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In vitro elimination of autoreactive B cells from rheumatoid arthritis patients by universal chimeric antigen receptor T cells
  1. Bo Zhang1,2,3,
  2. Yan Wang2,
  3. Yeshuang Yuan3,
  4. Jiaqi Sun2,
  5. Lulu Liu1,
  6. Dan Huang1,
  7. Jin Hu1,3,
  8. Min Wang3,4,
  9. Shengjie Li1,
  10. Wei Song1,
  11. Hua Chen4,
  12. Demin Zhou2,
  13. Xuan Zhang3,4
  1. 1 Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
  2. 2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
  3. 3 Clinical Immunology Center& Epigenetics Center, Peking Union Medical College Hospital, Chinese Academy of MedicalSciences and Peking Union Medical College, Beijing, China
  4. 4 Department of Rheumatology & Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
  1. Correspondence to Professor Xuan Zhang, Department of Rheumatology & Clinical Immunology, Peking Union Medical College Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; zxpumch2003{at}sina.com; Professor Demin Zhou, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; deminzhou{at}bjmu.edu.cn

Abstract

Objectives Autoreactive B cells play a crucial role in the pathogenesis of rheumatoid arthritis (RA), and B cell-depleting therapies using an antibodies, such as rituximab, have been suggested to be effective in RA treatment. However, transient B cell depletion with rituximab is associated with significant safety challenges related to global suppression of the immune system and thus increases the risks of infection and cancer development. To address selective and persistent issues associated with RA therapy, we developed a customised therapeutic strategy employing universal antifluorescein isothiocyanate (FITC) chimeric antigen receptor T cells (CAR-T cells) combined with FITC-labelled antigenic peptide epitopes to eliminate autoreactive B cell subsets recognising these antigens in RA.

Methods For a proof-of-concept study, four citrullinated peptide epitopes derived from citrullinated autoantigens, namely, citrullinated vimentin, citrullinated type II collagen, citrullinated fibrinogen and tenascin-C, and a cyclocitrulline peptide-1 were selected as ligands for targeting autoreactive B cells; Engineered T cells expressing a fixed anti-FITC CAR were constructed and applied as a universal CAR-T cell system to specifically eliminate these protein-specific autoreactive B cells via recognition of the aforementioned FITC-labelled autoantigenic peptide epitopes.

Results We demonstrated that anti-FITC CAR-T cells could be specifically redirected and kill hybridoma cells generated by immunisation with antigenic peptides, and autoreactive B cell subsets from RA patients via recognition of corresponding FITC-labelled citrullinated peptide epitopes. Additionally, the cytotoxicity of the CAR-T cells was dependent on the presence of the peptides and occurred in a dose-dependent manner.

Conclusions The approach described here provides a direction for precise, customised approaches to treat RA and can likely be applied to other systemic autoimmune diseases.

  • autoimmune diseases
  • anti-citrullinated protein antibodies
  • arthritis
  • rheumatoid

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Footnotes

  • Handling editor Josef S Smolen

  • BZ, YW and YY contributed equally.

  • Contributors BZ, YW, LL and DH designed the study; BZ, YW, YY, JS, LL and DH performed the experiments and analysed the data; JH and MW contributed to the collection and assembly of data, data analysis and interpretation; WS, SL and HC gave comments; BZ, DZ and XZ wrote and reviewed the manuscript. All authors reviewed the manuscript.

  • Funding This study was supported by grants from the National Natural Science Foundation of China (81788101, 81630044, 81803419, 91753202, 81821004), Chinese Academy of Medical Science Innovation Fund for Medical Sciences (CIFMS2016-12M-1–003, 2017–12 M-1-008, 2017-I2M-3–011, 2016–12 M-1-008), the PUMC Youth Fund (2017350001), Beijing Capital Health Development Fund (2020-2-4019), and Grant from Medical Epigenetics Research Center, Chinese Academy of Medical Sciences (2017PT31035).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval All studies reported here were approved by the Ethics Review Board of PUMC Hospital, Chinese Academy of Medical Science (CAMS).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.

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