STAT-1 decoy oligodeoxynucleotide inhibition of acute rejection in mouse heart transplants

2009 | journal article. A publication with affiliation to the University of Göttingen.

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​STAT-1 decoy oligodeoxynucleotide inhibition of acute rejection in mouse heart transplants​
Stojanovic, T.; Wagner, A. H.; Wang, S.; Kiss, E.; Rockstroh, N.; Bedke, J. & Groene, H.-J. et al.​ (2009) 
Basic Research in Cardiology104(6) pp. 719​-729​.​ DOI: https://doi.org/10.1007/s00395-009-0028-0 

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Authors
Stojanovic, Tomislav; Wagner, Andreas H.; Wang, S.; Kiss, Eva; Rockstroh, Nicolas; Bedke, Jens; Groene, Hermann-Josef; Hecker, Markus
Abstract
During acute rejection of cardiac transplants endothelial cell-leukocyte interaction fuelled by co-stimulatory molecules like CD40/CD154 may ultimately lead to graft loss. One key player in up-regulating the expression of such pro-inflammatory gene products is the interferon-gamma-dependent transcription factor STAT-1. Hence down-regulating interferon-gamma-stimulated pro-inflammatory gene expression in the graft endothelial cells by employing a decoy oligodeoxynucleotide (dODN) neutralising STAT-1 may protect the graft. To verify this hypothesis, heterotopic mouse heart transplantation was performed in the allogeneic B10.A(2R) to C57BL/6 and syngeneic C57BL/6 to C57BL/6 strain combination without immunosuppression. Graft vessels were pre-treated with STAT-1 dODN, mutant control ODN (10 mu M each) or vehicle (Ringer solution). Cellular rejection (vascular and interstitial component) was graded histologically and CD40, ICAM-1, VCAM-1, MCP-1, E-selectin and RANTES expression in the graft monitored by real time PCR 24 h and 9 days post-transplantation. Nine days after transplantation both rejection scores were significantly diminished by 85 and 70%, respectively, in STAT-1 dODN-treated allografts as compared to mutant control ODN-treated allografts. According to immunohistochemistry analysis, this was accompanied by a reduced infiltration of monocyte/macrophages and T cells into the graft myocardium. In addition, pro-inflammatory gene expression was strongly impaired by more than 80% in STAT-1 dODN-treated allografts 24 h post-transplantation but not in mutant control ODN or vehicle-treated allografts. This inhibitory effect on pro-inflammatory gene expression was no longer detectable 9 days post-transplantation. Single periprocedural treatment with a STAT-1 dODN thus effectively reduces cellular rejection in mouse heart allografts. This effect is associated both with an early decline in pro-inflammatory gene expression and a later drop in mononuclear cell infiltration.
Issue Date
2009
Status
published
Publisher
Springer
Journal
Basic Research in Cardiology 
ISSN
1435-1803; 0300-8428

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