ABSTRACT Dysregulated B-cell activation plays pivotal roles in systemic lupus erythematosus (SLE), which makes B-cell depletion a potential strategy for SLE treatment. The clinical success

of anti-CD19 CAR-T cells in treating B-cell malignancies has attracted the attention of researchers. In this study, we aimed to investigate the feasibility of applying anti-CD19 CAR-T cell

therapy to SLE treatment in a mouse disease model. We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic

function of the corresponding CAR-T cells by infusing them into MRL-lpr mice. Furthermore, anti-CD19 CAR-T cells were transferred to MRL-lpr mice before the onset of disease to determine

at a later stage after disease progression. We also tried to optimize the treatment strategy and found that compared with CAR-T cells with the CD28 costimulatory motif, CAR-T cells with the

4-1BB costimulatory motif showed better therapeutic efficiency without cell enrichment. Taken together, these results show that anti-CD19 CAR-T cell therapy was effective in the prevention

and treatment of a murine model of SLE, indicating its potential for clinical use in patients. Access through your institution Buy or subscribe This is a preview of subscription content,

access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 digital issues and online access to articles $119.00 per year only $9.92 per

issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL

ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS REGULATORY T CELLS EXPRESSING

CD19-TARGETED CHIMERIC ANTIGEN RECEPTOR RESTORE HOMEOSTASIS IN SYSTEMIC LUPUS ERYTHEMATOSUS Article Open access 27 March 2024 ANTI-CD19 CAR T CELL THERAPY FOR REFRACTORY SYSTEMIC LUPUS

ERYTHEMATOSUS Article 15 September 2022 2D4, A HUMANIZED MONOCLONAL ANTIBODY TARGETING CD132, IS A PROMISING TREATMENT FOR SYSTEMIC LUPUS ERYTHEMATOSUS Article Open access 17 November 2024

REFERENCES * Rahman, A. & Isenberg, D. A. Systemic lupus erythematosus. _N. Engl. J. Med._ 358, 929–939 (2008). Article  CAS  Google Scholar  * Arbuckle, M. R. et al. Development of

autoantibodies before the clinical onset of systemic lupus erythematosus. _N. Engl. J. Med._ 349, 1526–1533 (2003). Article  CAS  Google Scholar  * Xiong, W. & Lahita, R. G. Pragmatic

approaches to therapy for systemic lupus erythematosus. _Nat. Rev. Rheumatol._ 10, 97–107 (2014). Article  CAS  Google Scholar  * Isenberg, D. et al. Efficacy and safety of atacicept for

prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial). _Ann. Rheum. Dis._ 74, 2006–2015 (2015). Article  CAS

  Google Scholar  * Furie, R. A. et al. A phase 2, randomised, placebo-controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe

systemic lupus erythematosus, the PEARL-SC study. _Ann. Rheum. Dis._ 74, 1667–1675 (2015). Article  CAS  Google Scholar  * Vital, E. M. et al. B cell biomarkers of rituximab responses in

systemic lupus erythematosus. _Arthritis Rheum._ 63, 3038–3047 (2011). Article  CAS  Google Scholar  * Jonsdottir, T., Sundelin, B., Welin Henriksson, E., van Vollenhoven, R. F. &

Gunnarsson, I. Rituximab-treated membranous lupus nephritis: clinical outcome and effects on electron dense deposits. _Ann. Rheum. Dis._ 70, 1172–1173 (2011). Article  Google Scholar  *

Arce-Salinas, C. A., Rodriguez-Garcia, F. & Gomez-Vargas, J. I. Long-term efficacy of anti-CD20 antibodies in refractory lupus nephritis. _Rheumatol. Int._ 32, 1245–1249 (2012). Article

  CAS  Google Scholar  * Gregersen, J. W. & Jayne, D. R. B-cell depletion in the treatment of lupus nephritis. _Nat. Rev. Nephrol._ 8, 505–514 (2012). Article  CAS  Google Scholar  *

Odendahl, M. et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. _J. Immunol._ 165, 5970–5979 (2000). Article  CAS  Google Scholar  * Mei, H. E., Schmidt,

S. & Dorner, T. Rationale of anti-CD19 immunotherapy: an option to target autoreactive plasma cells in autoimmunity. _Arthritis Res. Ther._ 14(Suppl 5), S1 (2012). Article  Google

Scholar  * Jyothi, M. D., Flavell, R. A. & Geiger, T. L. Targeting autoantigen-specific T cells and suppression of autoimmune encephalomyelitis with receptor-modified T lymphocytes.

_Nat. Biotechnol._ 20, 1215–1220 (2002). Article  CAS  Google Scholar  * Ellebrecht, C. T. et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease.

_Science_ 353, 179–184 (2016). Article  CAS  Google Scholar  * Zhang, L. et al. Chimeric antigen receptor (CAR) T cells targeting a pathogenic MHC class II:peptide complex modulate the

progression of autoimmune diabetes. _J. Autoimmun._ 96, 50–58 (2019). Article  CAS  Google Scholar  * Fransson, M. et al. CAR/FoxP3-engineered T regulatory cells target the CNS and suppress

EAE upon intranasal delivery. _J. Neuroinflammation_ 9, 112 (2012). Article  CAS  Google Scholar  * Blat, D., Zigmond, E., Alteber, Z., Waks, T. & Eshhar, Z. Suppression of murine

colitis and its associated cancer by carcinoembryonic antigen-specific regulatory T cells. _Mol. Ther._ 22, 1018–1028 (2014). Article  CAS  Google Scholar  * MacDonald, K. G. et al.

Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor. _J. Clin. Investig._ 126, 1413–1424 (2016). Article  Google Scholar  * Kansal, R. et al. Sustained B cell

depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. Sci Transl Med. 11, eaav1648. https://doi.org/10.1126/scitranslmed.aav1648. (2019). Article  CAS 

PubMed  PubMed Central  Google Scholar  * Kochenderfer, J. N., Yu, Z., Frasheri, D., Restifo, N. P. & Rosenberg, S. A. Adoptive transfer of syngeneic T cells transduced with a chimeric

antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. _Blood_ 116, 3875–3886 (2010). Article  CAS  Google Scholar  * Feucht, J. et al. Calibration of CAR

activation potential directs alternative T cell fates and therapeutic potency. _Nat. Med._ 25, 82–88 (2019). Article  CAS  Google Scholar  * Cheadle, E. J. et al. Natural expression of the

CD19 antigen impacts the long-term engraftment but not antitumor activity of CD19-specific engineered T cells. _J. Immunol._ 184, 1885–1896 (2010). Article  CAS  Google Scholar  * Abraham,

P. M., Quan, S. H., Dukala, D. & Soliven, B. CD19 as a therapeutic target in a spontaneous autoimmune polyneuropathy. _Clin. Exp. Immunol._ 175, 181–191 (2014). Article  CAS  Google

Scholar  * Hofmann, K., Clauder, A. K. & Manz, R. A. Targeting B cells and plasma cells in autoimmune diseases. _Front. Immunol._ 9, 835 (2018). Article  Google Scholar  * Zhao, Z. et

al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. _Cancer Cell_ 28, 415–428 (2015). Article  CAS  Google Scholar  * Li, S.

et al. CD33-specific chimeric antigen receptor T cells with different co-stimulators showed potent anti-leukemia efficacy and different phenotype. _Hum. Gene Ther._ 29, 626–639 (2018).

Article  CAS  Google Scholar  * Priceman, S. J. et al. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate

cancer. _Oncoimmunology_ 7, e1380764 (2018). Article  Google Scholar  * Du, H. et al. Antitumor responses in the absence of toxicity in solid tumors by targeting B7-H3 via chimeric antigen

receptor T cells. _Cancer Cell_ 35, 221–37 e8 (2019). Article  CAS  Google Scholar  * Hamieh, M. et al. CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape.

_Nature_ 568, 112–116 (2019). Article  CAS  Google Scholar  * van Bekkum, D. W. Effectiveness and risks of total body irradiation for conditioning in the treatment of autoimmune disease with

autologous bone marrow transplantation. _Rheumatology_ 38, 757–761 (1999). Article  Google Scholar  * Zhao, J. et al. P2X7 blockade attenuates murine lupus nephritis by inhibiting

activation of the NLRP3/ASC/caspase 1 pathway. _Arthritis Rheum._ 65, 3176–3185 (2013). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS The authors thank Dr. Richard Sloan

(University of Edinburgh) for manuscript editing, Yingying Huang from the core facilities (ZJU School of Medicine) for technical assistance in FACS analysis, and Huihui Su from the ZJU

Affiliated Animal Hospital for technical assistance in the analysis of mouse samples. This work was supported by grants from the National Natural Science Foundation of China (31770954,

31530019 to L.L. and 31900628 to Q.X.) and the Fundamental Research Funds for the Central Universities (2018XZZX001-12 to L.L.). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Zhejiang

University–University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, 314400, PR China Xuexiao Jin, Kaixiang Zhu & Linrong Lu * Institute of Immunology, Zhejiang

University School of Medicine, Hangzhou, 310058, PR China Xuexiao Jin, Kaixiang Zhu, Yu Jiang & Linrong Lu * Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University

School of Medicine, Hangzhou, 310016, PR China Xuexiao Jin, Qin Xu, Yongmei Han & Linrong Lu * Innovative Cellular Therapeutics Co., Ltd., Shanghai, 201203, PR China Chengfei Pu, Cheng

Lu & Lei Xiao * Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, PR China Linrong Lu Authors *

Xuexiao Jin View author publications You can also search for this author inPubMed Google Scholar * Qin Xu View author publications You can also search for this author inPubMed Google Scholar

* Chengfei Pu View author publications You can also search for this author inPubMed Google Scholar * Kaixiang Zhu View author publications You can also search for this author inPubMed 

Google Scholar * Cheng Lu View author publications You can also search for this author inPubMed Google Scholar * Yu Jiang View author publications You can also search for this author

inPubMed Google Scholar * Lei Xiao View author publications You can also search for this author inPubMed Google Scholar * Yongmei Han View author publications You can also search for this

author inPubMed Google Scholar * Linrong Lu View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS X.J., C.P., C.L., L.X., and L.L. designed the

research; X.J., Q.X., K.Z., and Y.J. performed the research; X.J. and L.L. analyzed the data; and X.J., Y.H., L.X., and L.L. wrote the paper. CORRESPONDING AUTHORS Correspondence to Yongmei

Han or Linrong Lu. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY MATERIAL RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Jin, X., Xu, Q., Pu, C. _et al._ Therapeutic efficacy of anti-CD19 CAR-T cells in a mouse model of systemic lupus erythematosus. _Cell Mol

Immunol_ 18, 1896–1903 (2021). https://doi.org/10.1038/s41423-020-0472-1 Download citation * Received: 01 December 2019 * Accepted: 09 May 2020 * Published: 29 May 2020 * Issue Date: August

2021 * DOI: https://doi.org/10.1038/s41423-020-0472-1 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable

link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * Systemic lupus erythematosus * Autoimmune

disease * Treatment * T cells * B cells