title: Donor-specific cytotoxic hyporesponsiveness associated with high interleukin-10 messenger RNA expression in cardiac allograft patients.
abstract: BACKGROUND
  After transplantation, CD4+CD25+FOXP3+ and interleukin (IL) 10-producing regulatory cells might regulate immune responses toward donor antigens. In this study, we determined whether cardiac allograft recipients show donor-specific hyporesponsiveness and studied the underlying mechanisms.
  
  
  METHODS
  We analyzed the donor-specific T-cell responses by mixed lymphocyte reactions and limiting dilution assays to define whether cardiac allograft recipients (n = 21) show proliferative and cytotoxic hyporesponsiveness to donor antigens long after transplantation (range, 1.5-7 years). The mechanisms controlling immune responses, that is, FOXP3+/GITR+ T cells, and IL-10-producing cells, were studied by quantitative real-time polymerase chain reaction.
  
  
  RESULTS
  In the presence of a proliferative response to donor antigens, no cytotoxic responsiveness could be measured in a number of patients in the absence (73%) and presence of exogenous IL-2 (29%), IL-15 (31%), and IL-15 plus IL2Ralpha blockade (88%). Overall, the cytotoxic response to donor cells was significantly lower than the reactivity to third-party cells after the addition of IL-2 (p = 0.004) and IL-15 plus IL2Ralpha blockade (p < 0.001). After donor stimulation, the peripheral blood mononuclear cells expressed higher messenger RNA (mRNA) levels of IL-10, but not of FOXP3 or GITR, than after third-party stimulation (p = 0.003). Moreover, the IL-10 mRNA expression was inversely correlated with the donor-specific cytotoxic responsiveness (p = 0.01).
  
  
  CONCLUSIONS
  A significant proportion of patients showed donor-specific cytotoxic hyporesponsiveness long after heart transplantation, which was associated with high mRNA levels of IL-10 but not of FOXP3 or GITR. This observation suggests that IL-10-producing cells participate in the donor-specific cytotoxic hyporeactivity.
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, 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: Aggie H M M
authors.initials: AH
authors.lastname: Balk
authors.forename: Sander S
authors.initials: SS
authors.lastname: Korevaar
authors.forename: Alex P W M
authors.initials: AP
authors.lastname: Maat
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
mesh_terms: D005260:Female; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000276:immunology*; D014019:Tissue Donors
chemical_list: D012333:RNA, Messenger; D016753:Interleukin-10