title: Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells.
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.
authors.affiliation: Immunoregulation Laboratory, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, UK cristiano.scotta@kcl.ac.uk.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Scottà
authors.affiliation: Immunoregulation Laboratory, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, UK.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Fanelli
authors.affiliation: Immunoregulation Laboratory, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, UK.
authors.forename: Sec Julie
authors.initials: SJ
authors.lastname: Hoong
authors.affiliation: 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.
authors.forename: Marco
authors.initials: M
authors.lastname: Romano
authors.affiliation: Immunoregulation Laboratory, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, UK.
authors.forename: Estefania Nova
authors.initials: EN
authors.lastname: Lamperti
authors.affiliation: Immunoregulation Laboratory, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, UK.
authors.forename: Mitalee
authors.initials: M
authors.lastname: Sukthankar
authors.affiliation: Dipartimento di Biopatologia e Biotecnologie Mediche, University of Palermo, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Guggino
authors.affiliation: Immunoregulation Laboratory, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, UK.
authors.forename: Henrieta
authors.initials: H
authors.lastname: Fazekasova
authors.affiliation: Immunoregulation Laboratory, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, UK.
authors.forename: Kulachelvy
authors.initials: K
authors.lastname: Ratnasothy
authors.affiliation: Immunoregulation Laboratory, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, UK.
authors.forename: Pablo D
authors.initials: PD
authors.lastname: Becker
authors.affiliation: 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.
authors.forename: Behdad
authors.initials: B
authors.lastname: Afzali
authors.affiliation: Immunoregulation Laboratory, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, UK.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Lechler
authors.affiliation: Immunoregulation Laboratory, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, UK.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lombardi
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019707:Receptors, Chemokine / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C508609:IL10 protein, human; D007166:Immunosuppressive Agents; D019707:Receptors, Chemokine; D016753:Interleukin-10