Clinical‐grade preparation of human natural regulatory T‐cells encoding the thymidine kinase suicide gene as a safety gene

Guillot-Delost, Maude; Cheraï, Mustapha; Hamel, Yamina; Rosenzwajg, Michèlle; Baillou, Claude; Simonin, Ghislaine; Leclercq, Virginie; Mariotti‐Ferrandiz, Encarnita; Six, Adrien; Bon-Durand, Véronique; Maury, Sébastien; Salomon, Benoı̂t L.; Cohen, José L.; Klatzmann, David; Lemoine, François M.

doi:10.1002/jgm.1220

Cited by 21 publications

(24 citation statements)

References 45 publications

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“…(ii) control GVHD (Cohen, Boyer et al 1997;Cohen, Saron et al 2000;Cohen, Boyer et al 2001). Clinical protocol associated with injection of regulatory T cells expressing the TK gene as a safety gene to control GVHD are under assessment (Guillot-Delost, Cherai et al 2008). Applied upon an allograft this treatment allows delayed rejection (skin graft) or tolerance of the graft (vascularized heart allograft) (Braunberger, Cohen et al 2000;Braunberger, RaynalRaschilas et al 2000;Thomas-Vaslin, Bellier et al 2000).…”

Section: Specific Transient Depletion Of Dividing T Cells To Control mentioning

confidence: 99%

Immunodepression and Immunosuppression During Aging

Thomas‐Vaslin¹,

Six²,

Pham³

et al. 2012

Immunosuppression - Role in Health and Diseases

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Section: Specific Transient Depletion Of Dividing T Cells To Control mentioning

confidence: 99%

Immunodepression and Immunosuppression During Aging

Thomas‐Vaslin¹,

Six²,

Pham³

et al. 2012

Immunosuppression - Role in Health and Diseases

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“…5 Protocols for the expansion of human FOXP3 + Treg cells performed under conditions of good manufacturing practice (GMP) have been shown to be feasible. 3,[6][7][8] Importantly, these culture conditions are also highly advantageous for the expansion of effector CD25 + T cells, which may contaminate the starting peripheral FOXP3 + Treg cells. This obstacle can be bypassed by: (i) the use of cord blood Treg cells, 4 (ii) isolation of very pure peripheral Treg cells through flow-based cell sorters 3,9,10 or (iii) the addition of rapamycin to the culture, which preferentially inhibits proliferation of effector T cells while sparing Treg cells.…”

Section: Introductionmentioning

confidence: 99%

Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells

Tresoldi¹,

Dell’Albani²,

Stabilini³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundThe clinical use of ex vivo-expanded T-regulatory cells for the treatment of T-cell-mediated diseases has gained increasing momentum. However, the recent demonstration that FOXP3 + Tregulatory cells may contain interleukin-17-producing cells and that they can convert into effector cells once transferred in vivo raises significant doubts about their safety. We previously showed that rapamycin permits the ex vivo expansion of FOXP3 + T-regulatory cells while impairing the proliferation of non-T-regulatory cells. Here we investigated the Th17-cell content and the in vivo stability of rapamycin-expanded T-regulatory cells as pertinent aspects of cell-based therapy. Design and MethodsT-regulatory-enriched cells were isolated from healthy volunteers and were expanded ex vivo with rapamycin with a pre-clinical applicable protocol. T-regulatory cells cultured with and without rapamycin were compared for their regulatory activity, content of pro-inflammatory cells and stability. ResultsWe found that CD4+ T cells (i.e., precursor/committed Th17 cells) contaminate the T-regulatory cells cultured ex vivo in the absence of rapamycin. In addition, Th17 cells do not expand when rapamycin-treated T-regulatory cells are exposed to a "Th17-favorable" environment. Rapamycin-expanded T-regulatory cells maintain their in vitro regulatory phenotype even after in vivo transfer into immunodeficient NOD-SCID mice despite being exposed to the irradiation-induced pro-inflammatory environment. Importantly, no additional rapamycin treatment, either in vitro or in vivo, is required to keep their phenotype fixed. ConclusionsThese data demonstrate that rapamycin secures ex vivo-expanded human T-regulatory cells and provide additional justification for their clinical use in future cell therapy-based trials.Key words: T-regulatory cells, ex vivo expansion, rapamycin, cell therapy, T-regulatory-cell stability. + T regulatory cells. Haematologica 2011;96(9):1357-1365

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“…These results are not novel because we have previously demonstrated that rapamycin selectively blocks the in vitro expansion of human CD4 + CD25 − conventional T cells, while allowing nTreg growth [3,5]. In addition, the finding that rapamycin-expanded nTreg retain a broad T cell receptor (TCR) repertoire shown by Guillot-Delost et al [1] was also reported in our previous publications [5,8]. Finally, the authors state that 'Although several strategies that combined stimulation of TCR, CD28 and IL-2R have been developed for long-term culture and polyclonal expansion of nTreg in recent years [9][10][11], none of them were efficient enough to generate large numbers of nTreg'.…”

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confidence: 69%