Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells
Authors: Estefania Nova Lamperti
Giuliana Guggino
Pablo D Becker
Henrieta Fazekasova
Sec Julie Hoong
Kulachelvy Ratnasothy
Giorgia Fanelli
Mitalee Sukthankar
Marco Romano
Giovanna Lombardi
Cristiano Scottà
Robert I Lechler
Behdad Afzali
Journal: Haematologica (2016)
Discipline: CLINICAL MEDICINE
Keywords: Immunosuppressive drugs; transplantation tolerance; adoptive cell therapy; Tregs; tacrolimus
Affiliations: Immunoregulation Laboratory, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, UK ., Immunoregulation Laboratory, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, UK., Immunoregulation Laboratory, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, UK Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. & A. Seràgnoli", University of Bologna, Italy., Dipartimento di Biopatologia e Biotecnologie Mediche, University of Palermo, Italy., Immunoregulation Laboratory, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, UK Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institutes of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.

Abstract:  Immunosuppressive drugs in clinical transplantation are necessary to inhibit the immune response to donor antigens. Although they are effective in controlling acute rejection, they do not prevent long-term transplant loss from chronic rejection. In addition, immunosuppressive drugs have adverse side effects, including increased rate of infections and malignancies. Adoptive cell therapy with human Tregs represents a promising strategy for the induction of transplantation tolerance. Phase I/II clinical trials in transplanted patients are already underway, involving the infusion of Tregs alongside concurrent immunosuppressive drugs. However, it remains to be determined whether the presence of immunosuppressive drugs negatively impacts Treg function and stability. We tested in vitro and in vivo the effects of tacrolimus, mycophenolate and methylprednisolone (major ISDs used in transplantation) on ex vivo expanded, rapamycin-treated human Tregs. The in vitro results showed that these drugs had no effect on phenotype, function and stability of Tregs, although tacrolimus affected the expression of chemokine receptors and IL-10 production. However, viability and proliferative capacity were reduced in a dose-dependent manner by all the three drugs. The in vivo experiments using a humanized mouse model confirmed the in vitro results. However, treatment of mice with only rapamycin maintained the viability, function and proliferative ability of adoptively transferred Tregs. Taken together, our results suggest that the key functions of ex vivo expanded Tregs are not affected by a concurrent immunosuppressive therapy. However, the choice of the drug combination and their timing and dosing should be considered as an essential component to induce and maintain tolerance by Treg. 

Retracted: No

PubPeer comments:
 FACS images in Fig.3B (red boxes) were exactly the same. Could authors re-check the original data? ![file] , 
 Immunoblotting images of P53 and actin in Fig.4 reappeared in Fig.6. ![file] , 
 #1 Dear Cicindela Chrysippe, Thank you for your comments on this paper. We have carefully checked our original data, and confirmed that it was a mistake due to copy-and-paste error. We have revised the Fig. 3B (see below). The editorial office of Gynecologic Oncology has approved our correction request and published an online corrigendum soon. Thank you for your comment again. , 
 #2 Dear Cicindela Chrysippe, Thank you for your comments on this paper. The authors have carefully checked our original data, and confirmed that the immunobloting images in Fig. 4 was reused in Fig. 6 by mistake. We have revised the Fig. 6 (see below). The editorial office of Gynecologic Oncology has approved our erratum request and published an online corrigendum. Thank you for your comment again. ,