gms | German Medical Science

129. Kongress der Deutschen Gesellschaft für Chirurgie

Deutsche Gesellschaft für Chirurgie

24.04. - 27.04.2012, Berlin

Spiegelmer based blockade of SDF1/CXCR4-interaction inhibits chronic transplant vasculopathy by inhibition of vascular smooth muscle cell proliferation

Meeting Abstract

  • Michael Thomas - Chirurgische Klinik und Poliklinik der LMU Muenchen, Klinikum Grosshadern, Chirurgische Klinik und Poliklinik, München
  • Aivars Kalnins - Klinikum Grosshadern, Chirurgie, München
  • Martin Andrassy - Universitätsklinikum Heidelberg, Innere Medizin III, Heidelberg
  • Anne Tischer - Klinikum Grosshadern, Chirurgie, München
  • Markus Rentsch - Klinikum Grosshadern, Chirurgie, München
  • Michael Fischereder - Klinikum Grosshadern, Medizinische Klinik I, München
  • Karl-Walter Jauch - Klinikum Grosshadern, Chirurgie, München
  • Markus Guba - Klinikum Grosshadern, Chirurgie, München
  • Joachim Andrassy - Klinikum Grosshadern, Chirurgie, München

Deutsche Gesellschaft für Chirurgie. 129. Kongress der Deutschen Gesellschaft für Chirurgie. Berlin, 24.-27.04.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. Doc12dgch151

DOI: 10.3205/12dgch151, URN: urn:nbn:de:0183-12dgch1517

Published: April 23, 2012

© 2012 Thomas et al.
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Outline

Text

Introduction: Chronic transplant vasculopathy remains one of the major obstacles in transplant medicine. Efficient therapeutic strategies are lacking. Recent studies suggest a crucial role of the chemokine SDF-1 on neointima formation. Spiegelmers are mirror-image oligonucleotides that are able to bind to a pharmacologically relevant target molecule in a manner conceptually similar to an antibody that recognizes an antigen. Here we investigate the potential therapeutical effect of spiegelmer induced SDF-1/CXCR4 blockade (NOX A12) on the development of chronic transplant vasculopathy.

Materials and methods: Murine models of heterotopic heart (H-2bm12 to B6) and aortic (C57 Bl6 to Balbc) transplantation were used to asses chronic allograft vasculopathy. The control group was treated with the non-functional spiegelmer POC and the treatment group was injected with the spiegelmer NOX A12 .

Grafts were explanted and (immuno)histological staining was performed in order to evaluate chronic transplant vasculopathy associated pathologies.

In vitro, vascular smooth muscle cells were isolated and cultured from thoracic aortas of Balbc mice and a BrdU proliferation assay was performed.

In addition Rt-PCR for TGF-beta and IL6 was conducted from heart grafts 4 weeks after transplantation.

Results: We could demonstrate that spiegelmer inhibition of SDF-1 led to a significant decrease in neointima formation if compared to the control group as measured by intima/media ratio in vivo (1,81±0,1211 vs 0,996±0,0956, p<0,0001).

In vitro treatment of primary vascular smooth muscle cells isolated from the thoracic aorta with NoxA12 led to a significant decrease in proliferation as measured by BrdU incorporation (p=0,042).

RT-PCR data of the transplanted hearts revealed a 30% reduction of the cytokines TGF-beta and IL6, relevant for chronic rejection.

Conclusion: SDF-1/CXCR4 interaction plays a crucial role for the development of chronic transplant vasculopathy. Its inhibition results in a significant decrease in neointima formation in two murine models of chronic rejection through direct inhibition of proliferation of vascular smooth muscle cells.

Spiegelmer based blockade of SDF-1 may help for the treatment of chronic rejection.