

Chiu, Christopher ^{[9
]}

Sharp, Michael ^{[9
]}

Alvarez, John ^{[9
]}

Anderson, Ian ^{[1
]}

Madakamuti, Loui ^{[1
]}

Nagpal, Sunil ^{[1
]}

Guo, Yanxia ^{[1
]}

机构：

[1] Janssen Res, Immunol, 1400 McKean Rd, Spring House, PA 19477 USA

[2] Repatriat Gen Hosp, Rheumatol Unit, Adelaide, SA, Australia

[3] Flinders Univ S Australia, Adelaide, SA, Australia

[4] Royal Adelaide Hosp, Rheumatol Unit, Adelaide, SA, Australia

[5] Univ Adelaide, Discipline Med, Adelaide, SA, Australia

[6] Univ Coll Dublin, St Vincents Univ Hosp, Ctr Arthrit & Rheuamat Dis, Elm Pk, Dublin 4, Ireland

[7] Trinity Coll Dublin, Mol Rheumatol, Trinity Biomed Sci Inst, Dublin 24, Ireland

[8] Queen Mary Univ London, Charterhouse Sq, London EC1M 6BQ, England

[9] Janssen Res, Oncol, 1400 McKean Rd, Spring House, PA 19477 USA

来源：

ARTHRITIS RESEARCH & THERAPY | 2018年 / 20卷

关键词：

CD38; Plasma cell; Daratumumab; Rheumatoid arthritis; Systemic lupus erythematosus; MULTIPLE-MYELOMA; B-CELL; DARATUMUMAB MONOTHERAPY; CLINICAL-EFFICACY; SYNOVIAL TISSUE;

D O I：

10.1186/s13075-018-1578-z

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页数：14

共 35 条

[31] High frequency of autoantibody-secreting cells and long-lived plasma cells within inflamed kidneys of NZB/W F1 lupus mice [J].

Starke, Charlotte ;

Frey, Silke ;

Wellmann, Ute ;

Urbonaviciute, Vilma ;

Herrmann, Martin ;

Amann, Kerstin ;

Schett, Georg ;

Winkler, Thomas ;

Voll, Reinhard E. .

EUROPEAN JOURNAL OF IMMUNOLOGY, 2011, 41 (07) :2107-2112

[32] The Plasma Cell Signature in Autoimmune Disease [J].

Streicher, Katie ;

Morehouse, Christopher A. ;

Groves, Christopher J. ;

Rajan, Bhargavi ;

Pilataxi, Fernanda ;

Lehmann, Kim P. ;

Brohawn, Philip Z. ;

Higgs, Brandon W. ;

McKeever, Kathleen ;

Greenberg, Steven A. ;

Fiorentino, David ;

Richman, Laura K. ;

Jallal, Bahija ;

Herbst, Ronald ;

Yao, Yihong ;

Ranade, Koustubh .

ARTHRITIS & RHEUMATOLOGY, 2014, 66 (01) :173-184

[33] Serum anticyclic citrullinated protein antibody titers are correlated with the response to biological agents in patients with rheumatoid arthritis [J].

Takahashi, Ryo ;

Isojima, Sakiko ;

Umemura, Masayu ;

Miura, Yoko ;

Oguro, Nao ;

Ishii, Syo ;

Seki, Shinya ;

Tokunaga, Takahiro ;

Tsukamoto, Hiroyuki ;

Furuya, Hidekazu ;

Yanai, Ryo ;

Kasama, Tsuyoshi .

OPEN ACCESS RHEUMATOLOGY-RESEARCH AND REVIEWS, 2014, 6 :57-64

[34] Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma [J].

Usmani, Saad Z. ;

Weiss, Brendan M. ;

Plesner, Torben ;

Bahlis, Nizar J. ;

Belch, Andrew ;

Lonial, Sagar ;

Lokhorst, Henk M. ;

Voorhees, Peter M. ;

Richardson, Paul G. ;

Chari, Ajai ;

Sasser, A. Kate ;

Axel, Amy ;

Feng, Huaibao ;

Uhlar, Clarissa M. ;

Wang, Jianping ;

Khan, Imran ;

Ahmadi, Tahamtan ;

Nahi, Hareth .

BLOOD, 2016, 128 (01) :37-44

[35] Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma [J].

van de Donk, Niels W. C. J. ;

Moreau, Philippe ;

Plesner, Torben ;

Palumbo, Antonio ;

Gay, Francesca ;

Laubach, Jacob P. ;

Malavasi, Fabio ;

Avet-Loiseau, Herve ;

Mateos, Maria-Victoria ;

Sonneveld, Pieter ;

Lokhorst, Henk M. ;

Richardson, Paul G. .

BLOOD, 2016, 127 (06) :681-695

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