Combination of IL-2, rapamycin, DNA methyltransferase and histone deacetylase inhibitors for the expansion of human regulatory T cells - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Oncotarget Year : 2017

Combination of IL-2, rapamycin, DNA methyltransferase and histone deacetylase inhibitors for the expansion of human regulatory T cells

Abstract

FOXP3+ regulatory T cell (Treg) based cellular therapies represent promising therapeutic options in autoimmunity, allergy, transplantation and prevention of Graft Versus Host (GVH) Disease. Among human FOXP3-expressing CD4+T cells, only the CD45RA+ naïve Treg (nTreg) subset is suitable for in vitro expansion. However, FoxP3 expression decays in cells using currently described culture protocols. Rapamycin alone was not able to prevent FOXP3 loss in nTregs cells, as only a half of them maintained FOXP3 expression after 14 days of culture. In contrast we report a novel combined drug regimen that can drastically stabilize FOXP3 expression in cultured Tregs. IL-2, rapamycin, histone deacetylase and DNA methyltransferase inhibitors act in synergy to allow expansion of human regulatory T cells with sustained high expression of FOXP3 and CD15s with potent suppressive capacities in vitro and control of murine xeno-GVH reactions. Of note, an additional subsequent infusion of expanded nTreg cells did not improve survival of mice. Combination of IL-2, rapamycin, histone deacetylase and DNA methyltransferase inhibitors is optimal for the expansion in vitro of pure effective nTreg maintaining high levels of FOXP3 for therapeutic purposes.

Domains

Immunology
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Dates and versions

inserm-02368584 , version 1 (18-11-2019)

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Makoto Miyara, Driss Chader, Aude Burlion, Jérémie D. Goldstein, Delphine Sterlin, et al.. Combination of IL-2, rapamycin, DNA methyltransferase and histone deacetylase inhibitors for the expansion of human regulatory T cells. Oncotarget, 2017, 8 (62), pp.104733-104744. ⟨10.18632/oncotarget.10914⟩. ⟨inserm-02368584⟩
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