title: Discontinuation of calcineurin inhibitors treatment allows the development of FOXP3+ regulatory T-cells in patients after kidney transplantation.
abstract: This study investigated specific gene expression profiles in patients with donor-specific cytotoxic-hyporesponsiveness, reflected by cytotoxic T-lymphocyte precursor frequency (CTLpf). The effect of calcineurin inhibitor (CNI) withdrawal was studied on markers for cytotoxicity (perforin, granzyme B), apoptosis (Fas,FasL), Th1 and Th2 cytokines (IL-2, IL-10), Th1 and Th2 transcription factors (T-bet, GATA 3), Th17 transcription factor and cytokine (RORγt, IL-17), and for immune regulation/activation (CD25, FOXP3). Peripheral blood samples from renal allograft recipients (n = 18) more than two yr after transplantation with stable renal function were analyzed before and four months after CNI withdrawal. Additionally, systolic and diastolic blood pressure, cholesterol, serum creatinine and proteinuria were evaluated, and no significant differences were measured before and after CNI withdrawal. However, CNIs' discontinuation influenced peripheral gene expression profiles. After CNI withdrawal, the mRNA expression of Granzyme B, Perforin, Fas, FasL, T-bet, GATA3 and CD25 were significantly lower than during CNI treatment. After CNI discontinuation, donor-specific CTLpf decreased, while FOXP3 expression discriminated between detectable and non-detectable donor-specific cytolysis reactivity; FOXP3 transcript values were highest in absence of donor-specific cytotoxicity (p < 0.01). Our study shows CNI withdrawal in stable kidney transplant recipients two yr after transplantation is safe. Moreover, discontinuation of CNIs' treatment allows FOXP3+ regulatory T-cells development, resulting in a significant decrease of anti-donor immune reactivity.
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: van de Wetering
authors.forename: Periklis
authors.initials: P
authors.lastname: Koumoutsakos
authors.forename: Annemiek
authors.initials: A
authors.lastname: Peeters
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: van der Mast
authors.forename: Petronella
authors.initials: P
authors.lastname: de Kuiper
authors.forename: Jan N M
authors.initials: JN
authors.lastname: IJzermans
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
mesh_terms: D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016559:Tacrolimus / Q000627:therapeutic use; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D065095:Calcineurin Inhibitors; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D016572:Cyclosporine; D016559:Tacrolimus