Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells
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Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells. / Tresoldi, Eleonora; Dell'Albani, Ilaria; Stabilini, Angela; Jofra, Tatiana; Valle, Andrea; Gagliani, Nicola; Bondanza, Attilio; Roncarolo, Maria Grazia; Battaglia, Manuela.
in: HAEMATOLOGICA, Jahrgang 96, Nr. 9, 09.2011, S. 1357-65.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells
AU - Tresoldi, Eleonora
AU - Dell'Albani, Ilaria
AU - Stabilini, Angela
AU - Jofra, Tatiana
AU - Valle, Andrea
AU - Gagliani, Nicola
AU - Bondanza, Attilio
AU - Roncarolo, Maria Grazia
AU - Battaglia, Manuela
PY - 2011/9
Y1 - 2011/9
N2 - BACKGROUND: The 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(+) T-regulatory 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 METHODS: T-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.RESULTS: We found that CD4(+)CCR6(+)CD161(+) 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.CONCLUSIONS: These 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.
AB - BACKGROUND: The 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(+) T-regulatory 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 METHODS: T-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.RESULTS: We found that CD4(+)CCR6(+)CD161(+) 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.CONCLUSIONS: These 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.
KW - Animals
KW - CD4 Antigens
KW - Cell Proliferation
KW - Cells, Cultured
KW - Cytokines
KW - Female
KW - Forkhead Transcription Factors
KW - Humans
KW - Immunophenotyping
KW - Interleukin-2 Receptor alpha Subunit
KW - Leukocytes, Mononuclear
KW - Mice
KW - Mice, Inbred NOD
KW - Mice, SCID
KW - Sirolimus
KW - T-Lymphocytes, Regulatory
KW - Th17 Cells
KW - Journal Article
U2 - 10.3324/haematol.2011.041483
DO - 10.3324/haematol.2011.041483
M3 - SCORING: Journal article
C2 - 21565906
VL - 96
SP - 1357
EP - 1365
JO - HAEMATOLOGICA
JF - HAEMATOLOGICA
SN - 0390-6078
IS - 9
ER -