Copyright © 2006, European Society of Cardiology
STAT-1 and AP-1 decoy oligonucleotide therapy delays acute rejection and prolongs cardiac allograft survival
aUniversity Hospital Giessen, Department of Internal Medicine, Division of Cardiology, Giessen, Germany
bUniversity Hospital Heidelberg, Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, Im Neuenheimer Feld 326, D-69120 Heidelberg, Germany
cHannover Medical School, Department of Medicine, Division of Nephrology, Hannover, Germany
* Corresponding author. Tel.: +49 6221 544035; fax: +49 641 6221 544038. Email address: hecker{at}physiologie.uni-hd.de
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 µmol/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.
Conclusion 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.
KEYWORDS Endothelial function; Gene therapy; Leukocytes; Macrophages; Transplantation
1 Both authors contributed equally to this work.
Time for primary review 27 days
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