title: Thymus-Derived Regulatory T Cells Infiltrate the Cardiac Allograft Before Rejection.
abstract: BACKGROUND
  FOXP3+ regulatory T cells (Treg) either originate in the thymus (natural [n]Treg) or are induced in the periphery by antigen exposure and cytokines (induced [i]Treg). It is currently not elucidated which and to what extent these Treg subsets regulate intracardiac allogeneic responses in transplant patients.
  
  
  METHODS
  By using demethylation of the Treg-specific demethylated region in the FOXP3 gene as a marker for nTreg and FOXP3 messenger RNA expression as a marker for the total Treg population, we examined Treg in endomyocardial biopsies (EMBs) of both patients who developed an acute rejection necessitating therapy (rejectors; International Society for Heart and Lung Transplantation rejection grade ≥ 2R) and patients who remained free from rejection (nonrejectors).
  
  
  RESULTS
  In the presence of comparable messenger RNA levels of CD3, IL-10, TGFβ, IL2, IFNγ, and IL17A, the percentage of nTreg was significantly higher in EMB with histological signs of mild rejection (rejection grade 1R) collected before rejection than in 1R EMB of nonrejectors. The total Treg population was comparable in 1R EMB of nonrejectors and 1R EMB collected before rejection, which suggests the presence of iTreg in the EMB of nonrejectors. The relative high percentage of nTreg after rejection was not related to the number of rejections, whereas the total Treg population was inversely related to the number of rejections the first year after transplantation.
  
  
  CONCLUSIONS
  Our data indicate that intragraft nTreg are unable to restrain alloreactivity leading to rejection. Moreover, the indirect evidence of the presence of intragraft iTreg suggests a possible role of iTreg in the regulation of alloreactivity.
authors.affiliation: 1 Section Nephrology and Transplantation, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. 2 Department of Cardiology, Erasmus University Medical Center, Rotterdam, The Netherlands. 3 Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands. 4 Division of Gastroenterology and Nutrition, Department of Pediatrics, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands. 5 Department of Thoracic Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Karin
authors.initials: K
authors.lastname: Boer
authors.forename: Kadir
authors.initials: K
authors.lastname: Caliskan
authors.forename: Annemiek M A
authors.initials: AM
authors.lastname: Peeters
authors.forename: Marian C
authors.initials: MC
authors.lastname: van Groningen
authors.forename: Janneke N
authors.initials: JN
authors.lastname: Samsom
authors.forename: Alexander P W M
authors.initials: AP
authors.lastname: Maat
authors.forename: Michiel G H
authors.initials: MG
authors.lastname: Betjes
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D001706:Biopsy; D002634:Chemotaxis, Leukocyte; D019175:DNA Methylation; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D005819:Genetic Markers; D006084:Graft Rejection / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D060168:Thymocytes / Q000276:immunology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D005819:Genetic Markers; D007166:Immunosuppressive Agents; D012333:RNA, Messenger