Journal
ONCOTARGET
Volume 8, Issue 62, Pages 104733-104744Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10914
Keywords
human regulatory I cells; FOXP3; cell therapy; autoimmunity; GVH
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Funding
- Institut National de Ia Santa et de Ia Recherche Medicate
- Centre d'Investigation Biologiques (C.I.B.) Pitie-Salpetriere
- European Union (ATTACK project) [LHS-CT-2005-018914]
- Association Lupus France
- la Societe Nationale Francaise de Medecine Interne
- ARTHRITIS Fondation Courtin
- Grants-in-Aid for Scientific Research [16H06295] Funding Source: KAKEN
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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(+) naive 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.
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