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Combination of human umbilical cord mesenchymal stem (stromal) cell transplantation with IFN-γ treatment synergistically improves the clinical outcomes of patients with rheumatoid arthritis
  1. Xiao He1,2,3,
  2. Yi Yang1,4,
  3. Mengwei Yao1,5,
  4. Lei Yang6,
  5. Luoquan Ao1,2,
  6. Xueting Hu1,2,
  7. Zhan Li1,2,
  8. Xiaofeng Wu1,2,
  9. Yan Tan1,2,
  10. Wei Xing1,2,
  11. Wei Guo1,2,
  12. Joseph A Bellanti7,
  13. Song Guo Zheng8,
  14. Xiang Xu1,2,5
  1. 1 Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Military Medical University,Chongqing, Chongqing, China
  2. 2 Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing, China
  3. 3 PLA Rocket Force Characteristic Medical Center, Beijing, China
  4. 4 Department of Rheumatology and Clinical Immunology, Daping Hospital, Army Military Medical University, Chongqing, China
  5. 5 Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University, Chongqing, China
  6. 6 Force Health Team of 61365 Troops of the Chinese People's Liberation Army, Tianjin, China
  7. 7 Departments of Pediatrics and Microbiology-Immunology, Georgetown University Medical Center, Washington, DC, USA
  8. 8 Division of Rheumatology, Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, USA
  1. Correspondence to Dr Xiang Xu, Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Military Medical University, Chongqing, China; xiangxu{at}tmmu.edu.cn; Dr Song Guo Zheng, Division of Rheumatology, Department of Internal Medical, Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, USA; SongGuo.Zheng{at}osumc.edu

Abstract

Objectives To clarify the key role of circulating interferon-γ (IFN-γ) and to improve the clinical efficacy of mesenchymal stem cell (MSC) transplantation (MSCT) in patients with rheumatoid arthritis (RA).

Methods Study of wild-type or IFN-γR-/- MSCT was first evaluated in a murine model of collagen-induced arthritis (CIA) following which a phase 1/2 randomised controlled study was conducted in 63 patients with RA who responded poorly to regular clinical treatments. Subjects were randomly assigned to an MSCT monotherapy group (n=32) or an MSCT plus recombinant human IFN-γ treatment group (n=31), with 1 year of follow-up. The primary end points consisted of efficacy as assessed as good or moderate EULAR response rates and the proportion of patients at 3 months attaining American College of Rheumatology 20 (ACR20) response rates.

Results In the murine studies, wild-type MSCT significantly improved the clinical severity of CIA, while IFN-γR-/- MSCT aggravated synovitis, and joint and cartilage damage. Transitioning from the murine to the clinical study, the 3-month follow-up results showed that the efficacy and ACR20 response rates were attained in 53.3% patients with MSCT monotherapy and in 93.3% patients with MSCT combined with IFN-γ treatment (p<0.05). No new or unexpected safety issues were encountered in 1-year follow-up for either treatment group.

Conclusions The results of this study show that IFN-γ is a key factor in determining the efficacy of MSCT in the treatment of RA, and that an MSC plus IFN-γ combination therapeutic strategy can greatly improve the clinical efficacy of MSC-based therapy in RA patients.

  • arthritis, rheumatoid
  • therapeutics
  • inflammation
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Footnotes

  • XH and YY are joint first authors.

  • Handling editor Josef S Smolen

  • XH and YY contributed equally.

  • Correction notice This article ha been corrected since it published Online First. The order of authors has been corrected and affiliation one has been updated.

  • Contributors XH and XX conceptualised the study. XH, YY, MY, LY, LA, WX and WG developed the methodology. XH and ZL carried out the formal analysis. XW, LY, and YT conducted the investigation. YY and LY provided the resources. XH and YY wrote the original draft of the manuscript. JAB, SGZ and XX reviewed and edited the manuscript. XX acquired the funding and supervised the study.

  • Funding This study was supported by the National Natural Science Foundation of China (NSFC, NO. 81871568), the Military Biosafety Project (NO.19SWAQ18), Health Services-War injury treatment and the Military Medical Innovation Project (NO. 18CXZ002).

  • 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 The study was approved by the Ethics Committee of Daping Hospital, Army Military Medical University of the Chinese People's Liberation Army (YIYANLUNSHEN (2016) NO. 016).

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

  • Data availability statement Reasonable requests for additional data or materials will be fulfilled under appropriate agreements.

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