STAT-1 and AP-1 decoy oligonucleotide therapy delays acute rejection and prolongs cardiac allograft survival

• Published in: Cardiovascular research Vol. 71; no. 3; pp. 527 - 536
• Main Authors: HÖLSCHERMANN, Hans, STADLBAUER, Thomas H. W, WAGNER, Andreas H, FINGERHUTH, Horst, MUTH, Heidrun, SONG RONG, GÜLER, Faikah, TILLMANNS, Harald, HECKER, Markus
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-08-2006
• Subjects: Acute Disease; Animals; Biological and medical sciences; Blotting, Western; Cardiology. Vascular system; Genetic Therapy - methods; Graft Rejection - immunology; Graft Rejection - metabolism; Graft Rejection - pathology; Graft Rejection - prevention & control; Graft Survival; Heart Transplantation - immunology; Immunoenzyme Techniques; Intercellular Adhesion Molecule-1 - metabolism; Leukocytes, Mononuclear - pathology; Male; Medical sciences; Myocardium - metabolism; Oligonucleotides - genetics; Rats; Rats, Inbred Lew; Rats, Wistar; STAT1 Transcription Factor - genetics; Transcription Factor AP-1 - genetics; Vascular Cell Adhesion Molecule-1 - metabolism; Heart; Graft(material); Prognosis; Leukocyte; Acute; Transplantation; Endothelial function; Leukocytes; Homotransplantation; Macrophages; Survival; Delay; Rejection; Transcription factor STAT1; Treatment; Surgery; Graft; Oligonucleotide; Circulatory system; Cardiology; Gene therapy; Macrophage; Prolonged
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1016/j.cardiores.2006.05.021

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.
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.
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.
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.