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CD30-targeted therapy induces apoptosis of inflammatory cytokine-stimulated synovial fibroblasts and ameliorates collagen antibody-induced arthritis in mice

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Abstract

Objective

It has been reported that levels of soluble CD30 in serum and joint fluid are significantly elevated in patients with rheumatoid arthritis (RA). This study aimed to investigate whether CD30 could be a therapeutic target for RA.

Methods

The expression and localization of CD30 were examined by immunohistochemical and double immunofluorescence staining on synovial tissue samples obtained from patients with RA or osteoarthritis (OA) during surgery. Changes in CD30 expression of fibroblast-like synoviocytes (FLS) from RA patients with or without TNFα and IL-1β stimulation were examined by the polymerase chain reaction (PCR) and flow cytometry. Collagen antibody-induced arthritis (CAIA) was created in DBA/1 mice, and the therapeutic effect of brentuximab vedotin (BV) was examined by clinical score, histological findings and measurement of serum levels of SAA, IL-6, and TNFα.

Results

CD30 expression was significantly higher in samples from patients with RA than from those with OA. Double immunofluorescence showed a low rate of co-localization of CD30 with CD20 or CD90, but a high rate of co-localization of CD30 and CD138. CD30 mRNA expression was upregulated 11.7-fold in FLS following stimulation by inflammatory cytokines. The clinical scores of CAIA mice were significantly lower following both BV treatments, however, the histological scores of CAIA mice were significantly lower only following treatment with high dose BV (70 mg/kg).

Conclusions

CD30 was expressed on immunocompetent cells in synovial tissue from RA patients and in cytokine-stimulated FLS in vitro. High dose BV (70 mg/kg) showed significant therapeutic effects in ameliorating inflammation and joint destruction in CAIA mice, but low dose BV (30 mg/kg) was insufficient.

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Acknowledgements

Approval was obtained from the ethics committee of Okayama University Graduate School of Medicine (Approval No. 1712-026). The procedures used in this study adhered to the tenets of the Declaration of Helsinki. All patients gave informed consent to take part in the study. All the animal experiments were approved by the Animal Care and Use Committee, Okayama University (Approval No. OKU-2018446) and carried out in accordance with relevant guidelines and regulations.

Funding

This research was supported by JSPS KAKENHI under Grant Number JP20K09433. Partial financial support was received from Eisai Co., Ltd. (Grant number: HHCS20180824007), AbbVie GK (Grant number: 793), Mitsubishi Tanabe Pharma Corp. (Grant number: MTPS20190610039), and Chugai Pharmaceutical Co., Ltd (Grant number: AC-1-20200621233833-796001).

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kitaku, Okayama, Japan

    Minami Matsuhashi, Keiichiro Nishida, Aki Yoshida, Ryuichi Nakahara, Yoshihisa Nasu & Toshifumi Ozaki

  2. Division of Pathophysiology, Okayama University Graduate School of Health Sciences, Okayama, Japan

    Misa Sakamoto, Yuka Gion & Yasuharu Sato

  3. Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Takayuki Katsuyama & Yoshinori Matsumoto

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  1. Minami Matsuhashi
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Correspondence to Keiichiro Nishida.

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Matsuhashi, M., Nishida, K., Sakamoto, M. et al. CD30-targeted therapy induces apoptosis of inflammatory cytokine-stimulated synovial fibroblasts and ameliorates collagen antibody-induced arthritis in mice. Inflamm. Res. 71, 215–226 (2022). https://doi.org/10.1007/s00011-021-01537-z

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  • DOI: https://doi.org/10.1007/s00011-021-01537-z

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