Comparative Study of Immunomodulatory Agents to Induce Human T Regulatory (Treg) Cells: Preferential Treg-Stimulatory Ef
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ORIGINAL ARTICLE
Comparative Study of Immunomodulatory Agents to Induce Human T Regulatory (Treg) Cells: Preferential Treg‑Stimulatory Effect of Prednisolone and Rapamycin Michał Janyst1,3 · Beata Kaleta2 · Karolina Janyst1,3 · Radosław Zagożdżon2 · Ewa Kozlowska4 · Witold Lasek1 Received: 30 May 2019 / Accepted: 18 May 2020 © The Author(s) 2020
Abstract T regulatory (Treg) cells play a critical role in the maintenance of self-tolerance, as well as in inhibition of inflammation and exaggerated immune response against exogenous antigens. They develop in the thymus (tTreg cells) but also may be generated at the peripheral tissues, including tumor microenvironment (pTreg cells), or induced in vitro in the presence of transforming growth factor (TGF)-β (iTreg cells). Since tTreg cells constitute a minor fraction of peripheral blood lymphocytes in physiological conditions, an alternative way to obtain high number of functional Treg cells for therapeutic purposes is their generation in vitro from conventional T cells. In our studies, we compared effectiveness of several pharmacological agents with suggested immunomodulatory effects on Treg development (rapamycin, prednisolone, inosine pranobex, glatiramer acetate, sodium butyrate, and atorvastatin) to optimize Treg-inducing protocols. All but one (atorvastatin) immunomodulators augmented induction of polyclonal Treg cells in cultures. They were effective both in increasing the number of CD4+CD25highFoxp3high cells and Foxp3 expression. Rapamycin and prednisolone were found the most effective. Both drugs prolonged also phenotypic stability of Treg cells and induced fully active Treg cells in a functional assay. In the assay, prednisolone appeared superior versus rapamycin. The results, on the one hand, may be helpful in planning optimal protocols for generation of Treg cells for clinical application and, on the other hand, shed some light on mechanisms of the immunomodulatory activity of some tested agents observed in vivo. Keywords Treg cells · Prednisolone · Rapamycin · Glatiramer acetate · Inosine pranobex · Atorvastatin
Introduction T regulatory (Treg) cells are a fraction of C D4+ T lymphocytes responsible for suppression of immune response (Sakaguchi et al. 2008). Their number is low in neonates but in adults, probably due to immunomodulatory effects of environmental factors, percentage of Tregs is increased * Witold Lasek [email protected] 1
Department of Immunology, Centre of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
2
Department of Clinical Immunology, Medical University of Warsaw, Warsaw, Poland
3
Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
4
Department of Immunology, Faculty of Biology, University of Warsaw, Warsaw, Poland
(Zahran et al. 2019). Although Treg cells constitute minority of C D4+ T lymphocytes in blood, these cells play a crucial role in maintaining homeostasis of the immune system (Whibley et al. 2019). Their functions include: prev
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