Direct anti-proliferative effect of adipose-derived mesenchymal stem cells of ankylosing spondylitis patients on allogenic CD4+ cells

Ewa Kuca-Warnawin; Magdalena Plebańczyk; Krzysztof Bonek; Ewa Kontny

doi:10.5114/reum.2021.103940

Direct anti-proliferative effect of adipose-derived mesenchymal stem cells of ankylosing spondylitis patients on allogenic CD4+ cells

Reumatologia. 2021;59(1):12-22. doi: 10.5114/reum.2021.103940. Epub 2021 Feb 28.

Authors

Ewa Kuca-Warnawin¹, Magdalena Plebańczyk¹, Krzysztof Bonek², Ewa Kontny¹

Affiliations

¹ Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland.
² Clinic of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland.

Abstract

Objectives: T-cell-mediated adaptive immunity contributes to the development and persistence of ankylosing spondylitis (AS). Mesenchymal stromal/stem cells (MSCs) have immunomodulatory potential and are able to inhibit T-cell proliferation, but their functionality in AS patients is relatively unknown. The aim of the study was to assess the direct anti-proliferative effects of MSCs isolated from subcutaneous abdominal adipose tissue of AS patients (AS/ASCs) on allogeneic T lymphocytes, using commercially available ASC lines from healthy donors (HD/ASCs) as a control.

Material and methods: CD3+CD4+ T-cells were isolated from peripheral blood of healthy blood donors, activated with anti-CD3/CD28 beads, and co-cultured for 5 days with untreated and TNF+IFN-γ pre-stimulated HD/ASCs (5 cell lines) and AS/ASCs, obtained from 11 patients (6F/5M). The proliferative response of T-cells was analysed by flow cytometry, while the concentrations of kynurenines, prostaglandin E2 (PGE-2), interleukin 10 (IL-10), and interleukin 1 receptor antagonist (IL-1Ra) were measured spectrophotometrically or using a specific enzyme-linked immunosorbent assay (ELISA).

Results: HD/ASCs and AS/ASCs similarly reduced the T-cell proliferation response, i.e. the percentage of proliferating cells, the proliferation, and replication indices, and these effects were dependent mostly on soluble factors. In the co-cultures of activated CD4+ T-cells with HD/ASCs and AS/ASCs significant increases of kynurenines, PGE-2, and IL-1Ra, but not IL-10, production were observed. The release of these factors was dependent either on cell-to-cell contact (IL-10, IL-1Ra) or soluble factors (kynurenines, PGE-2). There was a moderate to strong negative correlation between T-cell proliferative response, and the concentrations of kynurenines, PGE-2, and IL-10, but not IL-1Ra. This association was more evident in the case of TI-treated AS/ASCs than HD/ASCs.

Conclusions: AS/ASCs, similar to HD/ASCs, exert a direct effective anti-proliferative impact on CD4+ T cells, acting via soluble factors that are released in cell contact-dependent (IL-10) and independent (kynurenines, PGE-2) pathways. Thus, our results suggest that AS/ASCs are potentially useful for therapeutic application.

Keywords: T-cell proliferation; adipose-derived mesenchymal stem cells; ankylosing spondylitis; kynurenines.