mTOR Inhibitor Everolimus in Regulatory T Cell Expansion for Clinical Application in Transplantation.

Autor:	Gedaly R; Transplant Division, Department of Surgery, University of Kentucky, College of Medicine, Lexington, KY., De Stefano F; Transplant Division, Department of Surgery, University of Kentucky, College of Medicine, Lexington, KY., Turcios L; Transplant Division, Department of Surgery, University of Kentucky, College of Medicine, Lexington, KY., Hill M; Department of Pathology and Laboratory Medicine, University of Kentucky, College of Medicine, Lexington, KY., Hidalgo G; Department of Pathology and Laboratory Medicine, University of Kentucky, College of Medicine, Lexington, KY., Mitov MI; Redox Metabolism (RM) Shared Resource Facility (SRF), Markey Cancer Center, University of Kentucky, College of Medicine, Lexington, KY.; Idaho College of Osteopathic Medicine (ICOM), Meridian, ID., Alstott MC; Redox Metabolism (RM) Shared Resource Facility (SRF), Markey Cancer Center, University of Kentucky, College of Medicine, Lexington, KY., Butterfield DA; Redox Metabolism (RM) Shared Resource Facility (SRF), Markey Cancer Center, University of Kentucky, College of Medicine, Lexington, KY.; Department of Chemistry, University of Kentucky, College of Medicine, Lexington, KY., Mitchell HC; Transplant Division, Department of Surgery, University of Kentucky, College of Medicine, Lexington, KY.; Asbury University, Wilmore, KY., Hart J; Department of Pathology and Laboratory Medicine, University of Kentucky, College of Medicine, Lexington, KY., Al-Attar A; Department of Pathology and Laboratory Medicine, University of Kentucky, College of Medicine, Lexington, KY., Jennings CD; Department of Pathology and Laboratory Medicine, University of Kentucky, College of Medicine, Lexington, KY., Marti F; Transplant Division, Department of Surgery, University of Kentucky, College of Medicine, Lexington, KY.
Jazyk:	angličtina
Zdroj:	Transplantation [Transplantation] 2019 Apr; Vol. 103 (4), pp. 705-715.
DOI:	10.1097/TP.0000000000002495
Abstrakt:	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.
Databáze:	MEDLINE
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