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Stimulation of TNF receptor type 2 expands regulatory T cells and ameliorates established collagen-induced arthritis in mice

Cellular & Molecular Immunologyvolume 16pages6574 (2019) | Download Citation

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Abstract

Tumor necrosis factor (TNF) and its receptors TNF receptor type 1 (TNFR1) and type 2 (TNFR2) have a central role in chronic inflammatory diseases. While TNFR1 mainly confers inflammation, activation of TNFR2 elicits not only pro-inflammatory but also anti-inflammatory effects. In this study, we wanted to investigate the anti-inflammatory therapeutic potential of selective activation of TNFR2 in mice with established collagen-induced arthritis. Mice with established arthritis induced by immunization with bovine collagen type II were treated with six injections of the TNFR2-specific agonist TNCscTNF80, given every second day. Two days after treatment cessation, the cell compositions of bone marrow, spleen and lymph nodes were analyzed. Mice were visually scored until day 30 after the start of therapy and the degree of joint inflammation was determined by histology. Treatment with TNCscTNF80 increased arthritis-induced myelopoiesis. Little effect was seen on the infiltration rate of inflammatory immature myeloid cells and on the reduction of lymphoid cells in secondary lymphoid organs. Upon treatment, frequency of regulatory T (Treg) cells in the CD4+ T-cell population was increased in both spleen and inguinal lymph nodes. In addition, the expression of TNFR2 on Treg cells was enhanced. The clinical score started to improve 1 week after cessation treatment and remained lower 30 days after initiation of therapy. The histological score also revealed amelioration of joint inflammation in TNCscTNF80-treated versus control mice. Activation of TNFR2 might provide a suitable therapeutic strategy in autoimmune arthritis by increasing the numbers of regulatory cell types, in particular Treg cells, and by attenuation of arthritis.

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Acknowledgements

We thank B Echtenacher for help with the animal experimentation and Melanie Werner-Klein for help with the figures for the manuscript. Part of the work has been funded by the Deutsche Forschungsgemeinschaft with grants to RHS (STR 511/32-1) and HW (WA 1025/31-1). Additionally, the work has been funded by the respective institutions.

Author contributions

VM, TS, DW-S, DZ and ZJ-L generated data on collagen type II-induced arthritis and respective parameters thereof. HW generated the TNCscTNF80 construct. RHS and DNM analyzed and interpreted the data. All authors contributed to figures and the draft manuscript. All authors read and approved the final manuscript.

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Affiliations

  1. Institute of Immunology, University of Regensburg, Regensburg, 93042, Germany

    • Vanessa Lamontain
    • , Tobias Schmid
    • , Dorothea Weber-Steffens
    • , David Zeller
    •  & Daniela N Männel
  2. Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine, University Hospital Regensburg, Regensburg, 93042, Germany

    • Zsuzsa Jenei-Lanzl
    •  & Rainer H Straub
  3. Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, 97070, Germany

    • Harald Wajant

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The authors declare no conflict of interest.

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Correspondence to Rainer H Straub.

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DOI

https://doi.org/10.1038/cmi.2017.138