mTOR Inhibitor Everolimus in Regulatory T Cell Expansion for Clinical Application in Transplantation.
Transplantation
; 103(4): 705-715, 2019 04.
Article
em En
| MEDLINE
| ID: mdl-30451741
ABSTRACT
BACKGROUND:
Experimental and preclinical evidence suggest that adoptive transfer of regulatory T (Treg) cells could be an appropriate therapeutic strategy to induce tolerance and improve graft survival in transplanted patients. The University of Kentucky Transplant Service Line is developing a novel phase I/II clinical trial with ex vivo expanded autologous Treg cells as an adoptive cellular therapy in renal transplant recipients who are using everolimus (EVR)-based immunosuppressive regimen.METHODS:
The aim of this study was to determine the mechanisms of action and efficacy of EVR for the development of functionally competent Treg cell-based adoptive immunotherapy in transplantation to integrate a common EVR-based regimen in vivo (in the patient) and ex vivo (in the expansion of autologous Treg cells). CD25 Treg cells were selected from leukapheresis product with a GMP-compliant cell separation system and placed in 5-day (short) or 21-day (long) culture with EVR or rapamycin (RAPA). Multi-parametric flow cytometry analyses were used to monitor the expansion rates, phenotype, autophagic flux, and suppressor function of the cells. phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway profiles of treated cells were analyzed by Western blot and cell bioenergetic parameters by extracellular flux analysis.RESULTS:
EVR-treated cells showed temporary slower growth, lower metabolic rates, and reduced phosphorylation of protein kinase B compared with RAPA-treated cells. In spite of these differences, the expansion rates, phenotype, and suppressor function of long-term Treg cells in culture with EVR were similar to those with RAPA.CONCLUSIONS:
Our results support the feasibility of EVR to expand functionally competent Treg cells for their clinical use.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transplante de Órgãos
/
Linfócitos T Reguladores
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Serina-Treonina Quinases TOR
/
Everolimo
/
Imunossupressores
Limite:
Humans
Idioma:
En
Revista:
Transplantation
Ano de publicação:
2019
Tipo de documento:
Article