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Methotrexate does not primarily affect Foxp3+ regulatory T cells in poly-articular juvenile idiopathic arthritis

Background

Methotrexate (MTX) is the most widely used disease modifying anti-rheumatic drug in juvenile idiopathic arthritis (JIA), inducing long-lasting remission in many patients. It usually takes 6–12 weeks before anti-inflammatory effects are clinically noticed, suggesting modulatory effects on T cells. We examined the effect of MTX on (induced) regulatory T cells (Treg) in JIA.

Materials and methods

We sampled 11 patients with active poly-articular JIA (poly-JIA) prior to and 3–6 months after initiating MTX. Moreover, 11 poly-JIA patients in remission on MTX were sampled prior to and 3–6 months after withdrawal of MTX. Frequency and characteristics of Foxp3+CD4+Treg and effector T cell subsets were analyzed by flowcytometry. Function of Treg was evaluated in suppression assays. Responses to human heat shock protein 60 (HSP60) were studied in proliferation assays.

Results

MTX-treatment resulted in a decrease of Foxp3+CD4+ Treg (3,7% to 2,8% of CD4+T cells). Suppressive function of Treg was not altered by MTX. Interestingly, stimulation with anti-CD3 resulted in increased proliferation of CD4+CD25- effector T cells after 3 months MTX compared to pre-MTX. Moreover, proliferative responses to human HSP60 increased after MTX-treatment. The quality of the HSP60-response changed with a less pro-inflammatory cytokine profile in supernatants after MTX-treatment. When JIA-patients in remission on MTX-treatment withdrawed MTX, the frequency of Treg increased (3,2 to 3,8% of CD4+ T cells) but their suppressive function remained unchanged.

Conclusion

MTX seems to exert its immune-modulating effects not by affecting Foxp3+ Treg. Instead, we observed changes in effector T cells and HSP60 specific T cells.

Author information

Correspondence to SJ Vastert.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Keywords

  • Heat Shock
  • Methotrexate
  • Heat Shock Protein
  • Modulative Effect
  • Juvenile Idiopathic Arthritis