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STAT-1 decoy oligonucleotide improves microcirculation and reduces acute rejection in allogeneic rat small bowel transplants

Gene Therapy volume 14, pages 883–890 (2007)Cite this article

Abstract

During acute rejection leukocyte–endothelial cell interaction fuelled by costimulatory molecules such as the CD40/CD154 receptor/ligand dyad disrupts microcirculation of the small bowel. Downregulating endothelial CD40 expression by employing a decoy oligonucleotide (dODN) neutralizing the transcription factor signal transducer and activator of transcription-1 (STAT-1) may protect the graft. Therefore allogenic small bowel transplantation was performed in the Brown Norway to Lewis rat model. Graft vessels were pretreated with STAT-1 dODN, mutant control ODN (20 μ M) or vehicle (n=8). CD40 antisense ODN and scrambled control ODN-treated transplants served as target control (n=3 each). Intravital microscopy, histology, immunohistochemistry and Western blot analyses were performed 7 days later. Functional capillary density, red blood cell velocity and perfusion index in STAT-1 dODN and CD40 antisense ODN-treated transplants were improved whereas stasis index was reduced. Leukocyte–endothelial cell interaction showed no difference. Histological parameters of rejection, infiltrating CD3-positive cells and apoptotic bodies were also reduced in STAT-1 dODN and CD40 antisense ODN-treated transplants 7 days post-transplantation. CD40 protein abundance was reduced to less than 10% of control in STAT-1 dODN-treated grafts. STAT-1 dODN blockade of CD40 expression improves mucosal perfusion, reduces graft rejection, T-cell infiltration and apoptosis in rat small bowel allografts during acute rejection.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (SFB 405 project B17). The expert technical assistance of Annette Bennemann is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Heart, Thoracic and Vascular Surgery, University Hospital Göttingen, Germany

    T Stojanovic & I Lautenschläger

  2. Institute of Physiology and Pathophysiology, University Hospital Heidelberg, Heidelberg, Germany

    L Scheele, A H Wagner & M Hecker

  3. Department of Pathology, University Hospital Göttingen, Göttingen, Germany

    P Middel

  4. Department of Urology, University Hospital Heidelberg, Heidelberg, Germany

    J Bedke

  5. Novosom AG, Halle, Germany

    I Leister

  6. Department of General Surgery, University Hospital Göttingen, Göttingen, Germany

    S Panzner

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  1. T Stojanovic
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  2. L Scheele
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Correspondence to T Stojanovic.

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Stojanovic, T., Scheele, L., Wagner, A. et al. STAT-1 decoy oligonucleotide improves microcirculation and reduces acute rejection in allogeneic rat small bowel transplants. Gene Ther 14, 883–890 (2007). https://doi.org/10.1038/sj.gt.3302931

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