title: STAT-1 and AP-1 decoy oligonucleotide therapy delays acute rejection and prolongs cardiac allograft survival.
abstract: OBJECTIVE
  Acute myocardial rejection is a cell-mediated process characterized by increased leukocyte recruitment into the graft myocardial tissue. Transcription factors like STAT-1 and AP-1 are critically involved in this process by regulating vascular adhesion molecule expression. The aim of our study was to investigate the effect of decoy oligodeoxynucleotide (dODN) treatment targeting transcription factors AP-1 and STAT-1 on acute cardiac allograft rejection in a rat transplant model.
  
  
  METHODS
  Wistar-Furth (WF) cardiac allografts were transplanted into Lewis (LEW) rats after perfusion with STAT-1 or AP-1 dODN solution (5 micromol/l), buffer or the corresponding mutant control ODNs. Grafts were harvested and processed for histologic and immunohistochemical evaluation.
  
  
  RESULTS
  As demonstrated by fluorescence dye-labelled dODN, exposure of the grafts to the dODNs during 45 min of warm ischemia resulted in a dominant uptake of naked DNA by the graft endothelium. Treatment with AP-1 and STAT-1 dODNs, but not with vehicle or the control dODNs, significantly prolonged cardiac allograft survival by approximately 40% from 5.6+/-0.5 days to 7.8+/-1.3 days and 7.4+/-0.5 days, respectively (mean+/-S.D., p<0.01, n=5 in each group). Immunohistochemical examination on days 1, 3 and 6 revealed a marked reduction of infiltrating leukocytes (AP-1 dODN: 85%, STAT-1 dODN: 50%), namely T-cells, in the dODN-perfused grafts at day 3 post transplantation. In addition, as demonstrated by immunohistochemical analysis, endothelial expression of ICAM-1 and VCAM-1 was found to be markedly reduced in dODN-treated grafts.
  
  
  CONCLUSIONS
  Both AP-1 and STAT-1 dODN treatments suppress graft endothelial adhesion molecule expression, reduce graft infiltration and in turn significantly delay acute rejection. The utilization of dODNs in the cardioplegic solution might be a novel strategy to protect transplanted organs from early damage during transplantation, to preserve organ function and bridge the critical phase after transplantation when standard immunosuppression is not yet completely effective.
authors.affiliation: University Hospital Giessen, Department of Internal Medicine, Division of Cardiology, Giessen, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Hölschermann
authors.forename: Thomas H W
authors.initials: TH
authors.lastname: Stadlbauer
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Wagner
authors.forename: Horst
authors.initials: H
authors.lastname: Fingerhuth
authors.forename: Heidrun
authors.initials: H
authors.lastname: Muth
authors.forename: Song
authors.initials: S
authors.lastname: Rong
authors.forename: Faikah
authors.initials: F
authors.lastname: Güler
authors.forename: Harald
authors.initials: H
authors.lastname: Tillmanns
authors.forename: Markus
authors.initials: M
authors.lastname: Hecker
mesh_terms: D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D015316:Genetic Therapy / Q000379:methods*; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology; D007124:Immunoenzyme Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D050794:STAT1 Transcription Factor / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000235:genetics*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D009841:Oligonucleotides; D050794:STAT1 Transcription Factor; D018808:Transcription Factor AP-1; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1