title: Variations in DNA methylation of interferon gamma and programmed death 1 in allograft rejection after kidney transplantation.
abstract: BACKGROUND
  The role of DNA methylation in the regulation of the anti-donor-directed immune response after organ transplantation is unknown. Here, we studied the methylation of two mediators of the immune response: the pro-inflammatory cytokineinterferon γ(IFNγ) and the inhibitory receptorprogrammed death 1(PD1) in naïve and memory CD8+ T cell subsets in kidney transplant recipients receiving immunosuppressive medication. Both recipients experiencing an episode of acute allograft rejection (rejectors) as well as recipients without rejection (non-rejectors) were included.
  
  
  RESULTS
  CpGs in the promoter regions of bothIFNγandPD1were significantly (p< 0.001) higher methylated in the naïve CD8+ T cells compared to the memory T cell subsets. The methylation status of bothIFNγandPD1inversely correlated with the percentage of IFNγ or PD1-producing cells. Before transplantation, the methylation status of bothIFNγandPD1was not significantly different from healthy donors. At 3 months after transplantation, irrespective of rejection and subsequent anti-rejection therapy, theIFNymethylation was significantly higher in the differentiated effector memory CD45RA+ (EMRA) CD8+ T cells (p= 0.01) whereas the PD1 methylation was significantly higher in all memory CD8+ T cell subsets (CD27+ memory;p= 0.02: CD27- memory;p= 0.02: EMRA;p= 0.002). Comparing the increase in methylation in the first 3 months after transplantation between rejectors and non-rejectors demonstrated a significantly more prominent increase in thePD1methylation in the CD27- memory CD8+ T cells in rejectors (increase in rejectors 14%, increase in non-rejectors 1.9%,p= 0.04). The increase in DNA methylation in the other memory CD8+ T cells was not significantly different between rejectors and non-rejectors. At 12 months after transplantation, the methylation of bothIFNγandPD1returned to baseline levels.
  
  
  CONCLUSIONS
  The DNA methylation of bothIFNγandPD1increases the first 3 months after transplantation in memory CD8+ T cells in kidney transplant recipients. This increase was irrespective of a rejection episode indicating that general factors of the kidney transplantation procedure, including the use of immunosuppressive medication, contribute to these variations in DNA methylation.
authors.affiliation: Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Room Na520, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Karin
authors.initials: K
authors.lastname: Boer
authors.affiliation: Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Room Na520, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: L Elly A
authors.initials: LE
authors.lastname: de Wit
authors.affiliation: Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Room Na520, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Fleur S
authors.initials: FS
authors.lastname: Peters
authors.affiliation: Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Room Na520, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Hesselink
authors.affiliation: Department of Internal Medicine, Section Endocrinology, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
authors.affiliation: Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Room Na520, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Michiel G H
authors.initials: MG
authors.lastname: Betjes
authors.affiliation: Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Caspar W N
authors.initials: CW
authors.lastname: Looman
authors.affiliation: Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Room Na520, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
mesh_terms: D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics* / Q000378:metabolism
chemical_list: C573415:IFNG protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma
keywords: Allograft rejection; CD8 T-cell subset; DNA methylation; IFNγ; Kidney transplant recipients; PD1