title: Intragraft FOXP3 mRNA expression reflects antidonor immune reactivity in cardiac allograft patients.
abstract: BACKGROUND
  Regulatory FOXP3+ T cells control immune responses of effector T cells. However, whether these cells regulate antidonor responses in the graft of cardiac allograft patients is unknown. Therefore, we analyzed the gene expression profiles of regulatory and effector T-cell markers during immunological quiescence and acute rejection.
  
  
  METHODS
  Quantitative real-time polymerase chain reaction was used to analyze mRNA expression levels in time-zero specimens (n=24) and endomyocardial biopsies (EMB; n=72) of cardiac allograft patients who remained free from rejection (nonrejectors; n=12) and patients with at least one histologically proven acute rejection episode (rejectors; International Society for Heart and Lung Transplantation [ISHLT] rejection grade>2; n=12).
  
  
  RESULTS
  For all analyzed regulatory and effector T-cell markers, mRNA expression levels were increased in biopsies taken after heart transplantation compared with those in time-zero specimens. Posttransplantation, the FOXP3 mRNA levels were higher in EMB assigned to a higher ISHLT rejection grade than the biopsies with grade 0: the highest mRNA levels were detected in the rejection biopsies (rejection grade>2; P=0.003). In addition, the mRNA levels of CD25, glucocorticoid-induced TNF receptor family-related gene, cytotoxic T lymphocyte-associated antigen 4, interleukin-2, and granzyme B were also significantly higher in rejecting EMB than in nonrejecting EMB (rejection grade<or=2). This increase in expression levels in relation to the histological rejection grade was only observed in patients who developed an acute rejection episode; the mRNA levels of nonrejectors remained stable irrespective of ISHLT rejection grade.
  
  
  CONCLUSIONS
  These observations suggest that, after clinical heart transplantation, FOXP3+ T cells do not prevent acute rejection, but rather are a response to antidonor effector T-cell activity.
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands. i.dijke@erasmusmc.nl
authors.forename: I Esmé
authors.initials: IE
authors.lastname: Dijke
authors.forename: Jurjen H L
authors.initials: JH
authors.lastname: Velthuis
authors.forename: Kadir
authors.initials: K
authors.lastname: Caliskan
authors.forename: Sander S
authors.initials: SS
authors.lastname: Korevaar
authors.forename: Alex P W M
authors.initials: AP
authors.lastname: Maat
authors.forename: Pieter E
authors.initials: PE
authors.lastname: Zondervan
authors.forename: Aggie H M M
authors.initials: AH
authors.lastname: Balk
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; D015703:Antigens, CD / Q000235:genetics; D000943:Antigens, Differentiation / Q000235:genetics; D060908:CTLA-4 Antigen; D004699:Endocardium / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015870:Gene Expression; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000235:genetics; D006084:Graft Rejection / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053804:Granzymes / Q000235:genetics; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D011184:Postoperative Period; D012333:RNA, Messenger / Q000378:metabolism*; D012720:Severity of Illness Index; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger; D053804:Granzymes